Emedastine Difumarate Preparation and Its Preparation Method

Abstract

The present invention relates to an emedastine fumarate preparation and a preparation method thereof, belonging to the technical field of sustained-release preparation preparation, and specifically comprising the following steps: mixing the raw material drug with purified water in proportion, stirring, and adding a pore-forming agent, a retardant, and a sustained-release auxiliary agent to obtain a mixed solution. Subsequently, this mixed solution is sprayed onto blank pellets to form base pellets and an isolation layer is coated. Then, a sustained-release layer coating material is prepared from modified shellac and a toughening agent, and the base pellets are coated. Finally, the pellets are screened and filled into capsules to complete the preparation of the preparation. This process combines modified materials with precise processes to improve the drug stability and enteric-coated effect. The prepared emedastine fumarate preparation has the characteristics of high stability and good sustained-release effect.

Description

Technical Field

[0001] The present application relates to the technical field of the preparation of sustained-release preparations, and more specifically, to an emedastine fumarate preparation and a preparation method thereof. Background Art

[0002] In the field of pharmaceutical preparations, as an important active ingredient, the stability and enteric-coated effect of emedastine fumarate preparations have an important impact on the therapeutic effect of drugs. However, traditional coating materials such as shellac often show problems such as poor toughness, low stability, and unsatisfactory enteric-coated effect in application, which greatly limits its application in emedastine fumarate sustained-release preparations.

[0003] As a coating material, although shellac has certain film-forming properties and barrier properties, it is prone to polymerization after long-term storage, resulting in an increase in cold alcohol-insoluble substances and a decrease in iodine value, thereby affecting its enteric-coated performance and stability. In addition, the shellac coating process is difficult to precisely control, resulting in significant differences in the enteric-coated performance of products in different batches, increasing the uncertainty and quality risks in the production process.

[0004] In view of the above problems, it is urgent to develop a new coating material or improve the existing coating technology to enhance the enteric-coated effect and stability of emedastine fumarate sustained-release preparations. At the same time, considering the sensitivity of the capsule shell to humidity and temperature, strict control of storage conditions is also a key link to ensure the effectiveness of the drug.

[0005] Based on the above statement, the present application provides an emedastine fumarate preparation and a preparation method thereof. Summary of the Invention

[0006] To solve the problems raised in the background art, the present application provides an emedastine fumarate preparation and a preparation method thereof. The raw drug is mixed and stirred with purified water in a certain proportion, and a pore-forming agent, a retardant, and a sustained-release adjuvant are added to obtain a mixed solution. Subsequently, this mixed solution is sprayed onto blank pellets to form base pellets and an isolation layer is coated. Then, a sustained-release layer coating material is prepared from modified shellac and a toughening agent, and the base pellets are coated. Finally, the pellets are screened and loaded into capsules to complete the preparation of the preparation. This process combines modified materials with precise processes to enhance the drug stability and enteric-coated effect. The prepared emedastine fumarate preparation has the characteristics of high stability and good sustained-release effect.

[0007] The present application provides an emedastine fumarate preparation and a preparation method thereof, adopting the following technical solutions:

[0008] A preparation method of an emedastine fumarate preparation specifically includes the following steps:

[0009] S1. Add emedastine fumarate raw material to purified water, stir for 10 - 30 minutes at room temperature, then add a pore-forming agent, continue stirring, and add a retarder and a sustained-release adjuvant to the system to obtain a mixed solution of the raw material drug.

[0010] S2. Take blank pellets, place them in a fluidized bed, turn on the blower, atomize and spray the mixed solution of the raw material drug obtained in step S1 onto the blank pellets until the system weight gain reaches 3 - 7 wt%, then end the spraying. After spray drying, balance for 5 - 10 minutes at room temperature to obtain the base pellets.

[0011] S3. Modify shellac material with silk fibroin polypeptide to obtain modified shellac; mix the modified shellac with a toughening agent to prepare a sustained-release layer coating material; use the sustained-release layer coating material to coat the base pellets obtained in step S2, then collect the materials, sieve to obtain pellets, and load them into hollow capsules to obtain an emedastine fumarate preparation.

[0012] Further, a preparation method of an emedastine fumarate preparation specifically includes the following steps:

[0013] S1. Add emedastine fumarate raw material to purified water according to the mass ratio of (8 - 12) g : (900 - 950) g, stir at a rate of 30 - 90 rpm for 10 - 30 minutes at room temperature, then add a pore-forming agent, continue stirring for 3 - 5 hours, and add a retarder and a sustained-release adjuvant to the system to obtain a mixed solution of the raw material drug.

[0014] S2. Take blank pellets, place them in a fluidized bed, turn on the blower, atomize and spray the mixed solution of the raw material drug obtained in step S1 onto the blank pellets until the system weight gain reaches 3 - 7 wt%, then end the spraying. After spray drying, balance for 5 - 10 minutes at room temperature to obtain the base pellets.

[0015] S3. Modify shellac material with silk fibroin polypeptide to obtain modified shellac; mix the modified shellac with a toughening agent to prepare a sustained-release layer coating material; use the sustained-release layer coating material to coat the base pellets obtained in step S2 until the system weight gain reaches 3 - 5 wt%, then end the spraying, then collect the materials, sieve to obtain 18 - 30 mesh pellets, and load them into hollow capsules to obtain an emedastine fumarate preparation.

[0016] Further, the retarder is ethyl cellulose; the pore-forming agent is hydroxypropyl cellulose; the sustained-release adjuvant is magnesium stearate.

[0017] Further, in step S1, the mass ratio of emedastine fumarate raw material, pore-forming agent, retarder, and sustained-release adjuvant is (8 - 12) g : (20 - 30) g : (10 - 20) g : (10 - 20) g.

[0018] Further, in step S2, during the atomization spraying process, the material temperature is controlled at 35 - 45°C, the air volume is 70 - 80 m 3 / h, the atomization pressure is 0.2 - 0.3 MPa, and the liquid spraying rate is 3 - 5 g / min.

[0019] Further, in step S3, the modified shellac is prepared by the following steps:

[0020] A1. Immerse silk fibers in an NaOH solution, then wash and cut them into pieces; then add the silk fibers to deionized water, raise the system temperature to 90 - 100°C, after treating for 30 - 60 minutes, add a chemical crosslinking agent to the system, lower the system temperature to 50 - 60°C, control the system pH value to be 7 - 8, after treating for 30 - 60 minutes, filter and dry to obtain silk fibroin polypeptide;

[0021] A2. Add 2 - morpholinoethanesulfonic acid and absolute ethanol to purified water, adjust the system pH value to 5 - 6, stir evenly and then add shellac, raise the system temperature to 30 - 40°C, after stirring for 30 - 60 minutes, pass an inert gas into the system and add 1 - (3 - dimethylaminopropyl) - 3 - ethylcarbodiimide hydrochloride, N - hydroxysuccinimide and silk fibroin polypeptide, after stirring for 20 - 30 hours, freeze - dry to obtain modified shellac.

[0022] Further, in step S3, the modified shellac is prepared by the following steps:

[0023] A1. Immerse silk fibers in a 0.02 mol / L NaOH solution according to a mass - to - volume ratio of 1 g:20 mL for 10 - 30 minutes, then wash with deionized water and cut into pieces; then add the silk fibers to deionized water according to a mass - to - volume ratio of 1 g:20 mL, raise the system temperature to 90 - 100°C, after treating for 30 - 60 minutes, add a chemical crosslinking agent to the system, lower the system temperature to 50 - 60°C, control the system pH value to be 7 - 8, the mass ratio of the chemical crosslinking agent to the silk fibers is (1 - 5):1, after treating for 30 - 60 minutes, filter and dry to obtain silk fibroin polypeptide;

[0024] A2. Add 2 - morpholinoethanesulfonic acid and absolute ethanol to purified water, adjust the system pH value to 5.1, stir evenly and then add shellac, raise the system temperature to 30 - 40°C, after stirring for 30 - 60 minutes, pass an inert gas into the system and add 1 - (3 - dimethylaminopropyl) - 3 - ethylcarbodiimide hydrochloride, N - hydroxysuccinimide and silk fibroin polypeptide, after stirring for 20 - 30 hours, freeze - dry to obtain modified shellac.

[0025] In step A1 of the above reaction process, the silk fiber is soaked in an alkali solution to remove impurities and grease on its surface. Subsequently, heat treatment is carried out to promote the removal of sericin in the silk fiber. Then, a chemical cross-linking agent is used to improve the stability of the silk fibroin polypeptide obtained from the silk and maintain a certain degree of water insolubility. In step A2, a reaction environment is constituted by 2-morpholinoethanesulfonic acid, ethanol and purified water. Under the action of EDC and NHS, the carboxyl group on the shellac is activated to react with the amino group of the silk fibroin polypeptide to form an amide bond, and the modified shellac is prepared.

[0026] Furthermore, the mass-volume ratio of 2-morpholinoethanesulfonic acid, absolute ethanol, shellac and silk fibroin polypeptide is (0.01 - 0.02) g : (3 - 5) mL : (5 - 10) g : (0.1 - 1.0) g.

[0027] Furthermore, in step S3, the toughening agent is obtained by mixing magnesium stearate and tea polyphenols in a mass ratio of 1 : (0.1 - 0.2).

[0028] Furthermore, in step S3, the mass ratio of the modified shellac to the toughening agent is 1 : (0.2 - 0.5).

[0029] In summary, the present invention has the following beneficial effects:

[0030] In the technical solution of the present invention, hydroxypropyl cellulose and ethyl cellulose are used in combination to prepare a mixed solution of the active pharmaceutical ingredient. By utilizing the swelling property of hydroxypropyl cellulose, ethyl cellulose can be uniformly dispersed in the mixed solution of the active pharmaceutical ingredient, and a porous structure can be formed after preparing the emedastine fumarate preparation product, increasing the drug release surface area and accelerating the drug release rate to balance the slow drug release in the intestine caused by using the shellac component. Ethyl cellulose has water insolubility, film-forming property and adhesiveness, and can form a uniform thin film on the surface of the drug particles, further enhancing the sustained-release effect. The combined action of several components helps to form a stable emedastine fumarate sustained-release system, protecting the drug from the influence of the external environment and improving the stability and bioavailability of the drug.

[0031] In the technical solution of the present invention, fibroin polypeptide is used to modify shellac for encapsulation of preparations. As a natural polymer material, silk protein has good biocompatibility. This means that it can coexist harmoniously with human tissues, cells and biological environment without causing rejection reactions or adverse reactions. Both silk protein and shellac have good biodegradability and can be enzymatically degraded or hydrolyzed in vivo, and finally decomposed into non-toxic small molecule substances and excreted from the body, avoiding the long-term residue problems that may be brought by traditional synthetic polymer materials. During the preparation process, the treatment of silk protein with sol solution is avoided, thereby improving the water solubility of fibroin polypeptide. A small amount of organic solvent is added to the system to promote the reaction. The amino group on fibroin polypeptide reacts with the carboxyl group on shellac to prepare modified shellac, improving the toughness and mechanical strength of shellac.

[0032] By using silk protein-modified shellac as an encapsulation material, the sustained release control of emedastine fumarate can be achieved. This material can regulate the drug release rate, keep the drug at a stable blood drug concentration in the body, reduce the fluctuation of the drug in the body, avoid the toxic and side reactions or insufficient efficacy caused by too high or too low blood drug concentration, thereby prolonging the action time of the drug, reducing the number of drug administrations, and improving the medication convenience of patients.

[0033] In the technical solution of the present invention, magnesium stearate and tea polyphenols are mixed and used as toughening agents for shellac. The chemical properties of magnesium stearate are relatively stable and it is not easy to undergo chemical reactions after being mixed with shellac, thus maintaining the long-term stability of shellac products. Tea polyphenols can effectively scavenge free radicals, delay the oxidative aging process of shellac and its products, and improve the weather resistance and service life of the products. The catechol structure contained in tea polyphenols can improve the crosslinking degree of the shellac system through hydrogen bond interaction, and utilize the catechol groups contained in tea polyphenols to generate hydrophobic interaction with the hydrophobic segments on fibroin polypeptide, making the shellac system more uniform and stable. Specific embodiments

[0034] Next, the technical solutions in the embodiments of the present invention will be clearly and completely described in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative efforts fall within the protection scope of the present invention.

[0035] In the specific embodiments of the present application:

[0036] Tea polyphenols: provided by Xi'an Huazhirui Food Ingredients Co., Ltd., with a purity of 98%;

[0037] Shellac: purple shellac, provided by Wuhan Lanabai Pharmaceutical Chemical Co., Ltd., with the product number SC561651654 and a purity of 99%;

[0038] Emedastine Difumarate Bulk Drug Substance: CAS No. is 87233-62-3, purity is 98%, provided by Wuhan Hongde Yuexin Pharmaceutical Technology Co., Ltd.;

[0039] Chemical cross-linking agent: Genipin, provided by Shanghai Yuanye Bio-Technology Co., Ltd., product number is B20635, purity ≥ 98%;

[0040] Collagen: provided by Hainan Huayan Collagen Technology Co., Ltd., product name is Collagen Tripeptide, the main raw material is tilapia fish scales;

[0041] Hollow Capsule: PS hollow capsule, size 0;

[0042] Blank Pellets: sucrose type, particle size is 500 - 700 μm.

[0043] Example 1

[0044] A preparation method of emedastine difumarate preparation, specifically including the following steps:

[0045] S1. Add emedastine difumarate bulk drug substance into purified water according to the mass ratio of 8 g: 900 g, stir at a rate of 30 rpm for 10 minutes at room temperature, then add a pore-forming agent, continue to stir for 3 hours, and then add a retarder and a sustained-release adjuvant to the system to obtain a mixed solution of the drug substance;

[0046] Among them, the retarder is ethyl cellulose; the pore-forming agent is hydroxypropyl cellulose; the sustained-release adjuvant is magnesium stearate; the mass ratio of emedastine difumarate bulk drug substance, pore-forming agent, retarder, and sustained-release adjuvant is 8 g: 20 g: 10 g: 10 g.

[0047] S2. Take the blank pellets, place them in a fluidized bed, turn on the blower, atomize and spray the mixed solution of the drug substance obtained in step S1 on the blank pellets until the weight of the system increases by 3 wt%, and then end the spraying. After spray drying and drying for 5 minutes, obtain the base pellets;

[0048] Among them, during the atomization spraying process, control the material temperature at 35 °C, the air volume at 70 m 3 / h, the atomization pressure at 0.2 MPa, and the liquid spraying rate at 3 g / min; the inlet temperature of spray drying is 80 °C, and the outlet temperature is 40 °C.

[0049] S3. Modify the shellac material with fibroin polypeptide to obtain modified shellac; mix the modified shellac with a toughening agent to prepare a sustained-release layer coating material; wherein, the toughening agent is obtained by mixing magnesium stearate and tea polyphenols in a mass ratio of 1:0.1, and the mass ratio of the modified shellac to the toughening agent is 1:0.2; subsequently, use the sustained-release layer coating material to coat the core pills obtained in step S2 until the system weight gain reaches 3wt%, then end the spraying, and then collect the materials, sieve to obtain 18-mesh pellets, and load them into hollow capsules to obtain an emedastine fumarate preparation;

[0050] Among them, the modified shellac is prepared by the following steps:

[0051] A1. Immerse silk fibers in a 0.02mol / L NaOH solution at a mass-to-volume ratio of 1g:20mL for 10 minutes, then wash with deionized water and cut into pieces; subsequently, add silk fibers to deionized water at a mass-to-volume ratio of 1g:20mL, raise the system temperature to 90°C, treat for 30 minutes, then add a chemical cross-linking agent to the system, lower the system temperature to 50°C, control the system pH value to 7, the mass ratio of the chemical cross-linking agent to silk fibers is 1:1, treat for 30 minutes, then filter and dry to obtain fibroin polypeptide;

[0052] A2. Add 0.01g of 2-morpholinoethanesulfonic acid and 3mL of absolute ethanol to 30mL of purified water, adjust the system pH value to 5.1, stir evenly, then add 5g of shellac, raise the system temperature to 30°C, stir for 30 minutes, then pass an inert gas into the system and add 0.192g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.115g of N-hydroxysuccinimide and 0.1g of fibroin polypeptide, stir for 20 hours and then freeze-dry to obtain modified shellac.

[0053] Example 2

[0054] A preparation method of an emedastine fumarate preparation specifically includes the following steps:

[0055] S1. Add the emedastine fumarate raw material drug to purified water at a mass ratio of 10g:925g, stir at a rate of 60rpm for 20 minutes at room temperature, then add a pore-forming agent, continue to stir for 4 hours, and then add a retarder and a sustained-release auxiliary agent to the system to prepare a raw material drug mixture;

[0056] Among them, the retarder is ethyl cellulose; the pore-forming agent is hydroxypropyl cellulose; the sustained-release auxiliary agent is magnesium stearate; the mass ratio of the emedastine fumarate raw material drug, the pore-forming agent, the retarder, and the sustained-release auxiliary agent is 10g:25g:15g:15g.

[0057] S2. Take blank pill cores and place them in a fluidized bed. Turn on the blower and atomize and spray the mixed solution of the active pharmaceutical ingredient obtained in step S1 onto the blank pill cores. After the spray drying is completed, equilibrate at room temperature for 8 minutes. Then atomize and continue to spray the isolating layer solution until the system weight gain reaches 5 wt%, and then end the spraying. After drying for 8 minutes, the base pills are obtained.

[0058] Among them, during the atomization spraying process, control the material temperature at 40 °C, the air volume at 75 m 3 / h, the atomization pressure at 0.25 MPa, and the liquid spraying rate at 4 g / min; the inlet temperature of the spray drying is 80 °C, and the outlet temperature is 40 °C.

[0059] S3. Modify the shellac material with silk fibroin polypeptide to obtain modified shellac; mix the modified shellac with a toughening agent to prepare a sustained-release layer coating material; among them, the toughening agent is obtained by mixing magnesium stearate and tea polyphenols according to a mass ratio of 1:0.15, and the mass ratio of the modified shellac to the toughening agent is 1:0.3; then use the sustained-release layer coating material to coat the base pills obtained in step S2 until the system weight gain reaches 4 wt%, and then end the spraying. Subsequently, collect the materials, sieve to obtain 25-mesh pellets, and load them into hollow capsules to obtain an emedastine fumarate preparation.

[0060] Among them, the modified shellac is prepared by the following steps:

[0061] A1. Immerse silk fibers in a 0.02 mol / L NaOH solution according to a mass-to-volume ratio of 1 g:20 mL for 20 minutes, then wash with deionized water and cut into pieces; then add silk fibers to deionized water according to a mass-to-volume ratio of 1 g:20 mL, raise the system temperature to 95 °C, after treating for 45 minutes, add a chemical crosslinking agent to the system, lower the system temperature to 55 °C, control the system pH value at 7.5, and the mass ratio of the chemical crosslinking agent to silk fibers is 3:1. After treating for 45 minutes, filter and dry to obtain silk fibroin polypeptide.

[0062] A2. Add 0.015 g of 2-morpholinoethanesulfonic acid and 4 mL of absolute ethanol to 30 mL of purified water, adjust the system pH value to 5.1, stir evenly, then add 8 g of shellac, raise the system temperature to 35 °C, stir for 45 minutes, then introduce an inert gas into the system and add 0.192 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.115 g of N-hydroxysuccinimide, and 0.5 g of silk fibroin polypeptide, stir for 25 hours and then freeze-dry to obtain modified shellac.

[0063] Example 3

[0064] A preparation method of an emedastine fumarate preparation specifically includes the following steps:

[0065] S1. Add the emedastine fumarate raw material into purified water according to the mass ratio of 10 g:950 g. Stir at a rate of 90 rpm for 30 minutes at room temperature, then add the pore-forming agent. After continuing to stir for 5 hours, add the retarder and the sustained-release adjuvant to prepare the raw material mixture solution;

[0066] Among them, the retarder is ethyl cellulose; the pore-forming agent is hydroxypropyl cellulose; the sustained-release adjuvant is magnesium stearate; the mass ratio of the emedastine fumarate raw material, the pore-forming agent, the retarder, and the sustained-release adjuvant is 12 g:30 g:20 g:20 g.

[0067] S2. Take the blank pellets and place them in a fluidized bed. Turn on the blower, atomize and spray the raw material mixture solution obtained in step S1 onto the blank pellets. After the spray drying is completed, balance at room temperature for 5 - 10 minutes, then atomize and continue to spray the isolation layer solution until the system weight gain reaches 7 wt%, and then end the spraying. After drying for 10 minutes, obtain the base pellets;

[0068] Among them, during the atomization spraying process, control the material temperature at 45 °C, the air volume at 80 m 3 / h, the atomization pressure at 0.3 MPa, and the liquid spraying rate at 5 g / min; the inlet temperature of the spray drying is 80 °C, and the outlet temperature is 40 °C.

[0069] S3. Modify the shellac material with silk fibroin polypeptide to obtain the modified shellac; mix the modified shellac with the toughening agent to prepare the sustained-release layer coating material; among them, the toughening agent is obtained by mixing magnesium stearate and tea polyphenols according to the mass ratio of 1:0.2, and the mass ratio of the modified shellac to the toughening agent is 1:0.5; then use the sustained-release layer coating material to coat the base pellets obtained in step S2 until the system weight gain reaches 5 wt%, then end the spraying, then collect the materials, screen to obtain 30-mesh pellets, and load them into hollow capsules to obtain an emedastine fumarate preparation;

[0070] Among them, the modified shellac is prepared by the following steps:

[0071] A1. Immerse silk fiber in 0.02 mol / L NaOH solution according to the mass-volume ratio of 1 g:20 mL for 30 minutes, then wash with deionized water and cut into pieces; then add silk fiber into deionized water according to the mass-volume ratio of 1 g:20 mL, raise the system temperature to 100 °C, process for 60 minutes, then add a chemical cross-linking agent to the system, lower the system temperature to 60 °C, control the system pH value at 8, the mass ratio of the chemical cross-linking agent to silk fiber is 5:1, process for 60 minutes, then filter and dry to obtain silk fibroin polypeptide;

[0072] A2. Add 0.02 g of 2-morpholinoethanesulfonic acid and 5 mL of absolute ethanol to 30 mL of purified water, adjust the pH value of the system to 5.1, stir evenly, then add 10 g of shellac, raise the temperature of the system to 40 °C, stir for 60 minutes, then introduce an inert gas into the system and add 0.192 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.115 g of N-hydroxysuccinimide and 1.0 g of silk fibroin polypeptide, stir for 30 hours and then freeze-dry to obtain modified shellac.

[0073] Comparative Example 1

[0074] The difference between this comparative example and Example 1 is that the S1 step in this comparative example is as follows:

[0075] Add the emedastine fumarate raw material drug to purified water according to a mass ratio of 8 g:900 g, stir at a rate of 30 rpm at room temperature for 3 hours, then add a retarder and a sustained-release adjuvant to the system to prepare a raw material drug mixture;

[0076] Among them, the retarder is ethyl cellulose; the sustained-release adjuvant is magnesium stearate; the mass ratio of the emedastine fumarate raw material drug, the retarder, and the sustained-release adjuvant is 8 g:10 g:10 g.

[0077] Comparative Example 2

[0078] The difference between this comparative example and Example 1 is that the S1 step in this comparative example is as follows:

[0079] Add the emedastine fumarate raw material drug to purified water according to a mass ratio of 8 g:900 g, stir at a rate of 30 rpm at room temperature for 10 minutes, then add a pore-forming agent, continue to stir for 3 hours, and then add a sustained-release adjuvant to the system to prepare a raw material drug mixture;

[0080] Among them, the pore-forming agent is hydroxypropyl cellulose; the sustained-release adjuvant is magnesium stearate; the mass ratio of the emedastine fumarate raw material drug, the pore-forming agent, and the sustained-release adjuvant is 8 g:20 g:10 g.

[0081] Comparative Example 3

[0082] A preparation method of an emedastine fumarate preparation specifically includes the following steps:

[0083] S1. Add the emedastine fumarate raw material drug to purified water according to a mass ratio of 8 g:900 g, stir at a rate of 30 rpm at room temperature for 10 minutes, then add a pore-forming agent, continue to stir for 3 hours, and then add a retarder and a sustained-release adjuvant to the system to prepare a raw material drug mixture;

[0084] Among them, the retarder is ethyl cellulose; the pore-forming agent is hydroxypropyl cellulose; the sustained-release adjuvant is magnesium stearate; the mass ratio of emedastine fumarate raw material drug, pore-forming agent, retarder, and sustained-release adjuvant is 8g:20g:10g:10g.

[0085] S2. Take blank pellets and place them in a fluidized bed. Turn on the blower, and atomize and spray the mixed solution of the raw material drug obtained in step S1 onto the blank pellets until the system weight gain reaches 3 wt%, then end the spraying. After spray drying and drying for 5 minutes, obtain the base pellets.

[0086] Among them, during the atomization and spraying process, control the material temperature at 35 °C, the air volume at 70 m 3 / h, the atomization pressure at 0.2 MPa, and the liquid spraying rate at 3 g / min; the inlet temperature of the spray drying is 80 °C, and the outlet temperature is 40 °C.

[0087] S3. Mix shellac and a toughening agent to prepare a sustained-release layer coating material; among them, the toughening agent is obtained by mixing magnesium stearate and tea polyphenols according to a mass ratio of 1:0.1, and the mass ratio of shellac to the toughening agent is 1:0.2; then use the sustained-release layer coating material to coat the base pellets obtained in step S2 until the system weight gain reaches 3 wt%, then end the spraying, then collect the materials, sieve to obtain 18-mesh pellets, and load them into hollow capsules to obtain an emedastine fumarate preparation.

[0088] Comparative Example 4

[0089] A preparation method of an emedastine fumarate preparation specifically includes the following steps:

[0090] S1. Add the emedastine fumarate raw material drug to purified water according to a mass ratio of 8g:900g, stir at a rate of 30 rpm for 10 minutes at room temperature, then add the pore-forming agent, continue to stir for 3 hours, and then add the retarder and the sustained-release adjuvant to the system to prepare a mixed solution of the raw material drug.

[0091] Among them, the retarder is ethyl cellulose; the pore-forming agent is hydroxypropyl cellulose; the sustained-release adjuvant is magnesium stearate; the mass ratio of emedastine fumarate raw material drug, pore-forming agent, retarder, and sustained-release adjuvant is 8g:20g:10g:10g.

[0092] S2. Take blank pellets and place them in a fluidized bed. Turn on the blower, and atomize and spray the mixed solution of the raw material drug obtained in step S1 onto the blank pellets until the system weight gain reaches 3 wt%, then end the spraying. After spray drying and drying for 5 minutes, obtain the base pellets.

[0093] Among them, during the atomization and spraying process, control the material temperature at 35 °C, the air volume at 70 m 3 / h, the atomization pressure is 0.2 MPa, and the liquid spraying rate is 3 g / min; the inlet temperature of spray drying is 80 °C, and the outlet temperature is 40 °C.

[0094] S3. Modify the shellac material with fibroin polypeptide to obtain modified shellac; mix the modified shellac with a toughening agent to prepare a sustained-release layer coating material; wherein, the toughening agent is obtained by mixing magnesium stearate and tea polyphenols in a mass ratio of 1:0.1, and the mass ratio of the modified shellac to the toughening agent is 1:0.2; subsequently, use the sustained-release layer coating material to coat the matrix pills obtained in step S2 until the system weight gain reaches 3 wt%, then end the spraying, and then collect the materials, sieve to obtain 18-mesh pellets, and load them into hollow capsules to obtain an emedastine fumarate preparation.

[0095] Among them, the modified shellac is prepared by the following steps:

[0096] Add 0.01 g of 2-morpholinoethanesulfonic acid and 3 mL of absolute ethanol to 30 mL of purified water, adjust the pH value of the system to 5.1, stir evenly, then add 5 g of shellac, raise the temperature of the system to 30 °C, stir for 30 minutes, then introduce an inert gas into the system and add 0.192 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.115 g of N-hydroxysuccinimide, and 0.1 g of collagen, stir for 20 hours, and then freeze-dry to obtain the modified shellac.

[0097] Comparative Example 5

[0098] The difference between this comparative example and Example 1 is that in step S3, the toughening agent is magnesium stearate.

[0099] Performance test

[0100] Perform storage stability tests on the emedastine fumarate preparations prepared in Examples 1-3 and Comparative Examples 1-5 of this application. Place the preparations prepared in different groups in an environment of 40 °C ± 2 °C, relative humidity of 60% ± 5%, and in the dark for 2 months. Subsequently, use analytical methods such as high-performance liquid chromatography to determine the content of emedastine fumarate, the solvent is 0.1 mol / L hydrochloric acid solution, and detect the absorption value at 285 nm, and count its loss percentage. Each sample is detected 5 times, and the average value is recorded. The specific performance test results are shown in Table 1 below.

[0101] Table 1 Storage stability test of emedastine fumarate preparations prepared in Examples 1-3 and Comparative Examples 1-5

[0102]

[0103] As can be seen from the results in Table 1, the emedastine fumarate preparation obtained in Example 2 has the best storage stability. As can be seen from the results in Comparative Examples 1 and 2, the combined use of pore-forming agents and retardants is beneficial to improving the storage stability of the sustained-release preparation product. As can be seen from the results in Comparative Examples 3-4, the modification of shellac with silk fibroin polypeptide can improve the protective effect of shellac. As can be seen from the results in Comparative Example 5, tea polyphenols can improve the crosslinking effect of shellac.

[0104] Now, the sustained-release effect tests are carried out on the emedastine fumarate preparations prepared in Examples 1-3 and Comparative Examples 1-5. Hydrochloric acid solution with a temperature of 37 °C and a pH value of 1.2 is used as dissolution medium A; phosphate buffer solution with a temperature of 37 °C and a pH value of 6.8 is used as dissolution medium B; the rotation speed is set at 60 rpm, and dissolution liquid samples are taken after 30 minutes, 90 minutes and 6 hours for dissolution test. Each sample is detected 5 times, and the average value is recorded. The specific performance test results are shown in Table 2 below.

[0105] Table 2 Sustained-release effect test of emedastine fumarate preparations prepared in Examples 1-3 and Comparative Examples 1-5

[0106]

[0107] As can be seen from the results shown in Table 2 above: The sustained-release performance of the emedastine fumarate preparations prepared in Examples 1-5 of the present application is significantly better than that of the emedastine fumarate preparations prepared in Comparative Examples 1-5. That is, within the limited technical solutions of the present application, the prepared emedastine fumarate preparations have excellent sustained-release performance.

[0108] In the description of the specification, the description referring to terms such as "one embodiment", "example", "specific example", etc. means that the specific features, structures, materials or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic expressions of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in a suitable manner in any one or more embodiments or examples.

[0109] The above content is only an example and illustration of the present invention. Those skilled in the art of the present technology make various modifications or supplements to the described specific embodiments or use similar methods for substitution, as long as they do not deviate from the invention or exceed the scope defined by the claims of the present invention, they should all fall within the protection scope of the present invention.

Claims

1. A method for preparing an emedastine fumarate preparation, characterized in that: The specific steps include: S1. Add emedastine fumarate API to purified water, stir for 10-30 minutes at room temperature, then add pore-forming agent, continue stirring, add retarder and sustained-release aid to the system to prepare API mixed solution; the retarder is ethyl cellulose; the pore-forming agent is hydroxypropyl cellulose; the sustained-release aid is magnesium stearate; S2, take a blank pill core, place it in a fluidized bed, turn on the fan, and spray the API mixture obtained in step S1 on the blank pill core until the system gains 3-7wt% and then finish spraying. After spray drying, balance at room temperature for 5-10 minutes to obtain a base pill; S3, using silk fibroin polypeptide to modify the shellac material to obtain modified shellac; The modified shellac is mixed with a toughening agent to prepare a sustained-release layer coating material; the base pellets obtained in step S2 are coated with the sustained-release layer coating material, and then the material is collected, pellets are sieved, and loaded into hollow capsules to obtain an emedastine fumarate preparation; Wherein, the modified shellac is prepared by the following steps: A1. Soak the silk fiber in a NaOH solution, then wash and chop it into pieces; then add the silk fiber into deionized water, raise the system temperature to 90-100°C, treat for 30-60 minutes, add a chemical crosslinking agent to the system, lower the system temperature to 50-60°C, control the system pH value to 7-8, treat for 30-60 minutes, filter out, and dry to obtain silk polypeptide; A2, 2-morpholineethanesulfonic acid and anhydrous ethanol are added to purified water, the pH value of the system is adjusted to 5-6, and shellac is added after stirring evenly, the system temperature is increased to 30-40°C, and after stirring for 30-60 minutes, an inert gas is introduced into the system and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N-hydroxysuccinimide and silk polypeptide are added, and after stirring for 20-30 hours, freeze-drying is performed to obtain modified shellac; The toughening agent is obtained by mixing magnesium stearate and tea polyphenols in a mass ratio of 1:0.1-1:0.

2.

2. The method for preparing an emedastine fumarate preparation according to claim 1, characterized in that: In step S1, the mass ratio of emedastine fumarate raw material, pore-forming agent, retardant and sustained-release aid is (8-12) g: (20-30) g: (10-20) g: (10-20) g.

3. The method for preparing an emedastine fumarate preparation according to claim 1, characterized in that: In step S2, during the atomization spray process, the material temperature is controlled at 35-45°C and the air volume is 70-80m 3 / h, atomization pressure 0.2-0.3MPa, spray rate 3-5g / min.

4. The method for preparing an emedastine fumarate preparation according to claim 1, characterized in that: The mass volume ratio of 2-morpholineethanesulfonic acid, anhydrous ethanol, shellac and silk polypeptide is (0.01-0.02) g: (3-5) mL: (5-10) g: (0.1-1.0) g.

5. The method for preparing an emedastine fumarate preparation according to claim 1, characterized in that: In step S3, the mass ratio of modified shellac to toughening agent is 1:0.2-1:0.

5.

6. An emedastine fumarate preparation obtained by the method for preparing the emedastine fumarate preparation according to any one of claims 1 to 5.

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