Emedastine fumarate preparation and preparation method thereof

Abstract

The invention relates to an emedastine fumarate preparation and a preparation method thereof, and belongs to the technical field of sustained release preparation preparation, and the preparation method specifically comprises the following steps: mixing and stirring raw material medicines and purified water in proportion, and adding a pore forming agent, a retardant and a sustained release auxiliary agent to prepare a mixed solution; then spraying the mixed solution on a blank pellet core to form a base pellet, and coating the base pellet with an isolating layer; and then, preparing a sustained-release layer coating material from the modified shellac and a toughening agent, and coating the base pill. And finally, screening the pellets and filling the pellets into capsules to complete the preparation of the preparation. In the process, a modified material and a precise process are combined, and the medicine stability and the enteric effect are improved. The prepared emedastine fumarate preparation has the characteristics of high stability and good slow release effect.

Description

Technical Field

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

[0002] In the field of pharmaceutical preparations, emedastine fumarate is an important active ingredient, and the stability and enteric effect of its preparations have an important impact on the efficacy of the drug. However, traditional coating materials such as shellac often show problems such as poor toughness, low stability and poor enteric 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 and barrier properties, it is easy to polymerize after being left for a long time, resulting in an increase in cold alcohol insoluble matter and a decrease in iodine value, thus affecting its enteric performance and stability. In addition, the shellac coating process is difficult to accurately control, resulting in significant differences in enteric performance between different batches of products, increasing 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 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 statements, the present application provides an emedastine fumarate preparation and a preparation method thereof. Summary of the invention

[0006] In order to solve the problems raised in the background technology, the present application provides an emedastine fumarate preparation and a preparation method thereof. The raw material drug and purified water are mixed and stirred in proportion, and a pore-forming agent, a blocker, and a sustained-release adjuvant are added to prepare a mixed solution. The mixed solution is then sprayed on the blank pill core to form a base pill and coated with an isolation layer. Then, a sustained-release layer coating material is made of modified shellac and a toughening agent, and the base pill is coated. Finally, the micropills are screened and loaded into capsules to complete the preparation. This process combines modified materials with precise processes to improve drug stability and enteric 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, which adopts the following technical scheme:

[0008] A method for preparing an emedastine fumarate preparation comprises the following steps:

[0009] 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;

[0010] 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;

[0011] S3, using silk fibroin polypeptide to modify the shellac material to obtain modified shellac; mixing the modified shellac with a toughening agent to prepare a sustained-release layer coating material; using the sustained-release layer coating material to coat the base pellets obtained in step S2, then collecting the material, sieving the pellets, and filling them into hollow capsules to obtain an emedastine fumarate preparation.

[0012] Furthermore, a method for preparing an emedastine fumarate preparation specifically comprises the following steps:

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

[0014] 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;

[0015] S3. Modifying the shellac material with silk polypeptide to obtain modified shellac; mixing the modified shellac with a toughening agent to prepare a sustained-release layer coating material; coating the base pellets obtained in step S2 with the sustained-release layer coating material until the system gains weight by 3-5wt% and then ending the spraying, then collecting the material, sieving to obtain pellets with 18-30 mesh, and filling them into hollow capsules to obtain an emedastine fumarate preparation.

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

[0017] Furthermore, 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.

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

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

[0020] 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;

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

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

[0023] A1. Soak the silk fiber in a 0.02 mol / L NaOH solution at a mass volume ratio of 1 g:20 mL for 10-30 minutes, then wash with deionized water and cut into pieces; then add the silk fiber to deionized water at a mass volume ratio of 1 g:20 mL, increase 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, and the mass ratio of the chemical crosslinking agent to the silk fiber to be (1-5):1. After treating for 30-60 minutes, filter out and dry to obtain a silk polypeptide;

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

[0025] In step A1 of the above reaction process, the silk fiber is soaked in alkali solution to remove impurities and grease on its surface, and then heat-treated to promote the removal of silk fiber colloid, and then a chemical cross-linking agent is used to improve the stability of the silk polypeptide obtained from the silk, and to maintain a certain water insolubility. In step A2, 2-morpholineethanesulfonic acid, ethanol and purified water are used to form a reaction environment, and under the action of EDC and NHS, the carboxyl group on the shellac is activated to react with the amino group of the silk polypeptide to form an amide bond, thereby preparing a modified shellac.

[0026] Furthermore, 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.

[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 modified shellac to 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 raw material drug mixture. The swelling characteristics of hydroxypropyl cellulose are utilized to make ethyl cellulose evenly dispersed in the raw material drug mixture, and a porous structure can be formed after preparing the emedastine fumarate preparation product, thereby increasing the release surface area of ​​the drug, accelerating the release rate of the drug, and balancing the slow release of the drug in the intestine caused by the use of shellac components. Ethyl cellulose has water insolubility, film-forming properties and adhesion, and can form a uniform thin film on the surface of drug particles, further enhancing the sustained-release effect. Several components work together to help form a stable emedastine fumarate sustained-release system, protect the drug from the influence of the external environment, and improve the stability and bioavailability of the drug.

[0031] In the technical solution of the present invention, silk protein is used to modify shellac for encapsulation of preparations. Silk protein, as a natural polymer material, has good biocompatibility. This means that it can coexist harmoniously with human tissues, cells and biological environment without causing rejection or adverse reactions. Both silk protein and shellac have good biodegradability, can be enzymolyzed or hydrolyzed in the body, and finally decomposed into non-toxic small molecules and excreted from the body, avoiding the long-term residual problem that traditional synthetic polymer materials may bring. In the preparation process, the use of sol liquid to treat silk protein is avoided, thereby improving the water solubility of silk protein polypeptide. A small amount of organic solvent is added to the system to promote the reaction, and the amino group on the silk protein polypeptide is used to react with the carboxyl group on the shellac to prepare modified shellac, thereby improving the toughness and mechanical strength of the shellac.

[0032] By using silk protein modified shellac as an encapsulation material, the sustained release of emedastine fumarate can be controlled. This material can adjust the release rate of the drug, maintain a stable blood concentration of the drug in the body, reduce the fluctuation of the drug in the body, and avoid toxic side effects or insufficient efficacy caused by excessively high or low blood concentrations, thereby prolonging the drug's action time, reducing the number of dosing times, and improving the convenience of medication for patients.

[0033] In the technical solution of the present invention, magnesium stearate and tea polyphenols are mixed as toughening agents for shellac. The chemical properties of magnesium stearate are relatively stable, and it is not easy to react chemically after mixing with shellac, thereby maintaining the long-term stability of shellac products. Tea polyphenols can effectively remove 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 interact through hydrogen bonds to increase the crosslinking degree of the shellac system, and the catechol groups contained in tea polyphenols are used to generate hydrophobic interactions with the hydrophobic segments on the silk polypeptide, making the shellac system more uniform and stable. DETAILED DESCRIPTION

[0034] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0035] The specific implementation methods of this application involve:

[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., product number SC561651654, purity 99%;

[0038] Emedastine fumarate API: CAS number 87233-62-3, purity 98%, provided by Wuhan Hongde Yuexin Pharmaceutical Technology Co., Ltd.

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

[0040] Collagen: provided by Hainan Huayan Collagen Technology Co., Ltd., the product name is collagen tripeptide, the main raw material is tilapia scale;

[0041] Empty capsule: PS empty capsule, size 0;

[0042] Blank pellet core: sucrose type, particle size 500-700 μm.

[0043] Example 1

[0044] A method for preparing an emedastine fumarate preparation comprises the following steps:

[0045] S1. Add emedastine fumarate API into purified water at a mass ratio of 8 g:900 g, stir at 30 rpm for 10 minutes at room temperature, then add pore-forming agent, continue stirring for 3 hours, then add retarder and sustained-release aid to the system to prepare API mixed solution;

[0046] Among them, the retarder is ethyl cellulose; the pore-forming agent is hydroxypropyl cellulose; the sustained-release aid is magnesium stearate; the mass ratio of emedastine fumarate raw material, pore-forming agent, retarder and sustained-release aid is 8g:20g:10g:10g.

[0047] 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 weight increases by 3wt%, and then finish spraying. After spray drying, dry for 5 minutes to obtain a base pill;

[0048] During the atomization spray process, the material temperature was controlled at 35°C and the air volume was 70m 3 / h, atomization pressure 0.2MPa, spray rate 3g / min; spray drying inlet temperature 80℃, outlet temperature 40℃.

[0049] S3, modifying the shellac material with silk polypeptide to obtain modified shellac; mixing 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; then coating the base pellets obtained in step S2 with the sustained-release layer coating material until the system gains weight by 3wt% and spraying is terminated, then collecting the material, sieving to obtain 18-mesh pellets, and filling them into hollow capsules to obtain an emedastine fumarate preparation;

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

[0051] A1. Soak the silk fiber in a 0.02 mol / L NaOH solution at a mass volume ratio of 1 g: 20 mL for 10 minutes, then wash with deionized water and cut into pieces; then add the silk fiber to deionized water at a mass volume ratio of 1 g: 20 mL, increase the system temperature to 90°C, treat for 30 minutes, add a chemical crosslinking agent to the system, lower the system temperature to 50°C, control the system pH value to 7, and the mass ratio of the chemical crosslinking agent to the silk fiber to be 1:1. After treating for 30 minutes, filter out and dry to obtain silk polypeptide;

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

[0053] Example 2

[0054] A method for preparing an emedastine fumarate preparation comprises the following steps:

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

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

[0057] S2, take a blank pill core, place it in a fluidized bed, turn on the fan, spray the API mixture obtained in step S1 on the blank pill core, balance it at room temperature for 8 minutes after spray drying, spray the isolation layer solution, and continue spraying until the system gains 5wt% and then finish spraying. Dry for 8 minutes to obtain base pills;

[0058] During the atomization spray process, the material temperature is controlled at 40°C and the air volume is 75m 3 / h, atomization pressure 0.25MPa, spray rate 4g / min; spray drying inlet temperature 80℃, outlet temperature 40℃.

[0059] S3, modifying the shellac material with silk polypeptide to obtain modified shellac; mixing 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 1:0.15, and the mass ratio of the modified shellac to the toughening agent is 1:0.3; then coating the base pellets obtained in step S2 with the sustained-release layer coating material until the system gains 4wt% and the spraying is terminated, then collecting the material, sieving to obtain 25-mesh pellets, and filling them into hollow capsules to obtain an emedastine fumarate preparation;

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

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

[0062] A2. 0.015 g of 2-morpholineethanesulfonic acid and 4 mL of anhydrous ethanol were added to 30 mL of purified water, the pH value of the system was adjusted to 5.1, and 8 g of shellac was added after stirring. The system temperature was raised to 35 ° C. After stirring for 45 minutes, an inert gas was introduced into the system, and 0.192 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.115 g of N-hydroxysuccinimide and 0.5 g of silk polypeptide were added. After stirring for 25 hours, freeze-dried to obtain modified shellac.

[0063] Example 3

[0064] A method for preparing an emedastine fumarate preparation comprises the following steps:

[0065] S1. Add emedastine fumarate API to purified water at a mass ratio of 10 g:950 g, stir at 90 rpm for 30 minutes at room temperature, then add a pore-forming agent, continue stirring for 5 hours, then add a retarder and a sustained-release aid to the system to prepare a API mixture;

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

[0067] S2, take a blank pill core, place it in a fluidized bed, turn on the fan, spray the API mixture obtained in step S1 on the blank pill core, balance at room temperature for 5-10 minutes after spray drying, spray the isolation layer solution, and continue spraying until the system gains 7wt% and then finish spraying. Dry for 10 minutes to obtain base pills;

[0068] During the atomization spray process, the material temperature is controlled at 45°C and the air volume is 80m 3 / h, atomization pressure 0.3MPa, spray rate 5g / min; spray drying inlet temperature 80℃, outlet temperature 40℃.

[0069] S3, modifying the shellac material with silk polypeptide to obtain modified shellac; mixing 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 1:0.2, and the mass ratio of the modified shellac to the toughening agent is 1:0.5; then coating the base pellets obtained in step S2 with the sustained-release layer coating material until the system gains 5wt% and the spraying is terminated, then collecting the material, sieving to obtain 30-mesh pellets, and filling them into hollow capsules to obtain an emedastine fumarate preparation;

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

[0071] A1. Soak the silk fiber in a 0.02 mol / L NaOH solution at a mass volume ratio of 1 g:20 mL for 30 minutes, then wash with deionized water and cut into pieces; then add the silk fiber to deionized water at a mass volume ratio of 1 g:20 mL, increase the system temperature to 100°C, treat for 60 minutes, add a chemical crosslinking agent to the system, lower the system temperature to 60°C, control the system pH value to 8, and the mass ratio of the chemical crosslinking agent to the silk fiber to be 5:1. After treating for 60 minutes, filter out and dry to obtain silk polypeptide;

[0072] A2. Add 0.02 g of 2-morpholineethanesulfonic acid and 5 mL of anhydrous ethanol to 30 mL of purified water, adjust the pH value of the system to 5.1, stir evenly, add 10 g of shellac, raise the system temperature to 40 ° C, stir for 60 minutes, introduce inert gas into the system, add 0.192 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.115 g of N-hydroxysuccinimide and 1.0 g of silk 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 step S1 in this comparative example is:

[0075] Emedastine fumarate API was added into purified water at a mass ratio of 8 g:900 g, and after stirring at 30 rpm for 3 hours at room temperature, a blocker and a sustained-release adjuvant were added into the system to prepare an API mixed solution;

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

[0077] Comparative Example 2

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

[0079] Emedastine fumarate API was added into purified water at a mass ratio of 8 g:900 g, and after stirring at 30 rpm for 10 minutes at room temperature, a pore-forming agent was added, and after continuing to stir for 3 hours, a sustained-release adjuvant was added into the system to prepare an API mixed solution;

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

[0081] Comparative Example 3

[0082] A method for preparing an emedastine fumarate preparation comprises the following steps:

[0083] S1. Add emedastine fumarate API into purified water at a mass ratio of 8 g:900 g, stir at 30 rpm for 10 minutes at room temperature, then add pore-forming agent, continue stirring for 3 hours, then add retarder and sustained-release aid to the system to prepare API mixed solution;

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

[0085] 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 weight increases by 3wt%, and then finish spraying. After spray drying, dry for 5 minutes to obtain a base pill;

[0086] During the atomization spray process, the material temperature was controlled at 35°C and the air volume was 70m 3 / h, atomization pressure 0.2MPa, spray rate 3g / min; spray drying inlet temperature 80℃, outlet temperature 40℃.

[0087] S3. Mix 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 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 gains weight by 3wt% and then finish spraying, then collect the material, sieve out 18-mesh micropellets, and put them into hollow capsules to obtain an emedastine fumarate preparation.

[0088] Comparative Example 4

[0089] A method for preparing an emedastine fumarate preparation comprises the following steps:

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

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

[0092] 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 weight increases by 3wt%, and then finish spraying. After spray drying, dry for 5 minutes to obtain a base pill;

[0093] During the atomization spray process, the material temperature was controlled at 35°C and the air volume was 70m 3 / h, atomization pressure 0.2MPa, spray rate 3g / min; spray drying inlet temperature 80℃, outlet temperature 40℃.

[0094] S3, modifying the shellac material with silk polypeptide to obtain modified shellac; mixing 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; then coating the base pellets obtained in step S2 with the sustained-release layer coating material until the system gains weight by 3wt% and spraying is terminated, then collecting the material, sieving to obtain 18-mesh pellets, and filling them into hollow capsules to obtain an emedastine fumarate preparation;

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

[0096] 0.01 g of 2-morpholineethanesulfonic acid and 3 mL of anhydrous ethanol were added to 30 mL of purified water, the pH value of the system was adjusted to 5.1, and 5 g of shellac was added after stirring evenly. The temperature of the system was raised to 30°C, and after stirring for 30 minutes, an inert gas was introduced into the system, and 0.192 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.115 g of N-hydroxysuccinimide and 0.1 g of collagen were added. After stirring for 20 hours, the mixture was freeze-dried to obtain 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 Testing

[0100] The emedastine fumarate preparations prepared in Examples 1-3 and Comparative Examples 1-5 of the present application were subjected to a storage stability test. The preparations prepared in different groups were stored at 40°C ± 2°C, relative humidity 60% ± 5% and in a dark environment for 2 months. Subsequently, the content of emedastine fumarate was determined using an analytical method such as high performance liquid chromatography, the solvent was a 0.1 mol / L hydrochloric acid solution, and the absorption value was detected at 285 nm, and the loss percentage was counted. Each sample was tested 5 times, and the average value was 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 shown in Table 1, the emedastine fumarate preparation prepared in Example 2 has the best storage stability. As shown in Comparative Examples 1 and 2, the combined use of pore-forming agents and retardants is beneficial to improving the storage stability of sustained-release preparation products. As shown in Comparative Examples 3-4, the use of silk polypeptide to modify shellac can improve the protective effect of shellac. As shown in Comparative Example 5, tea polyphenols can improve the cross-linking effect of shellac.

[0104] Now the sustained release effect of the emedastine fumarate preparations prepared in Examples 1-3 and Comparative Examples 1-5 was tested. A hydrochloric acid solution with a temperature of 37°C and a pH value of 1.2 was used as dissolution medium A; a phosphate buffer solution with a temperature of 37°C and a pH value of 6.8 was used as dissolution medium B; the rotation speed was set to 60 rpm, and samples of the dissolution solution were taken after 30 minutes, 90 minutes and 6 hours, and the dissolution test was performed. Each sample was tested 5 times, and the average value was 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] It can be seen from the results shown in Table 2 above that 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 technical scheme defined in the present application, the sustained-release performance of the emedastine fumarate preparations prepared is excellent.

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

[0109] The above contents are merely examples and explanations of the present invention. Those skilled in the art may make various modifications or additions to the specific embodiments described or replace them in a similar manner. As long as they do not deviate from the invention or exceed the scope defined by the claims, they shall 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; 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, the pellets are sieved, and loaded into hollow capsules to obtain an emedastine fumarate preparation.

2. The method for preparing an emedastine fumarate preparation according to claim 1, characterized in that: The retardant is ethyl cellulose; the pore-forming agent is hydroxypropyl cellulose; and the sustained-release aid is magnesium stearate.

3. 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.

4. 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.

5. The method for preparing an emedastine fumarate preparation according to claim 1, characterized in that: In step S3, 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. Add 2-morpholineethanesulfonic acid and anhydrous ethanol into purified water, adjust the pH value of the system to 5-6, stir evenly and add shellac, raise the system temperature to 30-40°C, stir for 30-60 minutes, introduce inert gas into the system and add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N-hydroxysuccinimide and silk polypeptide, stir for 20-30 hours and then freeze-dry to obtain modified shellac.

6. The method for preparing an emedastine fumarate preparation according to claim 5, 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.

7. The method for preparing an emedastine fumarate preparation according to claim 1, characterized in that: In step S3, the toughening agent is obtained by mixing magnesium stearate and silk fibroin in a mass ratio of 1:(0.2-0.5).

8. 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:(0.2-0.5).

9. An emedastine fumarate preparation obtained by the method for preparing the emedastine fumarate preparation according to any one of claims 1 to 8.

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