High-stability acetylcysteine direct-taking granules based on pH response and preparation process of high-stability acetylcysteine direct-taking granules

Abstract

The invention belongs to the field of pharmaceutical preparations, and discloses high-stability acetylcysteine direct granules based on pH response and a preparation process of the high-stability acetylcysteine direct granules. The preparation process comprises the following steps: (1) pretreatment: adding acetylcysteine and docusate sodium into a fluidized bed to prepare an inclusion compound; (2) preparation of a granulation solution: dissolving hydroxypropyl methyl cellulose in deoxygenated water, adding Eudragit L100-55, mixing, and adjusting the pH value to 7 or completely dissolving white particles; (3) preparing a soft material: mixing the inclusion compound with cane sugar, adjusting the rotating speed, and adding the granulation solution; (4) wet granulation; (5) drying; (6) total mixing; and (7) packaging. The docusate sodium-coated acetylcysteine clathrate compound is adopted to protect API, Eudragit L100-55 is adopted as a pH response mixture to endow the particles with the ability of selectively releasing acetylcysteine in the particles under different pH conditions, meanwhile, the pungent smell of API in the drug-containing particles can be blocked, swallowing by a patient is more convenient, and caking is not prone to occurring during storage.

Description

Technical Field

[0001] The invention relates to the field of pharmaceutical preparations, and in particular to a pH-responsive high-stability acetylcysteine ​​direct-take granule and a preparation process thereof. Background Art

[0002] Acetylcysteine ​​is mainly used to dissolve mucus and other effects. Because of its strong mucolytic effect, it is mainly used as a mucolytic agent. The sulfhydryl group contained in its molecule can break the disulfide bonds in the glycoprotein polypeptide chain in the sputum, thereby reducing the viscosity of the sputum, and making the sputum liquid and easier to cough up. It can also break the DNA fibers in purulent sputum, so it can not only dissolve white sticky sputum, but also dissolve purulent sputum. For patients who are generally ineffective with traditional expectorants, the use of this product can still achieve a certain mucolytic effect.

[0003] At present, the main oral dosage forms of acetylcysteine ​​are granules, effervescent tablets and solutions. However, each oral dosage form of acetylcysteine ​​has certain disadvantages. Granules are easy to agglomerate, effervescent tablets are only available abroad and have not been imported, and solutions have disadvantages such as poor patient compliance due to the pungent smell of acetylcysteine ​​and lack of efficacy due to the addition of a large amount of complexing agents to maintain its stability.

[0004] Among them, the patent CN102144978B uses acrylic acid to powder coat the API. After coating the API, the stability of the API in a humid environment is improved, while acetylcysteine ​​is unstable to oxygen and acid-base wet environments, but the patent does not study other impurity levels. Patent CN115634205B obtains blank particles by preparing and sieving and mixes them with API and sucrose crystals. The poor uniformity of acetylcysteine ​​particle content is solved by controlling the appropriate particle size for mixing, and the API is not exposed to moisture and heat, thereby solving the problem of poor API stability. However, this patent can only be applied to blank particles, sucrose crystals and API with special particle size distribution. Production efficiency and continuous production are limited by actual conditions.

[0005] In addition, the patent CN113750052B prepares pills containing API, moisture-proof matrix and isolation mechanism, and dry granulates them together with pharmaceutical excipients. This masks the special smell of API, and the granules are not easy to agglomerate. However, no further research has been conducted on the relevant substances. And the patent CN112206209B adds menthol and further granulates it in a fluidized bed, which increases the stability and bioavailability of the granules, but both menthol and API have a certain pungent smell that seriously affects the oral compliance of patients.

[0006] Therefore, the above-mentioned existing acetylcysteine ​​has poor stability, easy caking of particles, and poor mixing uniformity of particles. Therefore, a kind of efficient preparation method is needed to reduce the time of contact with unstable conditions on the basis of solving the problem of content uniformity, thereby increasing the stability of acetylcysteine ​​particles. At the same time, the caking of granules is also one of the difficulties encountered when storing granules, and granules are generally dissolved in water and taken orally, which is inconvenient to take. Therefore, the research and development of an efficient preparation process of acetylcysteine ​​particles that can be directly swallowed by inducing saliva in the oral cavity is very necessary. Summary of the invention

[0007] The invention aims to solve the technical defects of poor stability, easy agglomeration of particles and poor particle mixing uniformity of existing acetylcysteine, and provides a high-stability acetylcysteine ​​direct-take granules based on pH response and a preparation process thereof.

[0008] To achieve the above object, the present invention adopts the following technical solutions:

[0009] The first aspect of the present invention is to provide a preparation process of acetylcysteine ​​direct-take granules with high stability based on pH response, comprising the following steps:

[0010] (1) Pretreatment: acetylcysteine ​​and sucrose are sieved and crushed in advance, and then acetylcysteine ​​and docusate sodium are added to a fluidized bed and dried at 50° C. The moisture content in the fluidized bed is low, and after docusate sodium is heated and softened, acetylcysteine ​​is included in it. After drying, the temperature is cooled to room temperature and then discharged to obtain an inclusion complex of acetylcysteine ​​encapsulated by docusate sodium;

[0011] (2) Preparation of granulation solution: Hydroxypropyl methylcellulose was completely dissolved in deoxygenated water under continuous stirring, and Eudragit L100-55 was subsequently added and mixed, and then the pH was adjusted to 7 with 0.1 mol / L NaOH or until the white granules were completely dissolved, to prepare a granulation solution;

[0012] (3) preparing a soft material: adding the inclusion compound prepared in step (1) and sucrose to a wet mixing granulator and mixing for 10 minutes, adjusting the speed of the wet mixing granulator and adding the granulation solution prepared in step (2), controlling the liquid addition time to 1 to 3 minutes and the shearing time to 1 to 3 minutes, to prepare a soft material;

[0013] (4) Wet granulation: the soft material prepared in step (3) is passed through a 16-30 mesh steel wire / nylon sieve and granulated by a swing granulator to obtain acetylcysteine ​​wet granules;

[0014] (5) Drying: The wet acetylcysteine ​​granules obtained in step (4) are transferred to an electric heated air drying oven for drying to obtain dry acetylcysteine ​​granules;

[0015] (6) Total mixing: Mix the acetylcysteine ​​dry particles obtained in step (5) with anhydrous citric acid using a hopper mixer at 10 to 30 rpm for 2 to 8 minutes;

[0016] (7) Packaging: The acetylcysteine ​​direct-take granules are packaged in paper-aluminum packaging.

[0017] Preferably, in step (1), the acetylcysteine ​​is pre-sieved through a 60-mesh sieve, and the pulverized sucrose is pre-sieved through a 100-mesh sieve.

[0018] Preferably, in step (1), the dosage ratio of the acetylcysteine ​​to the docusate sodium is 1:1.5-2.5.

[0019] Preferably, in step (1), the dosage ratio of acetylcysteine ​​to docusate sodium is 1:1.8-2.2.

[0020] More preferably, in step (1), the dosage ratio of acetylcysteine ​​to docusate sodium is 1:2.

[0021] Preferably, in step (2), the dosage ratio of hydroxypropyl methylcellulose, Eudragit L100-55 and deoxygenated water is 3:1.5-2.5:5-8.

[0022] Preferably, in step (2), the dosage ratio of hydroxypropyl methylcellulose, Eudragit L100-55 and deoxygenated water is 3:1.8-2.2:5-6.

[0023] More preferably, in step (2), the dosage ratio of hydroxypropyl methylcellulose, Eudragit L100-55 and deoxygenated water is 3:2:5.

[0024] Deoxygenated water is used as a solvent only to dissolve the above materials. Its dosage has a great influence on the particle properties and drying time. The minimum amount of deoxygenated water is used to dissolve the above materials to achieve wetting and reduce drying time.

[0025] Preferably, in step (3), the ratio of the inclusion compound to the sucrose is 1:2-5 by mass.

[0026] Preferably, in step (3), the ratio of the inclusion compound to the sucrose is 1:2-4 by mass.

[0027] More preferably, in step (3), the ratio of the inclusion compound to the sucrose is 1:3 by mass.

[0028] Preferably, in step (3), the stirring speed of the wet mixing granulator is 50 to 500 rpm, and the cutting speed is 50 to 500 rpm; the adjusted stirring speed is 50 to 500 rpm, and the cutting speed is 1000 to 2000 rpm.

[0029] More preferably, in step (3), the stirring speed of the wet mixing granulator is 100-300 rpm, and the cutting speed is 100-300 rpm; the adjusted stirring speed is 100-300 rpm, and the cutting speed is 1200-1800 rpm.

[0030] Preferably, in step (4), the drying temperature of the acetylcysteine ​​wet granules is 40-60° C., until the moisture content of the dry granules is less than 0.5%.

[0031] Preferably, in step (4), the drying temperature of the acetylcysteine ​​wet granules is 50° C., until the moisture content of the dry granules is less than 0.5%.

[0032] Preferably, in step (6), the mass ratio of the acetylcysteine ​​dry particles to the anhydrous citric acid is 2.9:0.05-0.15.

[0033] Preferably, in step (6), the mass ratio of the acetylcysteine ​​dry particles to the anhydrous citric acid is 2.9:0.08-0.12.

[0034] Preferably, in step (6), the mass ratio of the acetylcysteine ​​dry particles to the anhydrous citric acid is 2.9:0.1.

[0035] Preferably, in step (6), the acetylcysteine ​​dry particles and the anhydrous citric acid are mixed with a hopper mixer at 5 to 30 rpm for 3 to 8 minutes.

[0036] More preferably, in step (6), the acetylcysteine ​​dry particles and the anhydrous citric acid are mixed with a hopper mixer at 15 rpm for 5 min.

[0037] The second aspect of the present invention is to improve a pH-responsive high-stability acetylcysteine ​​direct-take granule prepared by any of the above-mentioned processes, which comprises the following components by mass percentage:

[0038]

[0039] Preferably, the pH-responsive high-stability acetylcysteine ​​direct-take granules include the following components by mass percentage:

[0040]

[0041] The present invention adopts the above technical solution, which has the following technical effects compared with the prior art:

[0042] (1) The present invention uses a wet granulation process to ensure that the uniformity of the granule content meets the standard. After drying, granules with a suitable particle size distribution are selected by screening and coated. The coating powder Eudragit L100-55 is a pH-responsive ion exchange resin that does not dissolve when the pH is less than 5.5, but begins to dissolve and release the inclusion complex of acetylcysteine ​​and docusate sodium when the pH is greater than 5.5. At the same time, the anhydrous citric acid added during the total mixing serves as a saliva initiator. When it comes into contact with the tongue, the salivary glands secrete a large amount of saliva to swallow the granules as a whole.

[0043] (2) The present invention aims at the problem that the acetylcysteine ​​API itself is hygroscopic and unstable under oxygen and acid-base conditions. The present invention first prepares an inclusion complex of acetylcysteine ​​wrapped with docusate sodium to protect the API, then wet-granulates acetylcysteine ​​and powdered sugar using a neutral solution of Eudragit L100-55, and finally controls the moisture and impurity levels of the acetylcysteine ​​dry particles by parameters in the drying process. Eudragit L100-55, as a pH-responsive mixture, gives the particles the ability to selectively release acetylcysteine ​​under different pH conditions. At the same time, the pungent smell of the API in the drug-containing particles is blocked, making it more convenient for patients to swallow. There is no need to add flavors and sweeteners to correct the taste, and the particles are not easy to agglomerate during storage. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Figure 1 The dissolution curves of acetylcysteine ​​granules prepared in various embodiments and comparative examples of the present invention are shown in FIG. DETAILED DESCRIPTION

[0045] The present invention is described in detail and specifically by specific examples below to provide a better understanding of the present invention, but the following examples do not limit the scope of the present invention.

[0046] Example 1

[0047] A kind of acetylcysteine ​​direct-take granules, the component formula of which is shown in the following Table 1.

[0048] Table 1: Prescription of Example 1 Acetylcysteine ​​Granules (Specification 0.2g / 3g)

[0049]

[0050]

[0051] Based on the prescription in Table 1 above, the preparation method of the acetylcysteine ​​granules specifically comprises the following steps:

[0052] (1) Pretreatment: acetylcysteine ​​is passed through a 60-mesh sieve, and acetylcysteine ​​and docusate sodium are added into a fluidized bed and dried at 50° C. After drying, the mixture is cooled to room temperature and discharged to obtain an inclusion complex of acetylcysteine ​​encapsulated by docusate sodium; in addition, pulverized sucrose is passed through a 100-mesh sieve for later use;

[0053] (2) Preparation of acetylcysteine ​​granulation solution: Hydroxypropyl methylcellulose was completely dissolved in deoxygenated water under continuous stirring, and Eudragit L100-55 was subsequently added and mixed, and then the pH was adjusted to 7 with 0.1 mol / L NaOH or until the white granules were completely dissolved to prepare a granulation solution for later use;

[0054] (3) preparing a soft material: adding the inclusion compound prepared in step (1) and the crushed powdered sugar into a wet mixing granulator and mixing for 10 min (stirring speed 200 rpm, cutting speed 200 rpm); then adjusting the speed of the wet mixing granulator (stirring speed 200 rpm, cutting speed 1800 rpm), and adding the solution prepared in step (2) to prepare a soft material (liquid addition time 1.5 min, shearing time 2 min);

[0055] (4) Wet granulation: The soft material prepared in step (3) is passed through a 24-mesh steel wire / nylon sieve and granulated using a rocking granulator to obtain acetylcysteine ​​wet granules;

[0056] (5) Drying: The wet granules prepared in step (5) are transferred to an electric heating blast drying oven for drying at a temperature of 50° C. until the moisture content of the dry granules is less than 0.5%, thereby obtaining acetylcysteine ​​dry granules;

[0057] (6) Total mixing: Mix the dried granules with anhydrous citric acid using a hopper mixer (15 rpm, 5 min);

[0058] (7) Packaging: Use paper-aluminum packaging to pack it.

[0059] Example 2

[0060] An acetylcysteine ​​direct-take granule, the composition formula of which is shown in the following Table 2. The difference between Example 2 and Example 1 is that Eudragit L100-55 is not added in the prescription, and sucrose is used to make up the prescription amount.

[0061] Table 2: Prescription of Example 2 Acetylcysteine ​​Granules (Specification 0.2g / 3g)

[0062]

[0063]

[0064] Based on the prescription in Table 2 above, the preparation method of the acetylcysteine ​​granules specifically comprises the following steps:

[0065] (1) Pretreatment: acetylcysteine ​​is passed through a 60-mesh sieve, and acetylcysteine ​​and docusate sodium are added into a fluidized bed and dried at 50° C. After drying, the mixture is cooled to room temperature and then discharged to obtain an inclusion complex of acetylcysteine ​​encapsulated by docusate sodium; in addition, the pulverized sucrose is passed through a 100-mesh sieve;

[0066] (2) Preparation of acetylcysteine ​​granulation solution: Dissolve hydroxypropyl methylcellulose completely in deoxygenated water under continuous stirring to prepare a granulation solution for later use;

[0067] (3) preparing a soft material: adding the inclusion compound prepared in step (1) and the crushed powdered sugar into a wet mixing granulator and mixing for 10 min (stirring speed 200 rpm, cutting speed 200 rpm); then adjusting the speed of the wet mixing granulator (stirring speed 200 rpm, cutting speed 1500 rpm), and adding the solution prepared in step (2) to prepare a soft material (liquid addition time 1.5 min, shearing time 2 min);

[0068] (4) Wet granulation: The soft material prepared in step (3) is passed through a 24-mesh steel wire / nylon sieve and granulated using a rocking granulator to obtain acetylcysteine ​​wet granules;

[0069] (5) Drying: The wet granules prepared in step (4) are transferred to an electric hot air drying oven for drying at a temperature of 50° C. until the moisture content of the dry granules is less than 0.5%, thereby obtaining acetylcysteine ​​dry granules;

[0070] (6) Total mixing: Mix the dried granules with anhydrous citric acid using a hopper mixer (15 rpm, 5 min);

[0071] (7) Packaging: Use paper-aluminum packaging to pack it.

[0072] Example 3

[0073] An acetylcysteine ​​direct-take granule, the component formula of which is shown in the following Table 3. The difference between Example 3 and Example 1 is that the inclusion complex of acetylcysteine ​​encapsulated by docusate sodium is not prepared, and sucrose is used to make up the prescribed amount.

[0074] Table 3: Prescription of Example 3 Acetylcysteine ​​Granules (Specification 0.2g / 3g)

[0075]

[0076]

[0077] Based on the prescription in Table 3 above, the preparation method of the acetylcysteine ​​granules specifically comprises the following steps:

[0078] (1) Pretreatment: pass acetylcysteine ​​through a 60-mesh sieve and pass crushed sucrose powder through a 100-mesh sieve for later use;

[0079] (2) Preparation of acetylcysteine ​​granulation solution: Hydroxypropyl methylcellulose was completely dissolved in deoxygenated water under continuous stirring, and Eudragit L100-55 was subsequently added and mixed, and then the pH was adjusted to 7 with 0.1 mol / L NaOH or until the white granules were completely dissolved to prepare a granulation solution for later use;

[0080] (3) preparing a soft material: adding the acetylcysteine ​​prepared in step (1) and the crushed powdered sugar to a wet mixing granulator and mixing for 10 min (stirring speed 200 rpm, cutting speed 200 rpm); adjusting the speed of the wet mixing granulator (stirring speed 200 rpm, cutting speed 1500 rpm), and adding the solution prepared in step (2) to prepare a soft material (liquid addition time 1.5 min, shearing time 2 min);

[0081] (4) Wet granulation: The soft material prepared in step (3) is passed through a 24-mesh steel wire / nylon sieve and granulated using a rocking granulator to obtain acetylcysteine ​​wet granules;

[0082] (5) Drying: The wet granules prepared in step (4) are transferred to an electric hot air drying oven for drying at a temperature of 50° C. until the moisture content of the dry granules is less than 0.5%, thereby obtaining acetylcysteine ​​dry granules;

[0083] (6) Total mixing: Mix the dried granules with anhydrous citric acid using a hopper mixer (15 rpm, 5 min);

[0084] (7) Packaging: Use paper-aluminum packaging to pack it.

[0085] Example 4

[0086] A direct-take acetylcysteine ​​granule, the composition formula of which is shown in the following Table 4. The difference between Example 4 and Example 1 is that the dosage of docusate sodium is reduced, and sucrose is used to make up the prescription amount.

[0087] Table 4: Prescription of Example 4 Acetylcysteine ​​Granules (Specification 0.2g / 3g)

[0088] name Unit dosage (g) Unit preparation ratio (%) model Acetylcysteine ​​Granules 0.2 6.7 N / A Docusate Sodium 0.2 6.7 N / A sucrose 2.0 66.6 N / A Hydroxypropyl methylcellulose 0.3 10.0 K4M Eudragit 0.2 13.3 L100-55 Anhydrous citric acid 0.1 3.3 N / A sum 3 100

[0089] Based on the prescription in Table 4 above, the preparation method of the acetylcysteine ​​granules specifically comprises the following steps:

[0090] (1) Pretreatment: acetylcysteine ​​is passed through a 60-mesh sieve, and acetylcysteine ​​and docusate sodium are added into a fluidized bed and dried at 50° C. After drying, the mixture is cooled to room temperature and discharged to obtain an inclusion complex of acetylcysteine ​​encapsulated by docusate sodium; in addition, pulverized sucrose is passed through a 100-mesh sieve;

[0091] (2) Preparation of acetylcysteine ​​granulation solution: Hydroxypropyl methylcellulose was completely dissolved in deoxygenated water under continuous stirring, and Eudragit L100-55 was subsequently added and mixed, and then the pH was adjusted to 7 with 0.1 mol / L NaOH or until the white granules were completely dissolved to prepare a granulation solution for later use;

[0092] (3) preparing a soft material: adding the inclusion compound prepared in step (1) and the crushed powdered sugar into a wet mixing granulator and mixing for 10 min (stirring speed 200 rpm, cutting speed 200 rpm); adjusting the speed of the wet mixing granulator (stirring speed 200 rpm, cutting speed 1500 rpm), and adding the solution prepared in step (2) to prepare a soft material (liquid addition time 1.5 min, shearing time 2 min);

[0093] (4) Wet granulation: The soft material prepared in step (3) is passed through a 24-mesh steel wire / nylon sieve and granulated using a rocking granulator to obtain acetylcysteine ​​wet granules;

[0094] (5) Drying: The wet granules prepared in step (4) are transferred to an electric hot air drying oven for drying at a temperature of 50° C. until the moisture content of the dry granules is less than 0.5%, thereby obtaining acetylcysteine ​​dry granules;

[0095] (6) Total mixing: Mix the dried granules with anhydrous citric acid using a hopper mixer (15 rpm, 5 min);

[0096] (7) Packaging: Use paper-aluminum packaging to pack it.

[0097] Example 5

[0098] A direct-take acetylcysteine ​​granule, the composition formula of which is shown in the following Table 5. The difference between Example 5 and Example 1 is that the binder hydroxypropyl methylcellulose is not added, and sucrose is used to make up the prescription amount.

[0099] Table 5: Prescription of Example 5 Acetylcysteine ​​Granules (Specification 0.2g / 3g)

[0100] name Unit dosage (g) Unit preparation ratio (%) model Acetylcysteine ​​Granules 0.2 6.7 N / A Docusate Sodium 0.4 13.3 N / A sucrose 2.1 70.0 N / A Eudragit 0.2 13.3 L100-55 Anhydrous citric acid 0.1 3.3 N / A sum 3 100

[0101] Based on the prescription in Table 5 above, the preparation method of the acetylcysteine ​​granules specifically comprises the following steps:

[0102] (1) Pretreatment: acetylcysteine ​​is passed through a 60-mesh sieve, and acetylcysteine ​​and docusate sodium are added into a fluidized bed and dried at 50° C. After drying, the mixture is cooled to room temperature and discharged to obtain an inclusion complex of acetylcysteine ​​encapsulated by docusate sodium; in addition, pulverized sucrose is passed through a 100-mesh sieve;

[0103] (2) Preparation of acetylcysteine ​​granulation solution: Add Eudragit L100-55 to deoxygenated water with continuous stirring, and after mixing, adjust the pH to 7 with 0.1 mol / L NaOH or until the white granules are completely dissolved to prepare a granulation solution for later use;

[0104] (3) preparing a soft material: adding the inclusion compound prepared in step (1) and the crushed powdered sugar into a wet mixing granulator and mixing for 10 min (stirring speed 200 rpm, cutting speed 200 rpm); adjusting the speed of the wet mixing granulator (stirring speed 200 rpm, cutting speed 1500 rpm), and adding the solution prepared in step (2) to prepare a soft material (liquid addition time 1.5 min, shearing time 2 min);

[0105] (4) Wet granulation: The soft material prepared in step (3) is passed through a 24-mesh steel wire / nylon sieve and granulated using a rocking granulator to obtain acetylcysteine ​​wet granules;

[0106] (5) Drying: The wet granules prepared in step (5) are transferred to an electric heating blast drying oven for drying at a temperature of 50° C. until the moisture content of the dry granules is less than 0.5%, thereby obtaining acetylcysteine ​​dry granules;

[0107] (6) Total mixing: Mix the dried granules with anhydrous citric acid using a hopper mixer (15 rpm, 5 min);

[0108] (7) Packaging: Use paper-aluminum packaging to pack it.

[0109] Example 6

[0110] A direct-dose acetylcysteine ​​granule, the composition of which is shown in Table 6. The difference between Example 6 and Example 1 is that after adding Eudragit L100-55 in step (2), NaOH is not added to adjust the pH, and the subsequent process is directly carried out with the suspension.

[0111] Table 6: Prescription of Example 6 Acetylcysteine ​​Granules (Specification 0.2g / 3g)

[0112] name Unit dosage (g) Unit preparation ratio (%) model Acetylcysteine ​​Granules 0.2 6.7 N / A Docusate Sodium 0.4 13.3 N / A sucrose 1.8 60.0 N / A Hydroxypropyl methylcellulose 0.3 10.0 K4M Eudragit 0.2 13.3 L100-55 Anhydrous citric acid 0.1 3.3 N / A sum 3 100

[0113] Based on the prescription in Table 6 above, the preparation method of the acetylcysteine ​​granules specifically comprises the following steps:

[0114] (1) Pretreatment: acetylcysteine ​​is passed through a 60-mesh sieve, and acetylcysteine ​​and docusate sodium are added into a fluidized bed and dried at 50° C. After drying, the mixture is cooled to room temperature and then discharged to obtain an inclusion complex of acetylcysteine ​​encapsulated by docusate sodium; in addition, the pulverized sucrose is passed through a 100-mesh sieve;

[0115] (2) Preparation of acetylcysteine ​​granulation solution: Hydroxypropyl methylcellulose was completely dissolved in deoxygenated water under continuous stirring, and Eudragit L100-55 was subsequently added and mixed to prepare a granulation solution for later use;

[0116] (3) preparing a soft material: adding the inclusion compound prepared in step (1) and the crushed powdered sugar into a wet mixing granulator and mixing for 10 min (stirring speed 200 rpm, cutting speed 200 rpm); adjusting the speed of the wet mixing granulator (stirring speed 200 rpm, cutting speed 1500 rpm), and adding the solution prepared in step (2) to prepare a soft material (liquid addition time 1.5 min, shearing time 2 min);

[0117] (4) Wet granulation: The soft material prepared in step (3) is passed through a 24-mesh steel wire / nylon sieve and granulated by a swing granulator to obtain acetylcysteine ​​wet granules.

[0118] (5) Drying: The wet granules prepared in step (4) are transferred to an electric hot air drying oven for drying at a temperature of 50° C. until the moisture content of the dry granules is less than 0.5%, thereby obtaining acetylcysteine ​​dry granules;

[0119] (6) Total mixing: Mix the dried granules with anhydrous citric acid using a hopper mixer (15 rpm, 5 min);

[0120] (7) Packaging: Use paper-aluminum packaging to pack it.

[0121] Example 7

[0122] An acetylcysteine ​​direct-take granule, the component formula of which is shown in the following Table 7. The difference between Example 7 and Example 1 is that API: docusate sodium = 1:2.5, and the amount of sucrose is reduced to make up the prescribed amount.

[0123] Table 7: Prescription of Example 7 Acetylcysteine ​​Granules (Specification 0.2g / 3g)

[0124] name Unit dosage (g) Unit preparation ratio (%) model Acetylcysteine ​​Granules 0.2 6.7 N / A Docusate Sodium 0.5 16.6 N / A sucrose 1.7 56.7 N / A Hydroxypropyl methylcellulose 0.3 10.0 K4M Eudragit 0.2 6.7 L100-55 Anhydrous citric acid 0.1 3.3 N / A sum 3 100

[0125] (1) Pretreatment: acetylcysteine ​​is passed through a 60-mesh sieve, and acetylcysteine ​​and docusate sodium are added into a fluidized bed and dried at 50° C. After drying, the mixture is cooled to room temperature and discharged to obtain an inclusion complex of acetylcysteine ​​encapsulated by docusate sodium; in addition, pulverized sucrose is passed through a 100-mesh sieve for later use;

[0126] (2) Preparation of acetylcysteine ​​granulation solution: Hydroxypropyl methylcellulose was completely dissolved in deoxygenated water under continuous stirring, and Eudragit L100-55 was subsequently added and mixed, and then the pH was adjusted to 7 with 0.1 mol / L NaOH or until the white granules were completely dissolved to prepare a granulation solution for later use;

[0127] (3) preparing a soft material: adding the inclusion compound prepared in step (1) and the crushed powdered sugar into a wet mixing granulator and mixing for 10 min (stirring speed 200 rpm, cutting speed 200 rpm); then adjusting the speed of the wet mixing granulator (stirring speed 200 rpm, cutting speed 1800 rpm), and adding the solution prepared in step (2) to prepare a soft material (liquid addition time 1.5 min, shearing time 2 min);

[0128] (4) Wet granulation: The soft material prepared in step (3) is passed through a 24-mesh steel wire / nylon sieve and granulated using a rocking granulator to obtain acetylcysteine ​​wet granules;

[0129] (5) Drying: The wet granules prepared in step (5) are transferred to an electric heating blast drying oven for drying at a temperature of 50° C. until the moisture content of the dry granules is less than 0.5%, thereby obtaining acetylcysteine ​​dry granules;

[0130] (6) Total mixing: Mix the dried granules with anhydrous citric acid using a hopper mixer (15 rpm, 5 min);

[0131] (7) Packaging: Use paper-aluminum packaging to pack it.

[0132] Example 8

[0133] An acetylcysteine ​​direct-take granule, the component formula of which is shown in the following Table 8. The difference between Example 8 and Example 1 is that the amount of Eudragit is increased, and the amount of sucrose is reduced to make up the prescribed amount.

[0134] Table 8: Prescription of Example 8 Acetylcysteine ​​Granules (Specification 0.2g / 3g)

[0135] name Unit dosage (g) Unit preparation ratio (%) model Acetylcysteine ​​Granules 0.2 6.7 N / A Docusate Sodium 0.4 13.3 N / A sucrose 1.75 58.3 N / A Hydroxypropyl methylcellulose 0.3 10.0 K4M Eudragit 0.25 8.3 L100-55 Anhydrous citric acid 0.1 3.3 N / A sum 3 100

[0136] (1) Pretreatment: acetylcysteine ​​is passed through a 60-mesh sieve, and acetylcysteine ​​and docusate sodium are added into a fluidized bed and dried at 50° C. After drying, the mixture is cooled to room temperature and discharged to obtain an inclusion complex of acetylcysteine ​​encapsulated by docusate sodium; in addition, pulverized sucrose is passed through a 100-mesh sieve for later use;

[0137] (2) Preparation of acetylcysteine ​​granulation solution: Hydroxypropyl methylcellulose was completely dissolved in deoxygenated water under continuous stirring, and Eudragit L100-55 was subsequently added and mixed, and then the pH was adjusted to 7 with 0.1 mol / L NaOH or until the white granules were completely dissolved to prepare a granulation solution for later use;

[0138] (3) preparing a soft material: adding the inclusion compound prepared in step (1) and the crushed powdered sugar into a wet mixing granulator and mixing for 10 min (stirring speed 200 rpm, cutting speed 200 rpm); then adjusting the speed of the wet mixing granulator (stirring speed 200 rpm, cutting speed 1800 rpm), and adding the solution prepared in step (2) to prepare a soft material (liquid addition time 1.5 min, shearing time 2 min);

[0139] (4) Wet granulation: The soft material prepared in step (3) is passed through a 24-mesh steel wire / nylon sieve and granulated using a rocking granulator to obtain acetylcysteine ​​wet granules;

[0140] (5) Drying: The wet granules prepared in step (5) are transferred to an electric heating blast drying oven for drying at a temperature of 50° C. until the moisture content of the dry granules is less than 0.5%, thereby obtaining acetylcysteine ​​dry granules;

[0141] (6) Total mixing: Mix the dried granules with anhydrous citric acid using a hopper mixer (15 rpm, 5 min);

[0142] (7) Packaging: Use paper-aluminum packaging to pack it.

[0143] Comparative Example 1

[0144] A kind of acetylcysteine ​​granules, the component formula of which is shown in Table 9 below.

[0145] Table 9: Prescription of Comparative Example 1 Acetylcysteine ​​Granules (Specification 0.2g / 3g)

[0146] name Unit dosage (g) Unit preparation ratio (%) model Acetylcysteine ​​Granules 0.2 6.7 N / A Sucrose crystals 2.7 90.0 N / A Sweet orange powder flavor 0.05 1.67 N / A Saccharin Sodium 0.05 1.67 N / A sum 3 100

[0147] Based on the prescription in Table 9 above, the preparation method of the acetylcysteine ​​granules specifically comprises the following steps:

[0148] (1) Pretreatment: Pass acetylcysteine ​​through a 60-mesh sieve and ensure that acetylcysteine ​​cannot pass through a 100-mesh sieve; sieve the sucrose crystals according to the same standard as the API (sieve and mix at a relative humidity of <50 RCH) and set aside;

[0149] (2) Mixing 1: The materials were mixed using a hopper mixer using an equal amount increment method. First, 0.2 g of API was mixed with an equal amount of sucrose crystals (8 rpm, 10 min). After mixing, 0.4 g of sucrose crystals were added to the materials and continued to mix (8 rpm, 10 min). Then, 0.8 g of sucrose crystals were added and mixed. Finally, the remaining sucrose crystals were added and continued to mix.

[0150] (3) Mixing 2: Add saccharin sodium and sweet orange powder flavor to the material after mixing 1 and continue mixing (15 rpm, 5 min);

[0151] (4) Packaging: Use paper-aluminum packaging to pack it.

[0152] This comparative example 1 adopts the method of equal increment for mixing. First, because the API and sucrose crystals are too fine, they are obtained through the screening process. Because both API and sucrose have certain hygroscopicity, it is inconvenient to control the humidity during screening. Secondly, because of the screening, there is a certain proportion of raw and auxiliary materials that are not suitable for the particle size, resulting in a large amount of waste of raw and auxiliary materials, which increases the cost from an economic perspective. Because of the direct mixing process, the mixing uniformity is poor, and stratification is prone to occur during packaging and filling. And because the API and sucrose crystals are fine in particle size, agglomeration and other phenomena are prone to occur during storage.

[0153] Comparative Example 2

[0154] A kind of acetylcysteine ​​granules, the component formula of which is shown in Table 10 below.

[0155] Table 10: Prescription of Comparative Example 2 Acetylcysteine ​​Granules (Specification 0.2g / 3g)

[0156] name Unit dosage (g) Unit preparation ratio (%) model Acetylcysteine ​​Granules 0.2 6.7 N / A Sucrose crystals 2.7 90.0 N / A Sweet orange powder flavor 0.05 1.67 N / A Saccharin Sodium 0.05 1.67 N / A sum 3 100

[0157] Based on the prescription in Table 10 above, the preparation method of the acetylcysteine ​​granules specifically comprises the following steps:

[0158] (1) Pretreatment: Pass acetylcysteine ​​through a 50-mesh sieve and ensure that acetylcysteine ​​cannot pass through an 80-mesh sieve; sieve the sucrose crystals according to the same standard as the API (sieve and mix at a relative humidity of <50 RCH) and set aside;

[0159] (2) Mixing 1: The materials were mixed using a hopper mixer using an equal amount increment method. First, 0.2 g of API was mixed with an equal amount of sucrose crystals (8 rpm, 10 min). After mixing, 0.4 g of sucrose crystals were added to the materials and continued to mix (8 rpm, 10 min). Then, 0.8 g of sucrose crystals were added and mixed. Finally, the remaining sucrose crystals were added and continued to mix.

[0160] (3) Mixing 2: Add saccharin sodium and cherry powder flavor to the material after mixing 1 and continue mixing (15 rpm, 5 min);

[0161] (4) Packaging: Use paper-aluminum packaging to pack it.

[0162] Comparative Example 3

[0163] A kind of acetylcysteine ​​granules, the component formula of which is shown in the following Table 11.

[0164] Table 11: Prescription of Comparative Example 3 Acetylcysteine ​​Granules (Specification 0.2g / 3g)

[0165] name Unit dosage (g) Unit preparation ratio (%) model Acetylcysteine ​​Granules 0.2 6.7 N / A Sucrose powder 2.7 90.0 N / A Sweet orange powder flavor 0.05 1.67 N / A Saccharin Sodium 0.05 1.67 N / A sum 3 100

[0166] Based on the prescription in Table 11 above, the preparation method of the acetylcysteine ​​granules specifically comprises the following steps:

[0167] (1) Pretreatment: acetylcysteine ​​is passed through a 100-mesh sieve, sucrose crystals are crushed, and then passed through a 100-mesh sieve for later use;

[0168] (2) Preparation of granulation solution: dissolve saccharin sodium in an appropriate amount of purified water;

[0169] (3) preparing a soft material: adding the crushed material in step (1) to a wet mixing granulator and mixing for 10 min (stirring speed 50-500 rpm, cutting speed 50-500 rpm); adjusting the speed of the wet mixing granulator (stirring speed 50-500 rpm, cutting speed 1000-2000 rpm), and adding the solution prepared in step (2) to prepare a soft material (liquid addition time 1-3 min, shearing time 1-3 min);

[0170] (4) Wet granulation: the soft material prepared in step (3) is passed through a 24-mesh steel wire / nylon sieve and granulated by a rocking granulator;

[0171] (5) transferring the wet granules prepared in step (4) to an electric heated air drying oven for drying at a temperature of 50° C. until the moisture content of the dry granules is less than 0.5%, which indicates that the drying is complete;

[0172] (6) Total mixing: Mix the dried granules and the sweet orange powder flavor using a hopper mixer (15 rpm, 5 min);

[0173] (7) Packaging: Use paper-aluminum packaging to pack it.

[0174] Comparative Example 3 used a wet granulation process and had good mixing uniformity, but was prone to agglomeration during storage, and the increase in related substances during storage was large, and finally the related substances exceeded the limit and failed to meet the standard.

[0175] Comparative Example 4

[0176] A kind of acetylcysteine ​​granules, the component formula of which is shown in Table 12 below.

[0177] Table 12: Prescription of Comparative Example 4 Acetylcysteine ​​Granules (Specification 0.2g / 3g)

[0178] name Unit dosage (g) Unit preparation ratio (%) model Acetylcysteine ​​Granules 0.2 6.7 N / A Sucrose powder 0.9 30.0 N / A Sucrose crystals 1.8 60.0 N / A Sweet orange powder flavor 0.05 1.67 N / A Saccharin Sodium 0.05 1.67 N / A sum 3 100

[0179] Based on the prescription in Table 12 above, the preparation method of the acetylcysteine ​​granules specifically comprises the following steps:

[0180] (1) Pretreatment: acetylcysteine ​​was sieved through a 60-mesh sieve, and sucrose powder was crushed and sieved through a 100-mesh sieve;

[0181] (2) Preparation of granulation solution: dissolve saccharin sodium in an appropriate amount of purified water;

[0182] (3) preparing a soft material: adding the sucrose powder crushed in step (1) to a wet mixing granulator and mixing for 10 min (stirring speed 50-500 rpm, cutting speed 50-500 rpm); adjusting the speed of the wet mixing granulator (stirring speed 50-500 rpm, cutting speed 1000-2000 rpm), and adding the solution prepared in step (2) to prepare a soft material (liquid addition time 1-3 min, shearing time 1-3 min);

[0183] (4) Wet granulation: the soft material prepared in step (3) is passed through a 24-mesh steel wire / nylon sieve and granulated by a rocking granulator;

[0184] (5) transferring the wet granules prepared in step (4) to an electric heated air drying oven for drying at a temperature of 50° C. until the moisture content of the dry granules is less than 0.5%, which indicates that the drying is complete;

[0185] (6) Granulation: Pass the blank drug-containing granules through a 60-mesh sieve.

[0186] (7) Total mixing: The dried blank granules were mixed with acetylcysteine ​​(15 rpm, 10 min), and then mixed with the sweet orange powder flavor using a hopper mixer (15 rpm, 5 min).

[0187] (8) Packaging: Use paper-aluminum packaging.

[0188] Comparative Example 4 uses wet granulation to first prepare blank particles, and then mix them with flavors and API. The process has good mixing uniformity. However, preparing blank particles first and then screening the blank particles again will increase costs and further waste materials. Secondly, because the process route is long and too complicated, it causes exponential growth in energy consumption and is not suitable for large-scale production.

[0189] Verification test:

[0190] The dissolution curve was determined according to the Chinese Pharmacopoeia 2020 Edition. First, 750 ml of 0.1 mol / L hydrochloric acid solution was measured and placed in each dissolution cup. The deviation between the actual measured volume and the specified volume should be within ±1%. When the temperature of the dissolution medium is constant at 37°C ± 0.5°C, the dissolution test was started. When the dissolution test reached 2 hours, 250 ml of 0.2 mol / L sodium phosphate solution at a temperature of 37°C ± 0.5°C was added to the above acid solution (if necessary, 2 mol / L hydrochloric acid solution or 2 mol / L sodium hydroxide solution was used to adjust the pH value to 6.8). The operation was continued and the appropriate amount of dissolution solution was drawn at the specified sampling point according to the time specified under each variety item, and filtered. The sampling to filtration should be completed within 30 seconds. Determine according to the method specified under each variety item, and calculate the dissolution amount in the buffer solution in the dissolution cup under each dosage unit.

[0191] The acetylcysteine ​​granules prepared in Examples 1 to 6 were used as the experimental group, and the acetylcysteine ​​granules prepared in Comparative Examples 1 to 4 were used as the control group. The dissolution tests were performed using the above method. The test results are shown in FIG. Figure 1 The dissolution curve is shown.

[0192] The limits are as follows: the content uniformity RSD shall not exceed 5.0%. Impurity limits: each impurity A, impurity B, impurity C and impurity D shall not exceed 0.5%, and the total impurity shall be less than 1.0%. / indicates that it is not detected. If the particles are agglomerated, the storage period is directly deemed unqualified. The types of acetylcysteine ​​impurities are shown in Table 1 below, and the test results of the relevant substances of each embodiment and comparative example are shown in Table 14 and Table 15 below.

[0193] Table 13 Comparison table of acetylcysteine ​​impurities

[0194]

[0195] Table 14 List of related substances in content uniformity of examples and comparative examples (0 day)

[0196]

[0197]

[0198] Table 15 List of related substances in Examples and Comparative Examples (accelerated 6 months)

[0199] batch number Impurity A(%) Impurity B(%) Impurity C(%) Impurity D(%) Total impurities (%) Whether it is agglomerated Example 1 / / 0.13 0.18 0.31 no Example 2 / / 0.34 0.41 0.80 no Example 3 / / 0.54 0.61 1.23 no Example 4 / / 0.48 0.47 1.01 no Example 5 / / 0.58 0.63 1.34 yes Example 6 / / 0.61 0.76 1.81 yes Example 7 / / 0.45 0.41 0.87 no Example 8 / / 0.43 0.44 0.90 no Comparative Example 1 / / 0.09 0.12 0.29 yes Comparative Example 2 / / 0.14 0.16 0.45 yes Comparative Example 3 / / 1.93 2.17 5.84 yes Comparative Example 4 / / 0.43 0.38 0.84 no

[0200] Summarizing the above data, the specific analysis is as follows:

[0201] Example 1 is the preferred process of the present invention. Example 2 is to remove Eudragit L100-55, and as a result, the dissolution curve of this pH-responsive material is lost and becomes faster. Example 3 does not add sodium docusate to prepare the inclusion complex with API at the beginning. This example has impurities exceeding the standard in the stability acceleration of 6 months. Example 4 reduces the dosage of sodium docusate at the beginning, and the single impurity meets the standard but the total impurity exceeds the limit when accelerating for 6 months. Example 5 is that the binder hydroxypropyl methylcellulose is not present in the granulation solution. It is found that it affects the dissolution curve of the finished product. It is released too fast in the pH1.2 medium, and the single impurity exceeds the standard in 6 months. Example 6 is a prescription without NaOH to adjust the pH, Eudragit L100-55, and it is found that Eudragit L100-55 is not completely dissolved. It is speculated that it is not evenly wrapped on the surface of the complex. It is found that it affects the dissolution curve of the finished product. The release is too fast in the pH1.2 medium, and the product stability accelerates the single impurity exceeding the standard in 6 months. The dissolution endpoint of the dissolution curve of Example 7 is significantly reduced, and the impurity level is accelerated for 6 months, which is close to the limit. In Example 8, because the proportion of Eudragit L100-55 increased, more alkali was needed to dissolve the pH-responsive material. Compared with Example 1, the dissolution was slightly slower, and the impurity level was accelerated by 6 months, which was close to the limit.

[0202] Comparative Example 1 is a prescription for equal-incremental mixing, with a large RSD of mixing uniformity, and because the particle size is too fine, agglomeration occurs when the particle size is accelerated for 6 months. Comparative Example 2 is an equal-incremental mixing, but the humidity needs to be controlled and a large amount of material is wasted during screening, and agglomeration occurs when the particle size is accelerated for 6 months. Comparative Example 3 is a wet granulation, and the impurities in the accelerated particle size are all exceeded in 6 months, and agglomeration occurs. Comparative Example 4 is a blank granulation prepared first and then mixed with API and flavors. The process is long, complicated and energy-intensive. Impurities C and D mainly increased during the stability period, while impurities A and B were not detected.

[0203] The specific embodiments of the present invention are described in detail above, but they are only examples, and the present invention is not limited to the specific embodiments described above. For those skilled in the art, any equivalent modifications and substitutions made to the present invention are also within the scope of the present invention. Therefore, the equalization changes and modifications made without departing from the spirit and scope of the present invention should be included in the scope of the present invention.

Claims

1. A preparation process of acetylcysteine ​​direct-take granules with high stability based on pH response, characterized in that: The steps include: (1) Pretreatment: acetylcysteine ​​and sucrose are sieved and crushed in advance, and then acetylcysteine ​​and docusate sodium are added into a fluidized bed and dried at 50° C. After drying, the mixture is cooled to room temperature and discharged to obtain an inclusion complex of acetylcysteine ​​encapsulated by docusate sodium; (2) Preparation of granulation solution: Hydroxypropyl methylcellulose was completely dissolved in deoxygenated water under continuous stirring, and Eudragit L100-55 was subsequently added and mixed, and then the pH was adjusted to 7 with 0.1 mol / L NaOH or the white granules were completely dissolved to prepare a granulation solution; (3) preparing a soft material: adding the inclusion compound prepared in step (1) and sucrose to a wet mixing granulator and mixing for 10 minutes, adjusting the speed of the wet mixing granulator and adding the granulation solution prepared in step (2), controlling the liquid addition time to 1 to 3 minutes and the shearing time to 1 to 3 minutes, to prepare a soft material; (4) Wet granulation: the soft material prepared in step (3) is passed through a 16-30 mesh steel wire / nylon sieve and granulated by a swing granulator to obtain acetylcysteine ​​wet granules; (5) Drying: The wet acetylcysteine ​​granules obtained in step (4) are transferred to an electric heated air drying oven for drying to obtain dry acetylcysteine ​​granules; (6) Total mixing: Mix the acetylcysteine ​​dry particles obtained in step (5) with anhydrous citric acid using a hopper mixer at 10 to 30 rpm for 2 to 8 minutes; (7) Packaging: The acetylcysteine ​​direct-take granules are packaged in paper-aluminum packaging.

2. The preparation process according to claim 1, characterized in that: In step (1), the acetylcysteine ​​is pre-sieved through a 60-mesh sieve, and the pulverized sucrose is pre-sieved through a 100-mesh sieve.

3. The preparation process according to claim 1, characterized in that: In step (1), the dosage ratio of the acetylcysteine ​​to the docusate sodium is 1:1.5-2.

5.

4. The preparation process according to claim 1, characterized in that: In step (2), the dosage ratio of hydroxypropyl methylcellulose, Eudragit L100-55 and deoxygenated water is 3:1.5-2.5:5-8.

5. The preparation process according to claim 1, characterized in that: In step (3), the ratio of the inclusion compound to the sucrose is 1:2-5.

6. The preparation process according to claim 1, characterized in that: In step (3), the stirring speed of the wet mixing granulator is 50 to 500 rpm, and the cutting speed is 50 to 500 rpm; the adjusted stirring speed is 50 to 500 rpm, and the cutting speed is 1000 to 2000 rpm.

7. The preparation process according to claim 1, characterized in that: In step (4), the drying temperature of the acetylcysteine ​​wet granules is 40-60° C. until the moisture content of the dry granules is less than 0.5%.

8. The preparation process according to claim 1, characterized in that: In step (6), the dosage ratio of the acetylcysteine ​​dry particles to the anhydrous citric acid is 2.9:0.05-0.

15.

9. A pH-responsive, high-stability acetylcysteine ​​direct-take granule prepared according to the process of any one of claims 1 to 8, characterized in that: Calculated by mass percentage, it includes the following components:

10. The pH-responsive high-stability acetylcysteine ​​direct-take granules according to claim 9, characterized in that: Calculated by mass percentage, it includes the following components:

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