Acetylcysteine orally disintegrating tablet and preparation method thereof

Abstract

The application discloses an acetylcysteine orally disintegrating tablet and a preparation method thereof, and belongs to the field of pharmaceutical preparations. The orally disintegrating tablet is prepared from the following raw materials in percentage by mass: acetylcysteine 50-75%, filler A 5-22.3%, sweetening agent 1-2%, flavoring agent 1-2.5%, filler B 4.75-27.3%, disintegrating agent 2-4.5%, adhesive 5-16%, flow aid 1-2%, and lubricant 1-1.3%. The preparation method comprises the steps of premixing, dry granulation, total mixing and tablet pressing. The acetylcysteine orally disintegrating tablet has the advantages of short disintegration time, low production cost, controllable production safety and the like.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical preparations, in particular to an acetylcysteine orally disintegrating tablet and a preparation method thereof. BACKGROUND

[0002] Acetylcysteine is a sulfhydryl derivative, also known as N-acetylcysteine or NAC, which is a commonly used mucolytic agent. It is used to treat respiratory diseases such as chronic bronchitis, asthma, and cystic fibrosis. It reduces the viscosity of sputum and promotes sputum discharge, thereby relieving symptoms such as difficulty breathing.

[0003] The current dosage forms of acetylcysteine include injection, inhalation solution, eye drops, effervescent tablets, ordinary tablets, capsules, and granules. The administration routes are injection, external use, and oral administration. Among them, the oral tablets are large (Zambon 600mg specification, diameter 12.18x thickness 6.75mm, tablet weight 750mg), which is not convenient to swallow, especially for the elderly, children and other patients with difficulty swallowing. In addition, the raw material acetylcysteine has a special smell of rotten eggs. Therefore, the compliance of patients is poor.

[0004] Orally disintegrating tablets (ODTs) are a kind of tablets that can rapidly disintegrate or dissolve after contacting saliva. They have the advantages of convenience (no need for water assistance, suitable for special groups), rapid disintegration and absorption, and improved bioavailability. They can also reduce the risk of airway obstruction or suffocation due to physical obstruction during oral administration.

[0005] Chinese patent application CN 117159484 A discloses a preparation method of acetylcysteine orally disintegrating tablets, which specifically includes pre-coating acetylcysteine with povidone k30, then mixing it with other excipients uniformly, and directly compressing the powder to obtain the tablets. This method has at least the following disadvantages:

[0006] (1) Pre-coating is required, which consumes a lot of energy;

[0007] (2) Ethanol is used as a solvent to dissolve PVP K30 during coating, but ethanol is flammable and explosive, which is very troublesome for safe use and recycling, and is not suitable for industrial operation;

[0008] (3) The disintegration time is still more than 40s (although the disintegration time of the disclosed orally disintegrating tablets is 30s, but as disclosed in the specification, the hardness decreases by 69%, the compression rate is >20%, and the tablet surface is rough and has fine lines, which does not meet the pharmacopoeia standard);

[0009] (4) Since it needs to use ethanol, even if 95% ethanol is used, 5% water is contained in the ethanol, and acetylcysteine is unstable in water, so the drug efficacy can be affected;

[0010] (5) The content of the effective ingredient is only 25%, and the amount to be taken is large and the taste is poor. SUMMARY

[0011] One of the purposes of the present application is to provide an acetylcysteine orally disintegrating tablet to solve the above problems.

[0012] In order to achieve the above purpose, the technical solution adopted by the present application is as follows: an acetylcysteine orally disintegrating tablet is made from the following raw materials in the following mass percentages: acetylcysteine 50% to 75%, filler A 5% to 22.3%, sweetener 1% to 2%, flavoring agent 1% to 2.5%, filler B 4.75% to 27.3%, disintegrant 2% to 4.5%, binder 5% to 16%, glidant 1% to 2%, and lubricant 1% to 1.3%, with the total being 100%.

[0013] As a preferred technical solution, the filler A is a sugar alcohol; and the filler B is microcrystalline cellulose.

[0014] As a preferred technical solution, the filler A is selected from at least one of sucrose, mannitol, sorbitol, and erythritol.

[0015] As a preferred technical solution, the disintegrant is selected from at least one of cross-linked polyvinylpyrrolidone and cross-linked sodium carboxymethylcellulose; the flavoring agent is selected from at least one of peppermint essence, orange essence, and strawberry essence; and the sweetener is selected from at least one of aspartame and sodium saccharin.

[0016] The second purpose of the present application is to provide a preparation method for the above-mentioned acetylcysteine orally disintegrating tablet, and the technical solution adopted is as follows:

[0017] (1) Mix acetylcysteine and a part of filler B uniformly to obtain acetylcysteine premix powder; the mass of the filler B added is 15% to 28% of the total mass of the filler B, and the inventors have proved through a large number of tests that if the range is exceeded, the orally disintegrating tablet will not be qualified in terms of disintegration time limit, hardness, and compressibility;

[0018] (2) Dry granulation: dry granulate the acetylcysteine premix powder to obtain granules;

[0019] (3) Total mixing: mix filler A, the remaining filler B, disintegrant, binder, lubricant, flavoring agent, sweetener, and the granules obtained in step (2) uniformly, and then add glidant for mixing;

[0020] (4) tabletting.

[0021] As a preferred technical solution, in step (2), the acetylcysteine premixed powder is dry granulated, and then the granules are sieved (for example, using a 100-mesh sieve, and if there is a large amount of fine powder (for example, more than 50%) under the sieve, the fine powder is subjected to secondary granulation (the purpose of this control is that if the amount of fine powder is too large, the material flowability will be poor, which will affect the subsequent tabletting process, etc.), and then all the granules and powder are mixed together to determine the powder properties. According to the flowability evaluation standard in the 2020 edition of the Chinese Pharmacopoeia, the angle of repose is ≤45°.

[0022] CN 117159484 A needs to be coated before tabletting, and since the acetylcysteine raw material is in the form of a tablet, the flowability is poor. Therefore, the present application first performs dry granulation and then tabletting, rather than directly tabletting the powder, in order to stabilize the subsequent process. If the powder is not pre-granulated and is directly tabletted, the powder flowability and compressibility are poor, and the tablet weight difference is unqualified.

[0023] From the perspective of the prescription, the effective ingredient of the present application is 2-3 times that of CN 117159484 A, the amount to be taken is significantly reduced, and the taste is better.

[0024] In terms of preparation process, the present application first pre-mixes part of the microcrystalline cellulose with acetylcysteine, then dry granulates, and then adds mannitol and the remaining microcrystalline cellulose. This is to ensure the smooth progress of the entire preparation process, especially the dry granulation process. The microcrystalline cellulose of the present application has a certain auxiliary disintegration effect.

[0025] Compared with the prior art, the present application has the advantages that the process is smooth, the steps are simple, and the production cost is low. From the perspective of energy consumption, compared with powder pre-coating granulation, the energy consumption of the present application is reduced by about 60-70%, mainly due to the omission of the spray drying and hot air circulation steps. The production process is more convenient, has the advantages of short disintegration time, low production cost, and controllable production safety. DETAILED DESCRIPTION

[0026] The present application will be further described below with reference to examples.

[0027] Example 1

[0028] A kind of acetylcysteine oral disintegration tablet, the raw material ratio is shown in Table 1,

[0029] Table 1 Raw material ratio of oral disintegration tablet of Example 1

[0030]

[0031] The preparation method comprises the following steps:

[0032] (1) Premix: Acetylcysteine and 20% microcrystalline cellulose (18.8 g) were mixed evenly, the mixing speed was 15 rpm, and the mixing time was 10 min to obtain acetylcysteine premix powder;

[0033] (2) Dry granulation: The acetylcysteine premix powder was added to a dry granulator, the roller gap was set to 1.2 mm, the roller speed was 6 rpm, the oil pressure was 60 bar, the feeding speed was automatically adjusted by the instrument, the first-stage granulation speed was 120 rpm, the second-stage granulation speed was 120 rpm, the first-stage granulation screen was a 2.0 mm round hole screen, the second-stage granulation screen was a 1.0 mm round hole screen, and the granulation was started; after granulation, the granules were sieved with a 100 mesh screen, and when the fine powder under the screen was more than 50%, secondary granulation was performed, and then all the granules and powder were mixed together to determine the powder properties;

[0034] (3) Total mixing: The remaining excipients except for silicon dioxide were added and mixed evenly, and then silicon dioxide was added and mixed evenly; the granules for the subsequent process were weighed, and the remaining fillers, sugar alcohols, disintegrants, binders (which needed to be passed through a 40 mesh screen by hand), lubricants, flavorings, and sweeteners were added and mixed at a speed of 15 rpm for 10 min, and then magnesium stearate was added and mixed at a speed of 15 rpm for 5 min;

[0035] (4) Tabletting: The tablet weight was 400 mg ± 5%, the hardness was controlled to be 6-10 kg (i.e., 60 N-100 N), and tabletting was performed to obtain the oral disintegration tablets 1.

[0036] Example 2

[0037] An acetylcysteine oral disintegration tablet, the raw material ratio of which is shown in Table 2,

[0038] Table 2 Raw material ratio of oral disintegration tablets of Example 2

[0039]

[0040] The preparation method was the same as that of Example 1, and oral disintegration tablets 2 were obtained.

[0041] Example 3:

[0042] An acetylcysteine oral disintegration tablet, the raw material ratio of which is shown in Table 3,

[0043] Table 3 Raw material ratio of oral disintegration tablets of Example 3

[0044]

[0045] The preparation method was the same as that of Example 1, and oral disintegration tablets 3 were obtained.

[0046] Example 4

[0047] An acetylcysteine orally disintegrating tablet, whose raw material ratio is shown in Table 4,

[0048] Table 4 Raw material ratio of orally disintegrating tablet of Example 4

[0049]

[0050] The preparation method is the same as that of Example 1 to obtain orally disintegrating tablet 4.

[0051] Example 5

[0052] An acetylcysteine orally disintegrating tablet, whose raw material ratio is shown in Table 5,

[0053] Table 5 Raw material ratio of orally disintegrating tablet of Example 5

[0054]

[0055] Example 6

[0056] An acetylcysteine orally disintegrating tablet, whose raw material ratio is shown in Table 6,

[0057] Table 6 Raw material ratio of orally disintegrating tablet of Example 6

[0058]

[0059] The preparation method is the same as that of Example 1 to obtain orally disintegrating tablet 6.

[0060] Comparative Example 1

[0061] The raw material ratio of the present comparative example is shown in Table 7, and the preparation method is the same as that of Example 1.

[0062] Table 7 Raw material ratio of Comparative Example 1

[0063]

[0064] Comparative Example 2

[0065] The raw material ratio of the present comparative example is shown in Table 8, and the preparation method is the same as that of Example 1.

[0066] Table 8 Raw material ratio of Comparative Example 2

[0067]

[0068] Comparative Example 3

[0069] The raw material ratio of the present comparative example is shown in Table 9, and the preparation method is the same as that of Example 1. The adhesive of the present comparative example is less than 5%, and the hardness and friability are not good.

[0070] Table 9 Raw material ratio of Comparative Example 3

[0071]

[0072] Comparative Example 4

[0073] This comparative example is compared with Example 2, and the step of dry granulation is cancelled, and the powder is directly tableted, and the rest is the same as Example 2. The result is that the powder flowability and compressibility are poor, and the tablet weight difference is unqualified.

[0074] This comparative example cancels dry granulation, and the result is that the disintegration performance, hardness and friability are significantly worse than Example 2. The core problem is that the powder flowability is poor and the compressibility is insufficient, which ultimately leads to unqualified tablet quality (disintegration exceeds the limit, hardness is insufficient, and friability is unqualified).

[0075] Comparative Example 5

[0076] This comparative example is compared with Example 2, and all the microcrystalline cellulose is premixed with acetylcysteine, and the rest is the same as Example 2.

[0077] This comparative example premixes all the microcrystalline cellulose, which leads to disintegration performance degradation, hardness stability decline and unqualified friability. The core problem is that the distribution of microcrystalline cellulose is unbalanced: excessive use in the premixing stage makes it embedded inside the particles, weakening the disintegration effect; at the same time, the lack of microcrystalline cellulose in the total mixing stage leads to a decrease in process controllability. This result further verifies the necessity of adding microcrystalline cellulose in stages in Example 2 (considering compressibility and disintegration efficiency).

[0078] Comparative Example 6

[0079] This comparative example is compared with Example 2, and first premixes mannitol with acetylcysteine, then adds microcrystalline cellulose after dry granulation, and the rest is the same as Example 2.

[0080] The disintegration time of this comparative example is significantly prolonged to 60-108 seconds, which is much higher than 11-12 seconds of Example 2.

[0081] The reason is that microcrystalline cellulose, as a key disintegrant, is combined with acetylcysteine in Example 2 through premixing and uniformly distributed inside the particles to promote disintegration.

[0082] In this comparative example, microcrystalline cellulose is added after granulation and cannot be fully combined with the drug substance, resulting in uneven distribution and decreased disintegration performance. Although mannitol as a hydrophilic filler can assist in disintegration, the microcrystalline cellulose added after dry granulation cannot form an effective disintegration network.

[0083] The hardness of this comparative example fluctuates greatly, ranging from 6 to 8 kg (lower than 8.07 kg of Example 2).

[0084] The reason is that the compressibility of mannitol particles is poor, and microcrystalline cellulose (with good compressibility) is not used in the premixing stage, resulting in insufficient particle binding force. The microcrystalline cellulose added later is difficult to compensate for the loose structure of the particles, and the overall hardness of the tablets is low and unstable.

[0085] The friability of the comparative example is unqualified (loss on ignition > 1%).

[0086] The reason is that the particle structure is loose (caused by mannitol premixing), the internal binding force of the tablet is insufficient, and it is easy to break or wear during testing.

[0087] The distribution of lubricants (magnesium stearate) and glidants (silicon dioxide) may be affected by process steps, further exacerbating the friability problem.

[0088] Quality detection example

[0089] According to the 2020 edition of "Chinese Pharmacopoeia"

General 0921 Disintegration Time Limit Test Method

[0090]

[0091] Note: Regarding friability, the 2020 edition of "Chinese Pharmacopoeia" 0923 test method tablets with a weight of 0.65g or less take several tablets, so that their total weight is about 6.5g; tablets with a weight greater than 0.65g take 10 tablets. Use a hair dryer to blow off the powder that falls off the tablets, weigh accurately, place in a cylinder, rotate 100 times. Take out, remove the powder in the same way, weigh accurately, the loss on ignition should not exceed 1%, and there should be no broken, cracked and crushed tablets. This test is usually only done once. If the loss on ignition exceeds 1%, it should be retested twice, the average loss on ignition of 3 times should not exceed 1%, and there should be no broken, cracked and crushed tablets.

[0092] The essence listed in the above embodiments 1-6 can effectively mask the smell of rotten eggs, have good taste (endothermic when mannitol is dissolved, and cool taste), and effectively overcome the grit feeling of oral disintegration tablets. Comparative Example 1 does not add a flavoring agent and an alcohol-sugar filler, has a poor rotten egg smell and taste, and is difficult to swallow; Comparative Example 2 has a lubricant and a flow agent in a proportion lower than 1%, has a risk of sticking and cover separation during tabletting, has poor flowability, and cannot realize mechanized production; Comparative Example 3 has a binder in an amount lower than 5%, and even if the tabletting machine is adjusted to the maximum capacity, the compressible hardness is still lower than 6 kg, and the friability is poor; Embodiments 3-5 have slower disintegration than Embodiment 2, and the average hardness is somewhat at the lower limit, and if the hardness is increased, the disintegration speed is lower, and there is a certain risk in scale-up production. Embodiment 1 has disintegration and friability equivalent to Embodiment 2, the hardness of Embodiment 2 is easier to reach the target median value, and has the most optimal potential.

[0093] Therefore, in summary, Embodiment 2 is the most optimal embodiment.

[0094] The above only describes the preferred embodiments of the present application and is not intended to limit the present application. Any modification, equivalent replacement, and improvement made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A method for preparing an acetylcysteine orally disintegrating tablet, characterized in that, the acetylcysteine orally disintegrating tablet is prepared from raw materials in the following mass percentages: acetylcysteine 50-75%, filler A 9-22.3%, sweetener 1-2%, flavoring agent 1-2.5%, filler B 8.5-27.3%, disintegrant 2-4.5%, binder 5-16%, glidant 1-2%, lubricant 1-1.3%, and the total is 100%; wherein the filler A is a sugar alcohol; the filler B is microcrystalline cellulose; the flavoring agent is at least one selected from menthol flavor, orange flavor, and strawberry flavor; and the sweetener is at least one selected from aspartame and sodium saccharin. the method comprises the following steps: (1) premixing: uniformly mixing acetylcysteine and a part of filler B to obtain acetylcysteine premix powder, wherein the mass of the filler B added is 15-28% of the total mass of the filler B; (2) dry granulation: dry granulating the acetylcysteine premix powder to obtain granules; (3) total mixing: uniformly mixing filler A, the remaining filler B, disintegrant, binder, lubricant, flavoring agent, sweetener, and the granules obtained in step (2), and then adding glidant; (4) tabletting.

2. The process for preparing acetylcysteine orally disintegrating tablet according to claim 1, characterized in that, the filler A is at least one selected from mannitol, sorbitol, and erythritol.

3. The process for preparing the acetylcysteine orally disintegrating tablet according to claim 1, characterized by, the disintegrant is at least one selected from cross-linked polyvinylpyrrolidone and cross-linked sodium carboxymethyl cellulose. 4.The method for preparing an acetylcysteine orally disintegrating tablet according to claim 1, characterized in that, in step (2), the granules after granulation are sieved with a 100-mesh sieve, and when the fine powder under the sieve is more than 50%, the fine powder is subjected to secondary granulation.

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