A composition of ondansetron hydrochloride and a method for preparing the same
By using anhydrous lactose and microcrystalline cellulose with pregelatinized starch as fillers, combined with direct powder pressing and multiple co-sieving premixing, the problems of mixing uniformity and dissolution of ondansetron hydrochloride tablets were solved, achieving a stable preparation process and low-energy production, suitable for commercial applications.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- FUAN PHARM GRP NINGBO TIANHENG PHARM CO LTD
- Filing Date
- 2026-04-27
- Publication Date
- 2026-06-02
AI Technical Summary
The existing preparation process of ondansetron hydrochloride tablets has problems such as poor mixing uniformity, incomplete disintegration and dissolution, severe equipment wear and high production costs. In particular, it is difficult to achieve stability and compressibility under low drug loading conditions.
Anhydrous lactose and microcrystalline cellulose with pregelatinized starch were used as fillers. The mixture was premixed by direct powder pressing and multiple co-sieving, combined with appropriate lubricants and coating materials. The proportions of each component and the preparation process parameters were controlled to ensure uniform mixing and solubility.
It achieves good mixing uniformity and stable quality of ondansetron hydrochloride tablets, with dissolution curves similar to the reference formulation. The tableting process is non-sticky and has low energy consumption, making it suitable for large-scale commercial production.
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Figure CN122124041A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of pharmaceutical formulation technology, and in particular to a stable ondansetron hydrochloride composition, ondansetron hydrochloride tablets, and a method for preparing the same. Background Technology
[0002] Ondansetron hydrochloride, chemically named 2,3-dihydro-9-methyl-3-[(2-methylimidazol-1-yl)yl]-4(1H)-carbazolone hydrochloride, is a selective 5-hydroxytryptamine 3 (5-HT3) receptor antagonist. It exerts its antiemetic effect by blocking 5-HT3 receptors. At antiemetic doses, it can also enhance gastric emptying and help reduce nausea. It is mainly used to prevent and treat nausea and vomiting caused by chemotherapy, radiotherapy or surgery.
[0003] Ondansetron hydrochloride tablets were first developed by GlaxoSmithKline (GSK) in 1990. Ondansetron hydrochloride tablets contain ondansetron hydrochloride as ondansetron (C... 18 H 19 The N3O content is calculated to be 8mg and 4mg, with a low proportion of active pharmaceutical ingredient, resulting in a low drug loading tablet. Mixing uniformity is a problem that needs to be solved in the preparation of ondansetron hydrochloride tablets.
[0004] Patent application number US19860877805A discloses the powder direct compression process and wet granulation process for ondansetron hydrochloride tablets. In the powder direct compression process, the ondansetron hydrochloride raw material is first passed through a 60-mesh sieve, mixed with dicalcium phosphate, croscarmellose sodium, and magnesium stearate, and then directly compressed into tablets. Dicalcium phosphate accounts for a high proportion in the formulation, reaching 74.3%-92.3%. Dicalcium phosphate has a high hardness, and excessive use may lead to the following results: (1) It affects the compressibility of the tablets, resulting in tablets that are too hard, affecting disintegration and dissolution, and the tablets'... (1) Increased brittleness and easy breakage; (2) Excessive use of dicalcium phosphate may lead to decreased material flowability, especially in direct compression, where uneven filling is likely to occur during compression, resulting in increased tablet weight differences; (3) Reduced porosity of dicalcium phosphate, excessive use may cause the active pharmaceutical ingredient to be encapsulated in a dense excipient matrix, making it difficult to contact the dissolution medium, thus leading to incomplete dissolution of the active pharmaceutical ingredient; (4) Excessive use of dicalcium phosphate may accelerate the wear of the compression equipment, increase costs, affect the smoothness of the production process, and be detrimental to large-scale commercial production. At the same time, the powder direct compression process is prone to sticking during compression because the raw materials and excipients have not been granulated and the powder is relatively fine. Among them, the wet granulation process first sieves the ondansetron hydrochloride active pharmaceutical ingredient, mixes it with lactose, starch, and pregelatinized starch, adds water as a binder for wet granulation, dries it, performs dry granulation, and then adds magnesium stearate as a lubricant and compresses it. Compared with the powder direct compression process, the wet granulation process is more complex and energy-intensive, which will lead to high costs for large-scale commercial production. Therefore, there is a need to develop an ondansetron hydrochloride tablet with a simple preparation process, good mixing uniformity, and stable quality. Summary of the Invention
[0005] Purpose of the invention: The technical problem to be solved by the present invention is to provide ondansetron hydrochloride tablets and their preparation method, in order to address the shortcomings of the prior art.
[0006] To solve the above-mentioned technical problems, the present invention discloses the following technical solution:
[0007] In a first aspect, the present invention discloses an ondansetron hydrochloride composition.
[0008] In some embodiments, the composition comprises the following components in parts by weight:
[0009] 8-12 parts of ondansetron hydrochloride
[0010] First filler 158-228 parts
[0011] 68-142 parts of the second filler
[0012] Lubricant 0.1-7 parts
[0013] 5-15 parts of coating powder
[0014] The first filler is anhydrous lactose, and the second filler is microcrystalline cellulose and pregelatinized starch. The content of microcrystalline cellulose in the second filler is 55-95% wt, preferably 60-90% wt, such as 59%, 62%, 67%, 72%, 76%, 80%, 85%, or 88%. In some embodiments, the content of microcrystalline cellulose in the composition is 14-35%, such as 14%, 16%, 18%, 20%, 22%, 24%, 26%, 28%, 30%, 32%, or 34%.
[0015] In some embodiments, the composition comprises the following components in parts by weight:
[0016] Ondansetron hydrochloride 9.98 parts
[0017] First filler 160-226 parts
[0018] 72-140 parts of the second filler
[0019] 0.3-5 parts lubricant
[0020] 5-15 parts of coating powder
[0021] In some embodiments, the composition comprises the following components in parts by weight:
[0022] Ondansetron hydrochloride 9.98 parts
[0023] First filler 162-224 parts
[0024] 76-138 parts of the second filler
[0025] Lubricant 0.5-3 parts
[0026] 8-12 parts of coating powder
[0027] In some embodiments, the first filler in the composition is in parts by weight of 158, 163, 164, 168, 173, 178, 183, 184, 188, 193, 194, 198, 203, 208, 213, 218, 223 or 228 parts.
[0028] In some embodiments, the lubricant is selected from magnesium stearate, calcium stearate, zinc stearate, sodium fumarate stearate, or any combination thereof.
[0029] In some embodiments, the particle size D of the ondansetron hydrochloride 90 The particle size D of the microcrystalline cellulose in the second filler is 30-150 μm. 50The particle size is 70-130μm; in the second filler, pregelatinized starch particles with a diameter of less than 150μm account for more than 90% of the total mass, and particles with a diameter of more than 425μm account for less than 0.5% of the total mass.
[0030] Secondly, this invention discloses an ondansetron hydrochloride tablet.
[0031] In some embodiments, the composition is prepared into ondansetron hydrochloride tablets by direct powder compression.
[0032] In some embodiments, a method for preparing ondansetron hydrochloride tablets from the composition includes the following steps:
[0033] (1) Ondansetron hydrochloride and part of the first filler were sieved together to obtain the first premix;
[0034] (2) The remaining first filler and the first premix are sieved together to obtain the second premix;
[0035] (3) The second filler and the second premix are sieved together to obtain the third premix;
[0036] (4) The third premix is mixed in a mixer;
[0037] (5) Add lubricant for total mixing, tableting, and coating.
[0038] In some embodiments, the particle size D of the ondansetron hydrochloride 90 The particle size D of the microcrystalline cellulose in the second filler is 30-150 μm. 50 The particle size is 70-130μm; in the second filler, pregelatinized starch particles with a diameter of less than 150μm account for more than 90% of the total mass, and particles with a diameter of more than 425μm account for less than 0.5% of the total mass.
[0039] In step (1), the portion of the first filler is 40%-60% of the total mass of the first filler, such as 50%. In a rotary granulator, ondansetron hydrochloride raw material and a portion of the first filler are sieved together; the rotation speed of the rotary granulator is 800-1200 rpm, such as 1000 rpm, and the particle size of the sieve in the rotary granulator is 0.6-1.4 mm, such as 1.0 mm.
[0040] In step (2), the remaining first filler and the first premix are sieved together in a rotary granulator; the rotation speed of the rotary granulator is 600-1000 rpm, such as 800 rpm, and the particle size of the screen in the rotary granulator is 0.6-1.4 mm, such as 1.0 mm.
[0041] In step (3), the second filler and the second premix are sieved together in a rotary granulator; the rotation speed of the rotary granulator is 600-1000 rpm, such as 800 rpm, and the particle size of the screen in the rotary granulator is 0.6-1.4 mm, such as 1.0 mm.
[0042] In step (4), the obtained premix is mixed in a mixer; the mixing speed is 10-20 rpm, such as 15 rpm, and the time is 2-7 min, such as 5 min; the loading coefficient of the mixer is 45%-70%.
[0043] In step (5), lubricant is added to the mixer for mixing; the mixing speed is 10-20 rpm, such as 11 rpm, and the time is 1-5 min, such as 2 min; the loading coefficient of the mixer is 45%-70%.
[0044] In step (5), during the tableting process, the ambient humidity is controlled below 65%, such as 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, etc.; during the tableting process, the tablet weight difference is controlled within ±5%, and the hardness is 9.0-11.0 kg.
[0045] In step (5), the coating powder is the film coating premix YS-1-12606-CN from Calcare Company.
[0046] The ondansetron hydrochloride tablets of this invention have the following release characteristics: the dissolution medium is a pH 4.5 phosphate medium; after sampling at 10 minutes, sodium hydroxide solution is added to adjust the pH to 6.0; the dissolution conditions are basket dissolution at 20 rpm; the cumulative dissolution rate at 5 minutes is 6.9%-19.5%, at 10 minutes it is 39.3%-60.2%, at 15 minutes it is 72.1%-86.4%, and at 20 minutes it is 86.2%-95.5%; in some embodiments, the cumulative dissolution rate at 5 minutes is 8%-12%, at 10 minutes it is 45.9%-49.9%, and at 15 minutes it is 8%-12%. The dissolution rate is 78%-82%, and the cumulative dissolution rate at 20 minutes is 93.1%-96.1%; in some embodiments, the cumulative dissolution rate at 5 minutes is 9%-11%, at 10 minutes it is 46.9%-48.9%, at 15 minutes it is 79%-81%, and at 20 minutes it is 94.1%-96.1%; in some embodiments, the cumulative dissolution rate at 5 minutes is 6.9%-8.9%, at 10 minutes it is 48.6%-50.6%, at 15 minutes it is 81.3%-83.3%, and at 20 minutes it is 90.3%-92.3%.
[0047] The ondansetron hydrochloride tablets of this invention, after being accelerated at 40℃±2℃ and 75%RH±5% for 6 months, were dissolved in a phosphate medium at pH 4.5. After sampling every 10 minutes, sodium hydroxide solution was added to adjust the pH to 6.0. The dissolution conditions used were the basket method at 20 rpm, with a cumulative dissolution rate of 8.6%-19.2% over 5 minutes, such as 9.6%, 10.6%, 11.6%, 12.6%, 13.3%, 13.5%, 13.6%, and 14.6%. The concentrations were 14.8%, 15.6%, 16.6%, 17.1%, 17.6%, 18.2%, and 18.6%; the cumulative dissolution rate over 10 minutes was 39.2%-59.5%, such as 40.2%, 41.2%, 42.2%, 43.2%, 44.2%, 45.2%, 46.2%, 47.2%, 48.2%, 48.3%, 49.2%, 49.6%, 50.2%, 51.2%, 51.7%, and 52.2%. 53.2%, 54.2%, 55.2%, 56.2%, 56.4%, 57.2%, 58.2%, 58.5%, 59.2%; cumulative dissolution rate at 15 minutes was 73.5%-86.9%, such as 73.5%, 74.5%, 75.5%, 76.5%, 77.5%, 78.5%, 79.5%, 80.5%, 81.5%, 82.2%, 82.5%, 83.1%, 83.5%, 84.1%, 84.5%, 85.5%, 85.7%, 85.9%, 86.5%; cumulative dissolution rate at 20 minutes was 86.2%. -98.2%, such as 86.2%, 87.2%, 88.2%, 89.2%, 90.2%, 91.2%, 91.4%, 92.1%, 92.2%, 92.9%, 93.2%, 94.2%, 95.2%, 95.9%, 96.2%, 97.2%, 98.2%; in some embodiments, the cumulative dissolution rate at 5 min is 8.6%-10.6%, at 10 min it is 50.7%-52.7%, at 15 min it is 83.1%-85.1%, and at 20 min it is 91.1%-93.1%.
[0048] Thirdly, the present invention discloses a method for preparing ondansetron hydrochloride tablets as described in the second aspect above.
[0049] In some embodiments, the preparation method of the ondansetron hydrochloride tablets includes the following steps:
[0050] (1) Ondansetron hydrochloride and part of the first filler were sieved together to obtain the first premix;
[0051] (2) The remaining first filler and the first premix are sieved together to obtain the second premix;
[0052] (3) The second filler and the second premix are sieved together to obtain the third premix;
[0053] (4) The third premix is mixed in a mixer;
[0054] (5) Add lubricant for total mixing, tableting, and coating.
[0055] In some embodiments, the particle size D of the ondansetron hydrochloride 90 The particle size of ondansetron hydrochloride is 30-150 μm, which can be obtained by pulverization; the particle size D of the microcrystalline cellulose in the second filler is... 50 The particle size is 70-130μm; in the second filler, the pregelatinized starch particles with a diameter of less than 150μm account for more than 90% of its total mass, and the particles with a diameter of more than 425μm account for less than 0.5% of its total mass. In step (1), the portion of the first filler accounts for 40%-60% of the total mass of the first filler, such as 50%. In a rotary granulator, ondansetron hydrochloride raw material and a portion of the first filler are sieved together; the rotation speed of the granulator is 800-1200rpm, such as 1000rpm, and the particle size of the sieve in the granulator is 0.6-1.4mm, such as 1.0mm.
[0056] In step (2), the remaining first filler and the first premix are sieved together in a rotary granulator; the rotation speed of the granulator is 600-1000 rpm, such as 800 rpm, and the particle size of the sieve in the granulator is 0.6-1.4 mm, such as 1.0 mm.
[0057] In step (3), the second filler and the second premix are sieved together in a rotary granulator; the rotation speed of the granulator is 600-1000 rpm, such as 800 rpm, and the particle size of the sieve in the granulator is 0.6-1.4 mm, such as 1.0 mm.
[0058] In step (4), the obtained premix is mixed in a mixer; the mixing speed is 10-20 rpm, such as 15 rpm, and the time is 2-7 min, such as 5 min; the loading coefficient of the mixer is 45%-70%.
[0059] In step (5), lubricant is added to the mixer for mixing; the mixing speed is 10-20 rpm, such as 11 rpm, and the time is 1-5 min, such as 2 min; the loading coefficient of the mixer is 45%-70%.
[0060] In step (5), during the tableting process, the ambient humidity is controlled below 65%, such as 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, etc.; during the tableting process, the tablet weight difference is controlled within ±5%, and the hardness is 9.0-11.0 kg.
[0061] In step (5), the coating powder is the film coating premix YS-1-12606-CN from Calcare Company.
[0062] In the composition of the present invention, by using anhydrous lactose, microcrystalline cellulose and pregelatinized starch as fillers, and by controlling the proportions of each component and by using the preparation process of the present invention, the dissolution can be effectively controlled to be similar to that of the reference formulation, and the stability of the product can also be improved.
[0063] Beneficial effects:
[0064] The stable ondansetron hydrochloride tablets provided by this invention are composed of the active ingredient ondansetron hydrochloride, a first filler, a second filler, a lubricant, and a coating material. This invention involves pulverizing the active ingredient ondansetron hydrochloride and preparing the tablets using a direct powder compression process. Multiple co-sieving premixing methods are employed to ensure uniform mixing. Anhydrous lactose is used as a filler to reduce product moisture and ensure stability. Microcrystalline cellulose and pregelatinized starch are used as fillers to ensure good flowability and compressibility of the total powder mixture. This results in ondansetron hydrochloride tablets with a dissolution profile similar to the reference formulation and stable quality. Compared with existing processes, this invention has the advantages of simple and rapid preparation, non-stick tableting during compression, low energy consumption, low impurities, excellent stability, and good quality. Attached Figure Description
[0065] The present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments, and the advantages of the present invention in the above and / or other aspects will become clearer.
[0066] Figure 1 The dissolution curves of the formulations obtained in Examples 1-3, the reference formulation, and Comparative Examples 2-3 and S1-S3 on day 0 in phosphate medium at pH 4.5-6.0 are shown.
[0067] Figure 2 Examples 1-3, reference formulations, and comparative examples 2-3 are shown. The dissolution curves of the formulations obtained from comparative examples S1-S3 in phosphate medium at pH 4.5-6.0 in June are also shown. Detailed Implementation
[0068] The present invention can be better understood from the following embodiments. However, those skilled in the art will readily understand that the descriptions in the embodiments are for illustrative purposes only and should not, and will not, limit the invention as detailed in the claims.
[0069] Unless otherwise specified, the experimental methods described in the following examples are conventional methods; unless otherwise specified, the reagents and materials are commercially available.
[0070] The anhydrous lactose mentioned in the following examples is manufactured by DFE Pharma (model: SuperTab 24AN); the pregelatinized starch is manufactured by Carvacrol (model: 2001-NEC), with a moisture content of 7%~11%. According to the Chinese Pharmacopoeia General Chapter 0982, Method II, at least 90% of the sample amount can pass through a sieve with an inner diameter of 150 μm, and the amount of sample that cannot pass through a sieve with an inner diameter of 425 μm is no more than 0.5%; the DFE Pharmarol is a microcrystalline cellulose with a model of PH 112. 50 The microcrystalline cellulose has a particle size of 100 μm and a moisture content of ≤1.5%; it is a pH 200 microcrystalline cellulose. 50 The particle size is 180μm, and the moisture content is 2-5%; the magnesium stearate manufacturer is Anhui Shanhe (model: SH-YM-M), D 50 5-30μm; Sodium stearate fumarate, D 90 ≤55.0μm; the coating powder is the film coating premix YS-1-12606-CN from Calcon, and the formulation consists of hydroxypropyl methylcellulose, triacetin, titanium dioxide and iron oxide yellow.
[0071] Unless otherwise specified, all raw and auxiliary materials mentioned in this invention are used directly without drying.
[0072] The solid content mentioned in this invention is a mass percentage.
[0073] In this invention, the particle size of the active pharmaceutical ingredient, filler, and lubricant are all tested according to the particle size and particle size distribution determination method (General Rule 0982, Method 3, Dry Method) in Part IV of the Chinese Pharmacopoeia 2020 Edition.
[0074] Example 1
[0075] The preparation method of ondansetron hydrochloride tablets, when producing 10,000 tablets, includes the following steps:
[0076] (1) Weighing and pulverizing: Weigh each raw material and excipient according to the weight ratio, including 9.98 parts of ondansetron hydrochloride, 184 parts of anhydrous lactose, 86 parts of microcrystalline cellulose (pH 112), 32 parts of pregelatinized starch, 1.8 parts of magnesium stearate, and 10 parts of coating powder. The ondansetron hydrochloride raw material was mechanically pulverized, and the particle size D after pulverization was... 90 The size is 30-150μm.
[0077] (2) Premix 1: The raw material of ondansetron hydrochloride was pulverized and 50% anhydrous lactose was sieved together in a rotary granulator at a speed of 1000 rpm and a particle size of 1.0 mm to obtain premix 1.
[0078] (3) Premix 2: The remaining anhydrous lactose and the premix 1 obtained in step (2) are sieved together in a rotary granulator at a speed of 800 rpm and a sieve particle size of 1.0 mm to obtain premix 2.
[0079] (4) Premix 3: Microcrystalline cellulose, pregelatinized starch and premix 2 obtained in step (3) are sieved together in a rotary granulator at a speed of 800 rpm and a sieve particle size of 1.0 mm to obtain premix 3.
[0080] (5) Mixing: The premix 3 obtained in step (4) is added to the hopper and mixed in a mixer. The mixing speed is 15 rpm and the time is 5 min. The loading coefficient of the mixer is 60%.
[0081] (6) Total mixing: The intermediate obtained in step (5) is mixed with magnesium stearate. The mixing speed is 11 rpm, the time is 2 min, and the loading coefficient is 60%.
[0082] (7) Tableting: The total powder obtained in step (6) is filled into the mold for tableting. The ambient humidity is 50%. The weight of the tablets to be pressed is calculated based on the total powder content. The weight difference is controlled within ±5%. The hardness is 9.0-11.0 kg.
[0083] (8) Coating: Prepare a 10%wt concentration of coating powder, Carrefour Company film coating premix YS-1-12606-CN, and place the uncoated film obtained in step (7) into a coating pan for coating. The coating weight gain is 3%-4%.
[0084] (9) Packaging: The packaging uses solid pharmaceutical composite hard sheets of polyvinyl chloride / polyvinylidene chloride and pharmaceutical aluminum foil.
[0085] Example 2
[0086] Same as Example 1, except that the amounts of each component are different, as detailed below:
[0087] Example 2-1: 9.98 parts ondansetron hydrochloride, 164 parts anhydrous lactose, 106 parts microcrystalline cellulose (pH 112), 32 parts pregelatinized starch, 1.8 parts magnesium stearate, and 10 parts coating powder.
[0088] Example 2-2: 9.98 parts ondansetron hydrochloride, 224 parts anhydrous lactose, 46 parts microcrystalline cellulose (pH 112), 32 parts pregelatinized starch, 1.8 parts magnesium stearate, and 10 parts coating powder.
[0089] Examples 2-3: 9.98 parts ondansetron hydrochloride, 194 parts anhydrous lactose, 97.3 parts microcrystalline cellulose (pH 112), 12 parts pregelatinized starch, 0.5 parts magnesium stearate, and 10 parts coating powder.
[0090] Examples 2-4: 9.98 parts ondansetron hydrochloride, 162.8 parts anhydrous lactose, 86 parts microcrystalline cellulose (pH 112), 52 parts pregelatinized starch, 3 parts magnesium stearate, and 10 parts coating powder.
[0091] Example 3
[0092] Same as Example 1, except that 1.8 parts of magnesium stearate in the components are replaced with 1.8 parts of sodium stearate fumarate.
[0093] Example 4
[0094] The preparation method of ondansetron hydrochloride tablets, when producing 10,000 tablets, includes the following steps:
[0095] (1) Weighing and pulverizing: Weigh each raw material and excipient according to the weight ratio, including 9.98 parts of ondansetron hydrochloride, 184 parts of anhydrous lactose, 86 parts of microcrystalline cellulose (pH 112), 32 parts of pregelatinized starch, 5 parts of calcium stearate, and 10 parts of coating powder. The ondansetron hydrochloride raw material was mechanically pulverized, and the particle size D after pulverization was... 90 The size is 30-150μm.
[0096] (2) Premix 1: The raw material of ondansetron hydrochloride was pulverized and 60% anhydrous lactose was sieved together in a rotary granulator at a speed of 1200 rpm and a particle size of 1.4 mm to obtain premix 1.
[0097] (3) Premix 2: The remaining anhydrous lactose and the premix 1 obtained in step (2) are sieved together in a rotary granulator at a speed of 600 rpm and a sieve particle size of 0.6 mm to obtain premix 2.
[0098] (4) Premix 3: Microcrystalline cellulose, pregelatinized starch and premix 2 obtained in step (3) are sieved together in a rotary granulator at a speed of 600 rpm and a sieve particle size of 0.6 mm to obtain premix 3.
[0099] (5) Mixing: The premix 3 obtained in step (4) is added to the hopper and mixed in a mixer. The mixing speed is 20 rpm and the time is 7 min. The loading coefficient of the mixer is 70%.
[0100] (6) Total mixing: The intermediate obtained in step (5) is mixed with calcium stearate. The mixing speed is 10 rpm, the time is 5 min, and the loading coefficient is 45%.
[0101] (7) Tableting: The total powder obtained in step (6) is filled into the mold for tableting. The ambient humidity is 50%. The weight of the tablets to be pressed is calculated based on the total powder content. The weight difference is controlled within ±5%. The hardness is 9.0-11.0 kg.
[0102] (8) Coating: Prepare a 10%wt concentration of coating powder Carrefour film coating premix 32F280000-CN, place the uncoated film obtained in step (7) in a coating pan for coating, and the coating weight gain is 3%-4%.
[0103] (9) Packaging: Oral solid medicine is packaged in high-density polyethylene bottles.
[0104] Comparative Example 1
[0105] Same as Example 1, except that 184 parts of anhydrous lactose in the components are replaced with 184 parts of lactose monohydrate.
[0106] Comparative Example 2
[0107] Same as Example 1, except that the 86 parts of microcrystalline cellulose PH112 in the components are replaced with the 86 parts of microcrystalline cellulose PH200.
[0108] Comparative Example 2-1 is the same as Comparative Example 2, except that the microcrystalline cellulose PH200 is dried to a moisture content of less than 1.5% before use.
[0109] Comparative Example 3
[0110] Same as Example 1, except that 86 parts of microcrystalline cellulose PH112 in the components are replaced with 86 parts of low-substituted hydroxypropyl cellulose.
[0111] Comparative Example 4
[0112] Same as Example 1, except that 32 parts of pregelatinized starch in the components are replaced with 32 parts of corn starch.
[0113] Comparative Example S1
[0114] Same as in Example 1, except that the premixing 1 to 3 and mixing in steps (2) to (5) are replaced with the following mixing steps:
[0115] Mixing: The pulverized ondansetron hydrochloride, anhydrous lactose, microcrystalline cellulose PH112 and pregelatinized starch are added to the hopper and mixed in a mixer at a speed of 15 rpm for 30 min; the loading coefficient of the mixer is 60%.
[0116] Comparative Example S2
[0117] Same as Example 1, except that the amounts of each component are different: 9.98 parts ondansetron hydrochloride, 114 parts anhydrous lactose, 82 parts microcrystalline cellulose (pH 112), 40 parts pregelatinized starch, 2 parts magnesium stearate, and 10 parts coating powder.
[0118] Comparative Example S3
[0119] Same as Example 1, except that the amounts of each component are different: 9.98 parts ondansetron hydrochloride, 145.7 parts anhydrous lactose, 104.9 parts microcrystalline cellulose (pH 112), 51.2 parts pregelatinized starch, 2 parts magnesium stearate, and 10 parts coating powder.
[0120] Experiment 1
[0121] The tablet appearance inspection and content uniformity determination were carried out on the products of Examples 1-3, Comparative Example 1, Comparative Example S2 and Comparative Example 4. The experimental results are shown in the table below. The experimental results show that there was no sticking phenomenon in Examples 1-3 (the sticking rate was 0%), and the obtained tablets were intact and smooth, with uniform color, no blemishes, no foreign matter, and RSD of 1.16%~1.41%. The content uniformity met the requirements, and the tablet appearance inspection met the requirements.
[0122] Comparative Examples 1, S2, and 4 experienced sticking during tablet compression (sticking rates of 29.5%, 4.1%, and 35.7%, respectively), resulting in incomplete and damaged tablets that failed the appearance inspection and also led to poor content uniformity.
[0123] Table 1. Uniformity of tablet appearance and content in each group (%)
[0124]
[0125] Experiment 2
[0126] Dissolution curves were determined for samples prepared in Examples 1, 2, 3, the reference preparation, Comparative Example 2, Comparative Example 2-1, Comparative Example 3, and Comparative Examples S1-S3. The dissolution medium was a phosphate medium with a pH of 4.5. After sampling at 10 minutes, sodium hydroxide solution was added to adjust the pH to 6.0. The dissolution conditions were determined using the basket method at 20 rpm, and the first method (basket method) of the Chinese Pharmacopoeia for the determination of dissolution and release was used at 37°C.
[0127] The experimental results are shown in Table 2 and Figure 1As shown, the dissolution curves of the samples prepared in Examples 1, 2, and 3 of this invention are similar to the reference formulation, with F2 values greater than 50. Changing the microcrystalline cellulose to microcrystalline cellulose PH200 (Comparative Example 2), and drying the microcrystalline cellulose PH200 to a moisture content below 1.5% (Comparative Example 2-1), all resulted in slower dissolution rates, unlike the reference, with F2 values less than 50. Replacing the microcrystalline cellulose with low-substituted hydroxypropyl cellulose (Comparative Example 3) resulted in faster dissolution rates, unlike the reference, with F2 values less than 50. Changing the mixing method (Comparative Example S1) resulted in faster dissolution rates, unlike the reference, with F2 values less than 50. Changing the ratio of anhydrous lactose, microcrystalline cellulose, and pregelatinized starch, and increasing the proportion of microcrystalline cellulose and pregelatinized starch as disintegrants, resulted in faster dissolution rates for the formulations obtained in Comparative Examples S2 and S3, unlike the reference, with F2 values less than 50. The dissolution curve results of the accelerated (40℃±2℃, 75%RH±5%) 6-month samples showed that the accelerated 6-month samples of the reference formulation and the examples dissolved slightly faster than the 0-day samples, but the two were still similar, with F2 values greater than 50.
[0128] Table 2. Dissolution rate (%) of formulations obtained in Examples 1-3, Reference formulation, Comparative Example 2, Comparative Example 2-1, Comparative Example 3, and S1-S3 on day 0.
[0129]
[0130] Table 3. Accelerated dissolution rate (%) of formulations obtained in Examples 1-3, Reference formulation, Comparative Example 2, Comparative Example 2-1, Comparative Example 3, and S1-S3 at 6 months.
[0131]
[0132] Experiment 3
[0133] The coated tablets prepared in Example 1, Comparative Example 1, Comparative Example S1, and Comparative Example S2 were simultaneously subjected to influencing factors (high temperature 60°C, high humidity RH 75%, light intensity 4500±500 lux / h, 90 Mw / cm²). 2This study investigates the placement (naked) of the sample and compares the content of related substances. The liquid chromatography method follows the Chinese Pharmacopoeia method: High Performance Liquid Chromatography (General Chapter 0512, Chinese Pharmacopoeia 2020). Test solution: Take an appropriate amount of the fine powder (approximately equivalent to 4 mg of ondansetron), place it in a 10 ml volumetric flask, add mobile phase to dissolve ondansetron hydrochloride and dilute to the mark, shake well, filter, and collect the filtrate. Reference solution: Accurately measure 1 ml of the test solution, place it in a 100 ml volumetric flask, dilute to the mark with mobile phase, and shake well. Chromatographic conditions: Use cyanosilane-bonded silica gel as the stationary phase; use 0.02 mol / L sodium dihydrogen phosphate solution (adjusted to pH 5.4 with sodium hydroxide test solution) - acetonitrile (50:50) as the mobile phase; the detection wavelength is 216 nm; the injection volume is 10 μl. System suitability requirements: The theoretical plate number, calculated based on the ondansetron peak, should not be less than 2000. Determination method: Accurately measure the test solution and the control solution, inject them separately into the liquid chromatograph, and record the chromatograms up to 4 times the retention time of the main component peak.
[0134] The results showed that the products of Example 1 and Comparative Examples 1, S1, S2, and S3 had similar properties at each time point. They were all film-coated tablets, which were white or off-white after the coating was removed. In Example 1, the trend of changes in related substances at 15 days and 30 days was significantly better than that of Comparative Examples 1, S1, and S2, and slightly better than that of Comparative Example S3. For details, please refer to Table 4 below. The impurity BF is recorded in the section on ondansetron hydrochloride in the British Pharmacopoeia.
[0135] Table 4
[0136]
[0137] The other examples and comparative examples were tested according to Experiment 3, and the results are shown in Table 5. The impurities in Example 2 with different component amounts, Example 3 with the lubricant replaced by sodium stearate fumarate, Example 4 with adjusted process parameters, Comparative Example 2 with a different microcrystalline cellulose type, Comparative Example 3 with microcrystalline cellulose replaced by low-substituted hydroxypropyl cellulose, and Comparative Example 4 with pregelatinized starch replaced by corn starch were not significantly affected.
[0138] Table 5 Impurity content (%) for each group
[0139]
[0140] Experiment 4
[0141] Bioequivalence test of the formulation obtained in Example 1 and the reference formulation
[0142] In the bioequivalence study between the formulation obtained in Example 1 and the reference formulation, the experimental design involved two formulations, two cycles, and alternating single-dose fasting administration. Data analysis was used to calculate confidence intervals. Intervals within the 80-125% range were considered equivalent to the formulation obtained in Example 1 and the reference formulation (see "Technical Guidelines for Human Bioequivalence Studies of Generic Chemical Drugs Using Pharmacokinetic Parameters as Endpoints"). The bioequivalence study results indicate that the formulation obtained in Example 1 is equivalent to the reference formulation.
[0143] Table 6. Bioequivalence Data: Statistical Analysis Results of Ondansetron Hydrochloride Tablets (N=8)
[0144]
[0145] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these modifications and improvements all fall within the scope of protection of the present invention. Therefore, the scope of protection of this patent should be determined by the appended claims.
Claims
1. A composition containing ondansetron hydrochloride, characterized in that, The components include the following parts by weight: 8-12 parts of ondansetron hydrochloride First filler 158-228 parts 68-142 parts of the second filler Lubricant 0.1-7 parts 5-15 parts of coating powder The first filler is anhydrous lactose, and the second filler is microcrystalline cellulose and pregelatinized starch.
2. The ondansetron hydrochloride composition according to claim 1, characterized in that, The weight proportions of each component are as follows: Ondansetron hydrochloride 9.98 parts First filler 160-226 parts 72-140 parts of the second filler 0.3-5 parts lubricant 5-15 parts of coating powder.
3. The ondansetron hydrochloride composition according to claim 1, characterized in that, The weight proportions of each component are as follows: Ondansetron hydrochloride 9.98 parts First filler 162-224 parts 76-138 parts of the second filler Lubricant 0.5-3 parts 8-12 parts of coating powder The content of microcrystalline cellulose in the second filler is 55-95%wt.
4. The ondansetron hydrochloride composition according to any one of claims 1-3, characterized in that, The lubricant is selected from magnesium stearate, calcium stearate, zinc stearate, sodium fumarate stearate, or any combination thereof.
5. The ondansetron hydrochloride composition according to any one of claims 1-3, characterized in that, The particle size D of the ondansetron hydrochloride 90 The particle size D of the microcrystalline cellulose in the second filler is 30-150 μm. 50 The particle size is 70-130μm; in the second filler, pregelatinized starch particles with a diameter of less than 150μm account for more than 90% of the total mass, and particles with a diameter of more than 425μm account for less than 0.5% of the total mass.
6. A method for preparing ondansetron hydrochloride tablets, characterized in that, The composition according to any one of claims 1-5 is prepared by direct powder pressing.
7. The preparation method according to claim 6, characterized in that, The preparation method includes the following preparation steps: (1) Ondansetron hydrochloride and part of the first filler were sieved together to obtain the first premix; (2) The remaining first filler and the first premix are sieved together to obtain the second premix; (3) The second filler and the second premix are sieved together to obtain the third premix; (4) The third premix is mixed in a mixer; (5) Add lubricant for total mixing, tableting, and coating; In step (1), the portion of the first filler is 40%-60% of the total mass of the first filler.
8. A type of ondansetron hydrochloride tablet, characterized in that, Made by the method described in claim 6 or 7.
9. The ondansetron hydrochloride tablets according to claim 8, characterized in that, The ondansetron hydrochloride tablets have the following release characteristics: The dissolution medium was a pH 4.5 phosphate medium. After sampling every 10 minutes, sodium hydroxide solution was added to adjust the pH to 6.
0. The dissolution conditions were basket dissolution at 20 rpm. The cumulative dissolution rate was 6.9%-19.5% at 5 min, 39.3%-60.2% at 10 min, 72.1%-86.4% at 15 min, and 86.2%-95.5% at 20 min.
10. The ondansetron hydrochloride tablets according to claim 8, characterized in that, After the ondansetron hydrochloride tablets were accelerated for 6 months at 40℃±2℃ and 75%RH±5%, the dissolution medium was a pH 4.5 phosphate medium. After sampling every 10 minutes, sodium hydroxide solution was added to adjust the pH to 6.
0. The dissolution conditions were basket dissolution at 20 rpm. The cumulative dissolution rate was 8.6%-19.2% at 5 min, 39.2%-59.5% at 10 min, 73.5%-86.9% at 15 min, and 86.2%-98.2% at 20 min.