Etoricoxib orally disintegrating tablet and preparation method thereof

Abstract

The present invention belongs to the field of pharmaceutical preparation technology, specifically relating to an orally disintegrating tablet of etoricoxib and its preparation method. The orally disintegrating tablet of etoricoxib comprises etoricoxib, a filler, a disintegration stabilizer, a wetting agent, and a lubricant; the disintegration stabilizer is polacrilin potassium, styraxol, and glycine. The preparation process utilizes a wet granulation method. This invention addresses the difficult balance between disintegration rate, stability, and mouthfeel faced by conventional orally disintegrating tablets, demonstrating clinical application potential.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and particularly relates to an etoricoxib orally disintegrating tablet and a preparation method thereof. Background Art

[0002] Etoricoxib is a non-steroidal anti-inflammatory drug developed by Merck. It is a selective cyclooxygenase-2 (COX-2) inhibitor and is clinically used to treat osteoarthritis, rheumatoid arthritis, acute gouty arthritis and other diseases. It exerts anti-inflammatory and analgesic effects by inhibiting COX-2 and reducing prostaglandin synthesis.

[0003] Currently, common oral tablets and capsules of etoricoxib present significant inconvenience for patients with dysphagia, such as the elderly, children, and some patients with oral or throat diseases. While orally disintegrating tablets, a novel dosage form that rapidly disintegrates in the mouth and eliminates the need for water, hold great market potential, existing orally disintegrating tablets of etoricoxib struggle to achieve an ideal balance between disintegration rate, stability, and mouthfeel, limiting their clinical application and market expansion. Therefore, developing a superior orally disintegrating tablet of etoricoxib is of great practical significance.

[0004] Chinese Patent Publication No. CN108057025A discloses an orally disintegrating tablet of etoricoxib and its preparation method. The orally disintegrating tablet is a pharmaceutical composition comprising etoricoxib, a filler, a disintegrant, a wetting agent and binder, a flavoring agent, and a lubricant, produced using a wet granulation tableting method. However, no quality evaluations were made regarding disintegration, mouthfeel, and formulation stability.

[0005] It is well known to those skilled in the art that the main technical difficulties in developing orally disintegrating etoricoxib tablets lie in the selection of drugs and excipients, as well as the design of the preparation process. Therefore, developing a technology for preparing orally disintegrating etoricoxib tablets that balances disintegration rate, palate comfort, and formulation stability has become a core issue that needs to be addressed in this field. Summary of the Invention

[0006] To overcome the shortcomings of the prior art, the present invention provides an etoricoxib orally disintegrating tablet and a preparation method thereof, which exhibits significant technical advantages in terms of disintegration performance, stability, mouthfeel, etc. by optimizing the formulation composition and preparation process.

[0007] Specifically, the technical solutions of the present invention are as follows:

[0008] The orally disintegrating tablets of the present invention comprise: 30-120 parts by weight of etoricoxib, 50-200 parts by weight of a filler, 20-50 parts by weight of a disintegration stabilizer, 5-20 parts by weight of a wetting agent, and 1-4 parts by weight of a lubricant; the disintegration stabilizer is 10-30 parts by weight of polacrilin potassium, 5-10 parts by weight of salamanin, and 5-10 parts by weight of glycine.

[0009] The filler is selected from at least one of mannitol, lactose, microcrystalline cellulose, starch, dextrin, and sucrose. Furthermore, the filler is mannitol, lactose, and microcrystalline cellulose.

[0010] The wetting agent is ethanol and / or water. Furthermore, the wetting agent is a mixture of ethanol and water in a ratio of 7:3.

[0011] The lubricant is selected from at least one of magnesium stearate, micro-powder silica gel and talc, preferably magnesium stearate or micro-powder silica gel.

[0012] The particle size D90 of the etoricoxib raw material is less than 40 μm.

[0013] The present invention also provides a method for preparing the above-mentioned etoricoxib orally disintegrating tablets, comprising the following steps:

[0014] (1) Preparation of soft material: Add etoricoxib, filler, oxaliplatin, glycine, and 1 / 3 to 1 / 2 weight portion of polacrilin potassium into a granulator, stir and mix, and add a wetting agent to prepare a soft material;

[0015] (2) Granulation and drying: The soft material is squeezed into granules by a granulator; fluidized bed drying is performed to a moisture content of ≤2.0%;

[0016] (3) Granulation and total mixing: Granulate and add the remaining polacrilin potassium and lubricant into a three-dimensional mixer and mix;

[0017] (5) Tablet pressing.

[0018] Compared with the prior art, the technical effects of the present invention are:

[0019] (1) The present invention is the first to use a combination of polacrilin potassium, succinylcholine and glycine as a disintegration stabilizer, thereby achieving the effects of rapid disintegration, improved stability and optimized taste.

[0020] (2) The present invention solves the technical problem of the traditional orally disintegrating tablets that is difficult to achieve the desired balance of “disintegration, stability, and taste” by systematically optimizing the order of adding excipients and process parameters.

[0021] (3) The present invention provides an industrially scalable preparation scheme, laying a foundation for the clinical application and market promotion of orally disintegrating tablets of etoricoxib. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 : Disintegration time of etoricoxib orodisintegrating tablets in each group.

[0023] Figure 2 : Stability of etoricoxib orally disintegrating tablets in each group.

[0024] Figure 3 : Taste rating of etoricoxib orodisintegrating tablets. DETAILED DESCRIPTION

[0025] In order to make the purpose and technical solution of the present invention more clear, the present invention is further described below in conjunction with the embodiments, but the scope of protection of the present invention is not limited to these embodiments, and the embodiments are only used to illustrate the present invention. It should be understood by those skilled in the art that any changes or equivalent substitutions that do not deviate from the concept of the present invention are included in the scope of protection of the present invention.

[0026] Example 1 Etoricoxib orally disintegrating tablets

[0027] formula:

[0028]

[0029] Preparation method:

[0030] (1) Preparation of soft material: The raw materials and auxiliary materials are sieved through a 100-mesh sieve and set aside. Add the prescribed amount of etoricoxib, filler, oxalool, glycine, and 1 / 3 of the prescribed amount of polacrilin potassium into a granulator and stir at 15 rpm for 10 minutes until uniform. Slowly add the wetting agent to the mixed powder and granulate with a cutting knife at 1000 rpm for 4 minutes to prepare the soft material. The soft material is formed into a ball that can be kneaded by hand and falls apart when lightly pressed.

[0031] (2) Granulation: The soft material is squeezed into granules of 1.0~1.5mm through a granulator.

[0032] (3) Fluidized bed drying: The inlet air temperature is set at 55°C, the particle bed temperature is controlled at 45°C, and the drying time is 30 minutes, until the moisture content is ≤2.0%.

[0033] (4) Granulation and total mixing: The dried granules were sieved through a 20-mesh screen to break up the agglomerated granules. The granules were added to a three-dimensional mixer with the remaining polacrilin potassium and lubricant and mixed at 25 rpm for 15 minutes.

[0034] (5) Tablet pressing: Shallow concave punch, control the pressure to 1~5kN, and control the tablet hardness to 3.0kgf.

[0035] Example 2 Etoricoxib orally disintegrating tablets

[0036] formula:

[0037]

[0038] Preparation method:

[0039] (1) Preparation of soft material: The raw materials and auxiliary materials are sieved through a 100-mesh sieve and set aside. Add the prescribed amount of etoricoxib, filler, oxaliplatin, glycine, and 1 / 3 of the prescribed amount of polacrilin potassium into a granulator and stir at 100 rpm for 5 minutes until uniform. Slowly add the wetting agent to the mixed powder and granulate with a cutting knife at 800 rpm for 2 minutes to prepare the soft material. The soft material is formed into a ball that can be kneaded by hand and falls apart when lightly pressed.

[0040] (2) Granulation: The soft material is squeezed into granules of 1.0~1.5mm through a granulator.

[0041] (3) Fluidized bed drying: The inlet air temperature is set at 50°C, the particle bed temperature is controlled at 40°C, and the drying time is 20 minutes, until the moisture content is ≤2.0%.

[0042] (4) Granulation and total mixing: The dried granules were sieved through a 20-mesh screen to break up the agglomerated particles. The granules were added to a three-dimensional mixer with the remaining polacrilin potassium and lubricant and mixed at 20 rpm for 10 minutes.

[0043] (5) Tablet pressing: Shallow concave punch, control the pressure to 1~5kN, and control the tablet hardness to 2.5kgf.

[0044] Example 3 Etoricoxib orally disintegrating tablets

[0045] formula:

[0046]

[0047] Preparation method:

[0048] (1) Preparation of soft material: The raw materials and auxiliary materials are sieved through a 100-mesh sieve and set aside. Add the prescribed amount of etoricoxib, filler, oxalool, glycine, and 1 / 3 of the prescribed amount of polacrilin potassium into a granulator and stir at 200 rpm for 10 minutes until uniform. Slowly add the wetting agent to the mixed powder and granulate with a cutting knife at 1200 rpm for 5 minutes to prepare the soft material. The soft material is formed into a ball that can be kneaded by hand and falls apart when lightly pressed.

[0049] (2) Granulation: The soft material is squeezed into granules of 1.0~1.5mm through a granulator.

[0050] (3) Fluidized bed drying: The inlet air temperature is set at 60°C, the particle bed temperature is controlled at 50°C, and the particles are dried to a moisture content of ≤2.0%.

[0051] (4) Granulation and total mixing: The dried granules were sieved through a 20-mesh screen to break up the agglomerated granules, and added to a three-dimensional mixer with the remaining polacrilin potassium and lubricant, and mixed at 30 rpm for 15 minutes.

[0052] (5) Tablet pressing: Shallow concave punch, control the pressure to 1~5kN, and control the tablet hardness to 3.5kgf.

[0053] Particle size of etoricoxib

[0054] The particle size of etoricoxib raw material was measured using Malvern MS3000 particle size analyzer.

[0055] Table 1 Particle size distribution

[0056]

[0057] The data in Table 1 show that the particle size of the etoricoxib API used in the present invention is small and relatively concentrated, with 90% of the particles having a particle size below 40 μm, which facilitates rapid disintegration and release of the drug in the orally disintegrating tablets, and has positive significance for improving the efficacy of the orally disintegrating tablets and the patient's medication experience.

[0058] Verification of the effect of the disintegration stabilizer of the present invention

[0059] The blank control method and single factor variable method were used to verify the effects of disintegration stabilizers (polacrinalin potassium, chloranol, and glycine) and the order of addition on the disintegration effect, accelerated test stability, and taste of etoricoxib orally disintegrating tablets.

[0060] Experimental plan

[0061] Table 2 Experimental design of excipient group

[0062]

[0063] Table 3 Method experimental design

[0064]

[0065] Disintegration effect test

[0066] Instrument: Disintegration time tester (temperature 37℃±0.5℃).

[0067] Operation: Take 6 tablets and place them in the disintegration tester basket respectively. Start the instrument and record the time for the tablet to completely disintegrate.

[0068] Table 4 Disintegration time of etoricoxib orally disintegrating tablets in each group

[0069]

[0070] The disintegration time data for the blank group, Example 1, and various excipient groups in Table 4 clearly demonstrate that the three disintegration stabilizers (polacrinalin potassium, styraclostrobin, and glycine) are essential; the absence or substitution of any one component significantly reduces disintegration performance. The timing of disintegration stabilizer addition is a key process parameter influencing the disintegration efficiency of orally disintegrating tablets. By rationally separating the addition of polacrilin potassium and other excipients, tablet disintegration rates can be significantly improved, providing a scientific basis for optimizing orally disintegrating tablet formulations.

[0071] Accelerated stability testing

[0072] Conditions: Constant temperature and humidity chamber (40℃±2℃, RH75%±5%), placed for 6 months.

[0073] Testing time points: 0 month (initial), 1 month, 3 months, and 6 months.

[0074] Detection method:

[0075] Accurately weigh an appropriate amount of sample, dissolve and dilute with mobile phase, and determine the etoricoxib content by HPLC (chromatographic column: C18, mobile phase: methanol-water-glacial acetic acid = 70:30:0.1, detection wavelength: 254 nm).

[0076] Evaluation indicators:

[0077] Content change rate = (6th month - initial content) / initial content × 100%.

[0078] Table 5 Accelerated test stability

[0079]

[0080] As shown in Table 5, the combination of polacrilin potassium, styraxol, and glycine significantly improves the storage stability of etoricoxib orally disintegrating tablets. The absence of any of these three ingredients or an imbalance in their ratios can lead to decreased stability. The stepwise addition of disintegration stabilizers can reduce drug degradation, further ensuring stability. The formulation and process of this invention not only achieves rapid disintegration but also, through the scientific proportioning of excipients and process optimization, ensures drug quality control under complex storage conditions, meeting the clinical needs of long-term medication.

[0081] Taste evaluation experiment

[0082] Volunteer requirements: 10 volunteers, half male and half female, without oral diseases, and refrain from eating or drinking for 1 hour before the experiment.

[0083] Evaluation process:

[0084] The volunteers took the samples orally without drinking water and recorded the disintegration time (subjective feeling).

[0085] Score on the following scales (1 to 5, 5 being the best):

[0086] Disintegration rate: 5 points = rapid disintegration, 1 point = slow disintegration.

[0087] Bitterness masking: 5 points = no bitterness, 3 points = slight bitterness, 1 point = strong bitterness.

[0088] Grittiness: 5 = no gritty feeling, 3 = slightly gritty feeling, 1 = very gritty feeling.

[0089] Data processing: The mean and standard deviation of the scores of each group of volunteers were calculated. SPSS22.0 software was used to perform statistical analysis on the obtained data. The quantitative data were analyzed using ( The data were compared between multiple groups using one-way analysis of variance, and between two groups using independent sample T-test. P < 0.05 was considered statistically significant.

[0090] Table 6 Taste score

[0091]

[0092] Note: The control group does not contain the main drug, and the rest is the same as Example 1.

[0093] Compared with the commercial preparation group, *P<0.05.

[0094] This invention successfully addresses the bitterness challenge of etoricoxib orally disintegrating tablets through the design of a disintegration stabilizer and optimized wet granulation process, while ensuring rapid disintegration and a smooth mouthfeel. Experimental data demonstrates that the taste score significantly outperforms commercially available formulations and is similar to that of a blank excipient formulation. This demonstrates that this formulation and process offer significant technical advantages in balancing efficacy and patient experience, demonstrating its potential for clinical translation and market expansion.

Claims

1. An orally disintegrating tablet of etoricoxib, characterized in that: The formula of the orally disintegrating etoricoxib tablets is as follows: 30-120 parts by weight of etoricoxib, 50-200 parts by weight of a filler, 20-50 parts by weight of a disintegration stabilizer, 5-20 parts by weight of a wetting agent, and 1-4 parts by weight of a lubricant; the disintegration stabilizer is a combination of 10-30 parts by weight of polacrilin potassium, 5-10 parts by weight of salamanin, and 5-10 parts by weight of glycine; The preparation method of the etoricoxib orally disintegrating tablets comprises the following steps: (1) Preparation of soft material: Add etoricoxib, filler, oxaliplatin, glycine, and 1 / 3 to 1 / 2 of the prescribed amount of polacrilin potassium into a granulator, stir and mix, and add a wetting agent to prepare a soft material; (2) Granulation and drying: The soft material is squeezed into granules by a granulator; fluidized bed drying is performed to a moisture content of ≤2.0%; (3) Granulation and total mixing: Granulate and add the remaining polacrilin potassium and lubricant into a three-dimensional mixer and mix; (4) Tablet pressing.

2. The orally disintegrating tablet of etoricoxib according to claim 1, wherein The fillers are mannitol, lactose and microcrystalline cellulose.

3. The orally disintegrating tablet of etoricoxib according to claim 1, wherein The wetting agent is ethanol and / or water.

4. The orally disintegrating tablet of etoricoxib according to claim 1, wherein The wetting agent is a mixture of ethanol and water in a ratio of 7:

3.

5. The orally disintegrating tablet of etoricoxib according to claim 1, wherein The lubricant is selected from at least one of magnesium stearate, micropowder silica gel and talc.

6. The orally disintegrating tablet of etoricoxib according to claim 1, wherein The lubricant is magnesium stearate or micro powder silica gel.

7. The orally disintegrating tablet of etoricoxib according to claim 1, wherein The particle size D90 of etoricoxib is less than 40 μm.

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