Etoricoxib orally disintegrating tablet and preparation method thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to an etoricoxib orally disintegrating tablet and a preparation method thereof. The etoricoxib orally disintegrating tablet comprises etoricoxib, a filling agent, a disintegrating stabilizer, a wetting agent and a lubricating agent, the disintegration stabilizer is composed of polacrilin potassium, diethylaminol and glycine. The preparation process adopts wet granulation. According to the invention, the problem of balance among disintegration speed, stability and taste of the traditional orally disintegrating tablet is solved, and the orally disintegrating tablet has clinical transformation value.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to an etoricoxib orodisintegrating 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] At present, common oral tablets and capsules of etoricoxib are inconvenient for patients with dysphagia, such as the elderly, children, and some patients with oral or throat diseases. Although orodisintegrating tablets, as a new dosage form that can disintegrate rapidly in the oral cavity and does not require water for administration, have broad market potential, existing etoricoxib orodisintegrating tablets are difficult to achieve an ideal balance in terms of disintegration speed, stability, and taste, which limits their clinical application and market promotion. Therefore, it is of great practical significance to develop an orodisintegrating tablet of etoricoxib with excellent performance.

[0004] The Chinese patent with publication number CN108057025A discloses an orodisintegrating tablet of etoricoxib and a preparation method thereof, wherein the orodisintegrating tablet is a pharmaceutical composition comprising etoricoxib, a filler, a disintegrant, a wetting agent and a binder, a flavoring agent, and a lubricant, and is prepared by a wet granulation tableting method. However, no quality evaluation is made on the disintegration effect, taste, formulation stability, etc.

[0005] It is well known to those skilled in the art that the technical difficulties in studying etoricoxib orodisintegrating tablets are mainly the selection of drugs and excipients and the setting of the preparation process. Therefore, developing a preparation technology for etoricoxib orodisintegrating tablets that can take into account disintegration speed, mouth feel and formulation stability has become a core issue that needs to be solved urgently in this field. Summary of the invention

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

[0007] Specifically, the technical solution of the present invention is as follows: The orodisintegrating tablet of etoricoxib comprises: 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 salamanol, and 5-10 parts by weight of glycine.

[0008] Among them, the filler is selected from at least one of mannitol, lactose, microcrystalline cellulose, starch, dextrin, and sucrose. Further, the filler is mannitol, lactose, or microcrystalline cellulose.

[0009] Among them, the wetting agent is ethanol or / and water. Further, the wetting agent is a mixture of ethanol and water in a ratio of 7:3.

[0010] Among them, the lubricant is selected from at least one of magnesium stearate, colloidal silicon dioxide, and talc powder. Preferably, it is magnesium stearate or colloidal silicon dioxide.

[0011] The particle size D90 of the etoricoxib API is < 40 μm.

[0012] The present invention also provides a method for preparing the above-mentioned etoricoxib orally disintegrating tablets, which includes the following steps: (1) Preparing soft material: Add etoricoxib, filler, chomenol, glycine, and 1 / 3 - 1 / 2 parts by weight of potassium polacrilate to a granulator, stir and mix, then add the wetting agent to prepare soft material; (2) Granulating and drying: Extrude the soft material into granules through a granulator; dry in a fluidized bed until the moisture content ≤ 2.0%; (3) Screening and total mixing: Screen the granules, and add the remaining potassium polacrilate and lubricant to a three-dimensional mixer for mixing; (5) Tableting.

[0013] Compared with the prior art, the technical effects of the present invention are as follows: (1) The present invention first combines potassium polacrilate, chomenol, and glycine as a disintegration stabilizer, achieving the effects of rapid disintegration, improved stability, and optimized taste simultaneously.

[0014] (2) The present invention solves the technical problem that it is difficult to balance "disintegration - stability - taste" in traditional orally disintegrating tablets through systematic optimization of the addition sequence of excipients and process parameters.

[0015] (3) The present invention provides an industrially applicable preparation scheme, laying a foundation for the clinical application and market promotion of etoricoxib orally disintegrating tablets. Description of the Drawings

[0016] Figure 1 : Disintegration time limit of each group of etoricoxib orally disintegrating tablets.

[0017] Figure 2 : Stability of each group of etoricoxib orally disintegrating tablets.

[0018] Figure 3 : Taste score of etoricoxib orally disintegrating tablets. Detailed Embodiments

[0019] In order to make the objectives and technical solutions of the present invention clearer and more understandable, the following further describes the present invention in conjunction with embodiments. However, the protection scope of the present invention is not limited to these embodiments, and the embodiments are only used to explain the present invention. Those skilled in the art should understand that any changes or equivalent substitutions that do not deviate from the concept of the present invention are included in the protection scope of the present invention.

[0020] Example 1 Etoricoxib Orally Disintegrating Tablets Formulation: Preparation Method: (1) Preparation of soft mass: The raw and auxiliary materials are respectively sieved through a 100-mesh sieve and reserved. Add the prescribed amount of etoricoxib, filler, crospovidone, glycine, and 1 / 3 of the prescribed amount of potassium bicarbonate to the granulator, stir and mix at a speed of 15 rpm for 10 minutes until uniform. Slowly add the wetting agent to the mixed powder, and granulate with a cutter at a speed of 1000 rpm for 4 minutes to prepare a soft mass, forming a soft mass that can be kneaded into a ball by hand and dispersed when gently pressed.

[0021] (2) Granulation: Extrude the soft mass into particles with a size of 1.0 - 1.5 mm through a granulator.

[0022] (3) Fluidized bed drying: Set the inlet air temperature to 55 °C, control the particle bed temperature at 45 °C, and the time is 30 minutes, dry until the moisture content ≤ 2.0%.

[0023] (4) Screening and total mixing: Screen the dried particles through a 20-mesh sieve, break up the agglomerated particles, and add the remaining potassium bicarbonate and lubricant to a three-dimensional mixer, and mix at a speed of 25 rpm for 15 minutes.

[0024] (5) Tableting: Use a shallow concave punch, control the pressure at 1 - 5 kN, and control the tablet hardness at 3.0 kgf.

[0025] Example 2 Etoricoxib Orally Disintegrating Tablets Formulation: Preparation Method: (1) Preparation of soft mass: The raw and auxiliary materials are respectively sieved through a 100-mesh sieve and reserved. Add the prescribed amount of etoricoxib, filler, crospovidone, glycine, and 1 / 3 of the prescribed amount of potassium bicarbonate to the granulator, stir and mix at a speed of 100 rpm for 5 minutes until uniform. Slowly add the wetting agent to the mixed powder, and granulate with a cutter at a speed of 800 rpm for 2 minutes to prepare a soft mass, forming a soft mass that can be kneaded into a ball by hand and dispersed when gently pressed.

[0026] (2) Granulation: Extrude the soft mass into particles with a size of 1.0 - 1.5 mm through a granulator.

[0027] (3) Fluidized bed drying: The inlet air temperature is set at 50 °C, the temperature of the particle bed layer is controlled at 40 °C, and the time is 20 minutes until the moisture content ≤ 2.0%.

[0028] (4) Granule sizing and total mixing: The dried granules are sized through a 20-mesh sieve, the caked granules are broken, and the remaining potassium polacrilin and lubricant are added to a three-dimensional mixer and mixed at a speed of 20 rpm for 10 minutes.

[0029] (5) Tabletting: Use a shallow concave punch, control the pressure at 1 - 5 kN, and control the tablet hardness at 2.5 kgf.

[0030] Example 3 Etoricoxib orally disintegrating tablets Formula: Preparation method: (1) Preparation of soft mass: The raw and auxiliary materials are separately passed through a 100-mesh sieve and reserved. Add the prescribed amount of etoricoxib, filler, chlorpheniramine maleate, glycine, and 1 / 3 of the prescribed amount of potassium polacrilin to a granulator, stir and mix at a speed of 200 rpm for 10 minutes until uniform. Slowly add the wetting agent to the mixed powder, and granulate with a cutting knife at a speed of 1200 rpm for 5 minutes to prepare a soft mass that can be formed into a ball by hand and dispersed when lightly pressed.

[0031] (2) Granulation: Extrude the soft mass into granules with a size of 1.0 - 1.5 mm through a granulator.

[0032] (3) Fluidized bed drying: The inlet air temperature is set at 60 °C, the temperature of the particle bed layer is controlled at 50 °C, and dry until the moisture content ≤ 2.0%.

[0033] (4) Granule sizing and total mixing: The dried granules are sized through a 20-mesh sieve, the caked granules are broken, and the remaining potassium polacrilin and lubricant are added to a three-dimensional mixer and mixed at a speed of 30 rpm for 15 minutes.

[0034] (5) Tabletting: Use a shallow concave punch, control the pressure at 1 - 5 kN, and control the tablet hardness at 3.5 kgf.

[0035] Particle size of etoricoxib The particle size of etoricoxib raw material drug is detected by a Malvern MS3000 particle size analyzer.

[0036] Table 1 Particle size distribution The data in Table 1 show that the particle size of the etoricoxib raw material drug used in the present invention is relatively small and the distribution is relatively concentrated. Among them, 90% of the particle sizes are controlled below 40 μm, which helps the drug to rapidly disintegrate and release in the orally disintegrating tablets, and has a positive significance for improving the efficacy of the orally disintegrating tablets and the patient's medication experience.

[0037] Verification of the Effect of the Disintegration Stabilizer of the Invention By means of the blank control method and the single-factor variable method, verify the effects of the disintegration stabilizers (potassium polacrilate, menthol glycol, glycine) and the addition sequence on the disintegration effect, accelerated test stability, and taste of etoricoxib orally disintegrating tablets.

[0038] Experimental Scheme Table 2 Experimental Design Scheme of Excipient Groups Table 3 Experimental Scheme Design of Methods Detection of Disintegration Effect Instrument: Disintegration Time Limit Tester (temperature 37°C ± 0.5°C).

[0039] Operation: Take 6 tablets of the sample, place them in the basket of the disintegration tester respectively, start the instrument, and record the time when the tablets are completely disintegrated.

[0040] Table 4 Disintegration Time Limits of Etoricoxib Orally Disintegrating Tablets in Each Group It can be clearly concluded from the disintegration time limit data of the blank group, Example 1 and each excipient group in Table 4 that none of the three disintegration stabilizers (potassium polacrilate, menthol glycol, glycine) can be missing, and the absence or replacement of any one component will lead to a significant decrease in disintegration performance. The addition timing of the disintegration stabilizer is a key process parameter affecting the disintegration efficiency of orally disintegrating tablets. By reasonably splitting the addition stages of potassium polacrilate and other excipients, the disintegration speed of the tablets can be significantly improved, providing a scientific basis for optimizing the formulation process of orally disintegrating tablets.

[0041] Detection of Accelerated Test Stability Conditions: Thermostatic and Humid Chamber (40°C ± 2°C, RH75% ± 5%), place for 6 months.

[0042] Detection Time Points: 0 month (initial), 1 month, 3 months, 6 months.

[0043] Detection Method: Accurately weigh an appropriate amount of the sample, dissolve and dilute it with the mobile phase, and determine the content of etoricoxib by HPLC method (chromatographic column: C18, mobile phase: methanol - water - glacial acetic acid = 70:30:0.1, detection wavelength: 254 nm).

[0044] Evaluation Index: Content Change Rate = (content at the 6th month - initial content) / initial content × 100%.

[0045] Table 5 Accelerated Test Stability As can be seen from Table 5, the combination of potassium polacrilate, herbaceous menthol, and glycine significantly improves the storage stability of etoricoxib orally disintegrating tablets. The absence of any one of them or an imbalance in the ratio will lead to a decrease in stability. The disintegration stabilizer can reduce drug degradation step by step, further ensuring stability. The prescription process of the present invention not only achieves rapid disintegration, but also ensures the quality controllability of the drug under complex storage conditions through scientific proportioning of excipients and process optimization, meeting the long-term clinical medication needs.

[0046] Taste evaluation experiment Volunteer requirements: 10 volunteers, 5 males and 5 females, without oral diseases, fasting and abstaining from drinking for 1 hour before the experiment.

[0047] Evaluation process: Volunteers take the sample by buccal administration without drinking water, and record the disintegration time (subjective feeling).

[0048] Score according to the following dimensions (1 - 5 points, 5 points being the best): Disintegration speed: 5 points = rapid disintegration, 1 point = slow disintegration.

[0049] Bitter taste masking: 5 points = no bitter taste, 3 points = slight bitter taste, 1 point = strong bitter taste.

[0050] Gritty feeling: 5 points = no gritty feeling, 3 points = slight granular feeling, 1 point = obvious gritty feeling.

[0051] Data processing: Calculate the mean and standard deviation of the scores of each group of volunteers. Use SPSS 22.0 software to statistically analyze the obtained data. Measurement data are expressed in ( , and one-way ANOVA is used for comparison among multiple groups, and independent sample T-test is used for comparison between two groups. P < 0.05 is considered statistically significant.

[0052] Table 6 Taste scores Note: The control group refers to the group without the main drug, and the others are the same as in Example 1.

[0053] Compared with the commercially available preparation group, *P < 0.05.

[0054] Through the design of the disintegration stabilizer and the optimization of the wet granulation process, the present invention successfully solves the problem of bitter taste of etoricoxib orally disintegrating tablets, while ensuring rapid disintegration and delicate taste. Experimental data show that its taste score is significantly better than that of commercially available preparations, and is close to that of the blank excipient group, proving that this prescription process has significant technical advantages in balancing drug efficacy and patient experience, and has the value of clinical transformation and market promotion.

Claims

1. An etoricoxib orally disintegrating tablet, characterized in that, The formulation of the etoricoxib orally disintegrating tablets is as follows: 30 - 120 parts by weight of etoricoxib, 50 - 200 parts by weight of filler, 20 - 50 parts by weight of disintegration stabilizer, 5 - 20 parts by weight of wetting agent, and 1 - 4 parts by weight of lubricant; the disintegration stabilizer is a combination of potassium polacrilate, choline alcohol, and glycine.

2. The etoricoxib orally disintegrating tablet according to claim 1, wherein The disintegration stabilizer is 10 - 30 parts by weight of potassium polacrilate, 5 - 10 parts by weight of choline alcohol, and 5 - 10 parts by weight of glycine.

3. The etoricoxib orally disintegrating tablet according to claim 1, wherein, The filler is mannitol, lactose, or microcrystalline cellulose.

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

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

3.

6. The etoricoxib orally disintegrating tablet according to claim 1, wherein The lubricant is selected from at least one of magnesium stearate, colloidal silicon dioxide, and talc powder.

7. The etoricoxib orally disintegrating tablet according to claim 1, wherein The lubricant is magnesium stearate or colloidal silicon dioxide.

8. The etoricoxib orally disintegrating tablet according to claim 1, characterized in that, The particle size D90 of the etoricoxib is less than 40 μm.

9. A preparation method of the etoricoxib orally disintegrating tablet according to claim 1, characterized in that, The preparation method includes the following steps: (1) Preparing the soft material: Add etoricoxib, filler, choline alcohol, glycine, and 1 / 3 - 1 / 2 of the prescribed amount of potassium polacrilate to a granulator, stir and mix, then add the wetting agent to prepare the soft material; (2) Granulating and drying: Extrude the soft material into granules through a granulator; dry in a fluidized bed until the moisture content is ≤ 2.0%; (3) Screening and total mixing: Screen the granules, and add the remaining potassium polacrilate and lubricant to a three-dimensional mixer for mixing; (4) Tabletting.

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