Celecoxib orally disintegrating tablet and preparation process thereof

Abstract

The invention relates to the field of pharmaceutical preparations, and particularly discloses a celecoxib orally disintegrating tablet and a preparation process thereof. The invention relates to a preparation process of a celecoxib orally disintegrating tablet. The preparation method comprises the following steps: adding beta-cyclodextrin into deionized water, dissolving to obtain an emulsion, adding celecoxib into the emulsion, and stirring to obtain a matrix liquid; the preparation method comprises the following steps: adding bacterial cellulose into deionized water, adding ammonium carbonate, and carrying out vacuum filtration to obtain a fiber cake; dipping the fiber cake into an absolute ethyl alcohol solution of tetraethyl silicate, washing, drying and grinding to obtain a carrier; adding the carrier into the matrix liquid, stirring at room temperature, centrifuging, and freeze-drying the centrifugate to obtain an inclusion compound; uniformly mixing the inclusion compound with a filling agent, a slipping agent, an adhesive and a sweetening agent, adding pure water, stirring, emulsifying, vacuumizing, defoaming, sub-packaging into bubble caps, pre-freezing, freeze-drying and sub-packaging. The orally disintegrating tablet prepared by the invention is high in disintegration speed, convenient to take, slightly sweet in taste and high in medication compliance of patients.

Description

Technical Field

[0001] The present application relates to the technical field of pharmaceutical preparations, and more specifically, to a celecoxib orodisintegrating tablet and a preparation process thereof. Background Art

[0002] Celecoxib (4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide) is a coxib nonsteroidal anti-inflammatory drug (NSAIDs) with analgesic, anti-inflammatory and antipyretic effects. It is mainly used to treat rheumatoid arthritis, osteoarthritis and ankylosing spondylitis. It is also used to treat acute pain, dysmenorrhea, colorectal polyps and postoperative analgesia.

[0003] Celecoxib has extremely poor water solubility, with a solubility in pure water of only about 0.007 mg / ml. Its special properties make it difficult for the drug to dissolve in the body and be absorbed by the gastrointestinal epithelial cell mucosa after administration in the form of an oral preparation, resulting in low bioavailability of the drug and inability to effectively exert its therapeutic effect.

[0004] In order to improve bioavailability, in the prior art, a Chinese invention patent document with application number CN2013101340256 discloses a celecoxib effervescent tablet and a preparation method thereof, wherein the celecoxib effervescent tablet is composed of the following weight percentages: celecoxib 10-90%, organic acid 0.1-5%, inorganic base 0.1-5%, flavoring agent 0.001-5%, colorant 0.001-0.5%, lubricant 0.5-5%, and filler balance.

[0005] Regarding the above-mentioned related technologies, bubbles are generated by the reaction of organic acids and inorganic bases to promote the rapid disintegration of tablets, thereby improving bioavailability. However, the disintegration time of 80% of the celecoxib effervescent tablets is 2-4 minutes, and it is impossible to complete the disintegration in the mouth. Drinking water is still needed to take it. It is still difficult to meet the needs of the elderly, children and other people with dysphagia and those who are not convenient to take water when traveling. Summary of the invention

[0006] In order to increase the disintegration rate of celecoxib tablets and facilitate the taking of celecoxib tablets by patients who have difficulty swallowing and have difficulty in taking water, the present application provides a celecoxib orodisintegrating tablet and a preparation process thereof.

[0007] In a first aspect, the present application provides a preparation process of celecoxib orally disintegrating tablets, which adopts the following technical scheme: a preparation process of celecoxib orally disintegrating tablets, preparing a base liquid: adding β-cyclodextrin to deionized water, stirring and dissolving to obtain an emulsion, adding celecoxib to the emulsion, stirring evenly, and obtaining a base liquid, wherein the mass ratio of β-cyclodextrin to celecoxib is 8-10:1, and the concentration of celecoxib is 10-12 mg / ml; Preparation of carrier: adding bacterial cellulose to deionized water, diluting to a concentration of 0.1-0.2wt%, adding ammonium carbonate, vacuum filtering, and obtaining a fiber cake; impregnating the fiber cake into an anhydrous ethanol solution of tetraethyl silicate, reacting at 50-60°C for 10-12h, washing, drying, and grinding to obtain a carrier; Preparation of inclusion complex: adding the carrier to the matrix liquid, stirring at room temperature for 2.5-2.7 hours and then centrifuging, freeze-drying the centrifuge to obtain the inclusion complex, the solid-liquid ratio of the carrier to the matrix liquid is 50:20-24; Freeze-drying: Evenly mix the inclusion compound with the filler, lubricant, binder and sweetener, add pure water, stir, emulsify, vacuum degas, pack into blisters, pre-freeze and freeze-dry, pack to obtain celecoxib orodisintegrating tablets.

[0008] By adopting the above technical scheme, first, celecoxib is included in β-cyclodextrin. β-cyclodextrin has a unique molecular structure and combines with the unpleasant-tasting components in celecoxib, thereby masking its peculiar smell, improving the bitterness of celecoxib, improving the acceptability of celecoxib and the patient's medication experience, and at the same time increasing the solubility of celecoxib, so that celecoxib dissolves more quickly and completely in the mouth.

[0009] Then, bacterial cellulose, tetraethyl orthosilicate and ammonium carbonate are used to prepare a carrier through chemical foaming. Bacterial cellulose is a natural nanofiber material with a three-dimensional network structure, and has the characteristics of high aspect ratio, excellent liquid wettability and high mechanical strength. By using ammonium carbonate as a chemical foaming agent, ammonia and carbon dioxide gas are generated through thermal decomposition, which weakens the interaction between cellulose nanofibers, promotes the formation of pore structure, further increases the number of pores between bacterial cellulose, and makes the structure looser. In addition, ammonia generated by the decomposition of ammonium carbonate dissolves in water to form ammonia water, thereby making the solution alkaline. Tetraethyl orthosilicate undergoes a hydrolysis reaction in an alkaline environment, thereby decomposing to produce ethanol and silicon dioxide, thereby obtaining silicon dioxide nanoparticles on the fiber cake, thereby making the surface of the fiber cake rougher and providing more pores, thereby loading celecoxib, reducing its bitterness, improving taste, and reducing irritation to the oral mucosa. The porous carrier made of bacterial cellulose and silicon dioxide has a porous structure and a rough surface, contains a large number of interconnected holes, has a large surface area, can quickly absorb water and swell, has a strong water absorption capacity, and can promote faster disintegration of the drug.

[0010] Freeze-drying is used to make inclusion compounds into orodisintegrating tablets, forming a loose porous structure, which is conducive to the penetration and diffusion of saliva, thereby accelerating the dissolution process of celecoxib in the mouth. In addition, the two freeze-drying processes can remove excess moisture and impurities, improve purity and taste comfort, make orodisintegrating tablets more delicate and easy to accept, and help reduce or avoid the first-pass effect of the liver, reduce gastrointestinal irritation, and improve patient compliance with medication, providing new ideas for the development of drug models for the elderly, children and people with certain special diseases.

[0011] Optionally, the mass ratio of ammonium carbonate, bacterial cellulose and tetraethyl orthosilicate is 1:0.1-0.2:0.1-0.2.

[0012] By adopting the above technical scheme and controlling the dosage of ammonium carbonate, bacterial cellulose and ethyl orthosilicate in an appropriate dosage ratio, the carrier can have sufficient porosity and high roughness, thereby increasing the celecoxib loading amount while having a high hygroscopic disintegration effect.

[0013] Optionally, in the freeze-drying step, the weight proportions of the raw materials are as follows: 74.8-75.6 parts of inclusion compound, 34.8-35.5 parts of filler, 35.04-37.85 parts of lubricant, 52.5-53.8 parts of binder, 0.05-0.06 parts of sweetener, and pure water is added to 400 parts.

[0014] By adopting the above technical scheme, the orally disintegrating tablets prepared by mixing and emulsifying the above raw materials have fast disintegration speed, high bioavailability, easy administration, low bad smell and bitterness, and high medication compliance.

[0015] Optionally, propylene glycol and soybean lecithin are further added to the emulsion, and the mass ratio of propylene glycol, soybean lecithin and β-cyclodextrin is 0.1-0.2:0.2-0.4:1.

[0016] By adopting the above technical scheme, propylene glycol has good solubility and can be used as a penetration enhancer to help the absorption of drugs through biological membranes. Its dissolution and penetration effects help accelerate the disintegration of the drug, allowing celecoxib to be released and dissolved faster; and propylene glycol itself has a certain sweetness and taste improvement effect, which can cover up the bitterness of the drug. Soy lecithin has good dispersibility and wettability, can increase the decomposition degree and solubility of celecoxib, and has good taste and dispersibility, which can improve the overall taste of the drug.

[0017] Optionally, the lubricant comprises micro-powder silica gel and fenugreek gum in a mass ratio of 1:0.5-1.

[0018] By adopting the above technical scheme, the micro-powder silica gel has a large specific surface area. As a lubricant, it can improve the surface smoothness of the orally disintegrating tablet, make the tablet formable and fuller, and because of its large specific surface area and porosity, it has excellent water absorption, a faster water absorption rate constant, and a shorter water absorption lag time, so that the water absorption performance is strong, and a developed microporous channel is formed in the orally disintegrating tablet, which is convenient for the rapid penetration of water and accelerates the wetting of the center of the orally disintegrating tablet. In addition, the micro-powder silica gel can also form a certain barrier between the inclusion compounds, reduce the cohesive force between the inclusion compounds, and objectively create a microenvironment that is conducive to disintegration. However, it is not easy to swell and disintegrate itself. Therefore, it is used in combination with fenugreek gum, which has strong hygroscopicity and is easy to swell when hygroscopic, to improve the disintegration time of the orally disintegrating tablet, and effectively improve the structural integrity of the tablet, and reduce the generation of cracks.

[0019] Optionally, the adhesive comprises pullulan and hyaluronic acid in a mass ratio of 1:0.3-0.5.

[0020] By adopting the above technical solution, pullulan has good film-forming property and can form a transparent, tasteless, flexible, stable and high-strength film. This film can give the orodisintegrating tablet a good smoothness on the surface and maintain the integrity of the medicine. It also has good adhesion, and the inclusion compounds are easily adhered to each other to form a uniform bonding layer between the inclusion compounds, thereby increasing the gloss of the orodisintegrating tablet and improving the structural stability of the tablet. In addition, it can also improve the storage stability of the medicine to a certain extent. Hyaluronic acid has a strong moisturizing ability and can absorb and lock a large amount of water. A moisturizing film is formed between the inclusion complex and the hyaluronic acid, which helps to reduce the moisture content of the drug, improve the crack resistance of the drug, and enhance the structural stability of the orodisintegrating tablet to prevent it from splitting or cracking during freeze-drying. In addition, hyaluronic acid can increase the lubricity of the inclusion complex, reduce the friction of other raw materials on the inclusion complex, improve the stability of the inclusion complex, and prevent it from being damaged and cracked. The high moisture absorption capacity of hyaluronic acid can also increase the water absorption and expansion of the drug, enhance its disintegration ability, and shorten the disintegration time. Therefore, using pullulan and hyaluronic acid as adhesives can produce orodisintegrating tablets with a relatively smooth surface, stable structure, and fast dissolution rate.

[0021] Optionally, the filler comprises mannitol and glycine in a mass ratio of 1:1-2.

[0022] By adopting the above technical solution, the sweetness of glycine is 0.8 times that of sucrose, and it has a soft sweetness different from sugar. It can not only provide a sweet taste, but also reduce bitterness and remove the unpleasant taste of celecoxib. It is mixed with mannitol as a filler. The orally disintegrating tablets prepared are white in appearance, uniform in color, smooth in appearance, full in tablets, without cracked edges or flakes, and have a certain degree of brittleness and disintegrate very quickly.

[0023] Optionally, the sweetener is selected from at least one of neohesperidin dihydrochalcone, stevioside, trehalose and lactose.

[0024] By adopting the above technical solution, the above sweeteners can improve the taste of celecoxib, improve the compliance of patients, increase the stability of the drug, and extend the shelf life of the drug.

[0025] Optionally, in the step of preparing the inclusion compound, the freeze-drying method is to keep warm at -(30-35)°C for 10 minutes, evacuate to 190-200 μbar, heat to -(20-25)°C, keep warm for 45 minutes, heat to -(1-5)°C, keep warm for 50 minutes, heat to 20-25°C, and keep warm for 60 minutes.

[0026] By adopting the above technical solution and performing freeze drying at the above temperature, a porous structure can be obtained with a crisp taste, which is convenient for the rapid dissolution of the drug. In addition, the orodisintegrating tablet has a low water content and is not easily oxidized, which is conducive to long-distance transportation and long-term storage, reduces the growth of microorganisms, and improves the shelf life of the product.

[0027] In a second aspect, the present application provides a celecoxib orally disintegrating tablet, which adopts the following technical solution: A celecoxib orodisintegrating tablet is prepared by the preparation process of the celecoxib orodisintegrating tablet.

[0028] By adopting the above technical solution, the celecoxib orodisintegrating tablets made by a specific process have a fast disintegration speed in the oral cavity, low unpleasant taste, good taste and taste, and are suitable for people with swallowing difficulties such as the elderly and children.

[0029] In summary, this application has the following beneficial effects: 1. Since the present application uses β-cyclodextrin to pretreat celecoxib to reduce the unpleasant taste of celecoxib and increase the solubility of celecoxib, bacterial cellulose, ammonium carbonate and ethyl orthosilicate are then used to synthesize a carrier with a porous structure and strong hygroscopicity. The carrier has many voids and a rough surface, which is convenient for loading celecoxib, reduces the bitter taste, and can also absorb water and swell, thereby promoting the disintegration of the drug. In addition, freeze drying is used to prepare orally disintegrating tablets, which can increase the looseness of the orally disintegrating tablets, increase the diffusion and penetration of water, accelerate the disintegration process, and improve the fineness and mouth feel of the orally disintegrating tablets, thereby improving medication compliance.

[0030] 2. In the present application, micro-powdered silica gel and fenugreek gum are preferably used as lubricants, which can increase the fluidity of each raw material, improve the smoothness of the tablet, and improve the structural integrity of the orally disintegrating tablet, while improving the hygroscopic expansion of the tablet and enhancing the disintegration rate of the orally disintegrating tablet.

[0031] 3. In the present application, pullulan and hyaluronic acid are preferably used as binders, which can improve the fullness of the tablets, reduce collapse and cracking, avoid shrinkage and tablet peeling, increase surface smoothness, and at the same time increase the disintegration rate and shorten the disintegration time. DETAILED DESCRIPTION

[0032] The following examples further illustrate the present application in detail. Example

[0033] Embodiment 1: A preparation process of celecoxib orally disintegrating tablets, comprising the following steps: S1. Prepare a base liquid: add 10 g of β-cyclodextrin to deionized water, stir and dissolve to obtain an emulsion, add 1.25 g of celecoxib to the emulsion, stir and uniformly obtain a base liquid, the mass ratio of β-cyclodextrin to celecoxib is 8:1, and the concentration of celecoxib in deionized water is 12 mg / ml; S2. Prepare the carrier: add 0.1g bacterial cellulose to deionized water, dilute to a concentration of 0.2wt%, add 1g ammonium carbonate, and vacuum filter to obtain a fiber cake; immerse the fiber cake in a solution formed by 0.1g tetraethyl silicate and 50ml anhydrous ethanol, react at 60°C for 10h, wash with anhydrous ethanol, dry, and grind at 500rpm for 1h to obtain a carrier. The bacterial cellulose case is Guilin Qihong Technology, the type is a dispersion, and the solid content is 1%; S3, preparation of inclusion compound: 50 mg of the carrier was added to 20 ml of the base liquid, stirred at room temperature for 2.5 h, centrifuged, pre-frozen at -60 ° C for 10 min, and then freeze-dried at -72 ° C for 48 h to obtain the inclusion compound; S4. Freeze-drying: 75.6 mg of the inclusion compound was mixed evenly with 35.5 mg of a filler, 35.04 mg of a lubricant, 53.8 mg of a binder and 0.06 mg of a sweetener, 400 mg of pure water was added, the mixture was stirred evenly, and shear emulsification was performed at a speed of 2500 r / min for 5 min, and vacuum degassing was performed until there were no bubbles, and the drug solution was injected into the blister at a volume of 400 μL per tablet using a pipette, and the tablets were pre-frozen at -60°C for 30 min, freeze-dried, and packaged to obtain celecoxib orodisintegrating tablets. The freeze-drying process was specifically as follows: put into the box at -30°C, keep warm at -30°C for 10 min, vacuumize to 20 0μbar, then heated to -20°C at a rate of 1°C / min, kept warm for 45min, then heated to -5°C at a rate of 1°C / min, kept warm for 50min, then heated to 20°C at a rate of 1°C / min, kept warm for 60min; the filler comprises mannitol and glycine in a mass ratio of 1:2, the lubricant comprises micro-powder silica gel and fenugreek gum in a mass ratio of 1:1, the micro-powder silica gel is selected from Qingdao Yonghai Silica Gel, the sieve residue (45μm) is ≤0.5%, the adhesive comprises pullulan in a mass ratio of 1:0.5 and hyaluronic acid with a molecular weight of 800,000 Daltons, and the sweetener is stevioside.

[0034] Embodiment 2: A preparation process of celecoxib orally disintegrating tablets, comprising the following steps: S1. Prepare a base liquid: add 10 g of β-cyclodextrin to deionized water, stir to dissolve, and prepare an emulsion; add 1 g of celecoxib to the emulsion, stir evenly, and prepare a base liquid; the mass ratio of β-cyclodextrin to celecoxib is 10:1, and the concentration of celecoxib in deionized water is 10 mg / ml; S2. Prepare the carrier: add 0.2g bacterial cellulose to deionized water, dilute to a concentration of 0.1wt%, add 1g ammonium carbonate, and vacuum filter to obtain a fiber cake; immerse the fiber cake in a solution formed by 0.2g tetraethyl silicate and 50ml anhydrous ethanol, react at 50°C for 12h, wash with anhydrous ethanol, dry, and grind at 500rpm for 1h to obtain a carrier. The bacterial cellulose case is Guilin Qihong Technology, the type is a dispersion, and the solid content is 1%; S3, preparation of inclusion compound: 50 mg of the carrier was added to 24 ml of the base solution, stirred at room temperature for 2.7 h, centrifuged, pre-frozen at -60°C for 10 min, and then freeze-dried at -72°C for 48 h to obtain the inclusion compound; S4. Freeze-drying: 74.8 mg of the inclusion compound was mixed evenly with 34.8 mg of a filler, 37.85 mg of a lubricant, 52.5 mg of a binder and 0.05 mg of a sweetener, 400 mg of pure water was added, the mixture was stirred evenly, and shear emulsification was performed at a speed of 2500 r / min for 5 min, and vacuum degassing was performed until there were no bubbles, and the drug solution was injected into the blister at a volume of 400 μL per tablet using a pipette, and the tablets were pre-frozen at -60°C for 30 min, freeze-dried, and packaged to obtain celecoxib orodisintegrating tablets. The freeze-drying process was specifically as follows: entering the box at -35°C, keeping warm at -35°C for 10 min, vacuumizing to 190 μL, and then drying the tablets. r, then heating to -25°C at a rate of 1°C / min, keeping warm for 45 minutes, then heating to -1°C at a rate of 1°C / min, keeping warm for 50 minutes, then heating to 25°C at a rate of 1°C / min, keeping warm for 60 minutes; the filler comprises mannitol and glycine in a mass ratio of 1:1, the lubricant comprises micro-powder silica gel and fenugreek gum in a mass ratio of 1:0.5, the micro-powder silica gel is selected from Qingdao Yonghai Silica Gel, the sieve residue (45μm) is ≤0.5%, the adhesive comprises pullulan in a mass ratio of 1:0.3 and hyaluronic acid with a molecular weight of 800,000 Daltons, and the sweetener is neohesperidin dihydrochalcone.

[0035] Embodiment 3: A preparation process of celecoxib orally disintegrating tablets, comprising the following steps: S1. Prepare a base liquid: add 9 g of β-cyclodextrin to deionized water, stir and dissolve to obtain an emulsion, add 1 g of celecoxib to the emulsion, stir evenly to obtain a base liquid, the mass ratio of β-cyclodextrin to celecoxib is 9:1, and the concentration of celecoxib in deionized water is 11 mg / ml; S2. Prepare a carrier: add 0.15g bacterial cellulose to deionized water, dilute to a concentration of 0.1wt%, add 1g ammonium carbonate, and vacuum filter to obtain a fiber cake; immerse the fiber cake in a solution formed by 0.15g tetraethyl silicate and 50ml anhydrous ethanol, react at 55°C for 11h, wash with anhydrous ethanol, dry, and grind at 500rpm for 1h to obtain a carrier. The bacterial cellulose case is Guilin Qihong Technology, the type is a dispersion, and the solid content is 1%; S3, preparation of inclusion compound: 50 mg of the carrier was added to 22 ml of the base liquid, stirred at room temperature for 2.6 h, centrifuged, pre-frozen at -60°C for 10 min, and then freeze-dried at -72°C for 48 h to obtain the inclusion compound; S4. Freeze-drying: 75 mg of the inclusion compound was mixed evenly with 35 mg of a filler, 36.95 mg of a lubricant, 53 mg of a binder and 0.05 mg of a sweetener, 400 mg of pure water was added, the mixture was stirred evenly, and shear emulsification was performed at a speed of 2500 r / min for 5 min, and vacuum degassing was performed until there were no bubbles, and the drug solution was injected into the blister at a volume of 400 μL per tablet using a pipette, and the tablets were pre-frozen at -60°C for 30 min, freeze-dried, and packaged to obtain celecoxib orodisintegrating tablets. The freeze-drying process was specifically as follows: entering the box at -33°C, keeping warm at -33°C for 10 min, and vacuumizing to 190 μbar. , then heated to -23°C at a rate of 1°C / min, kept warm for 45 minutes, then heated to -3°C at a rate of 1°C / min, kept warm for 50 minutes, then heated to 22°C at a rate of 1°C / min, kept warm for 60 minutes; the filler includes mannitol and glycine in a mass ratio of 1:1.5, the lubricant includes micro-powder silica gel and fenugreek gum in a mass ratio of 1:0.8, the micro-powder silica gel is selected from Qingdao Yonghai Silica Gel, the sieve residue (45μm) ≤0.5%, the adhesive includes pullulan in a mass ratio of 1:0.4 and hyaluronic acid with a molecular weight of 800,000 Daltons, and the sweetener is trehalose.

[0036] Example 4: A process for preparing celecoxib orally disintegrating tablets. The difference from Example 1 is that no fenugreek gum is added to the lubricant, and the lubricant is only micro-powdered silica gel.

[0037] Example 5: A process for preparing celecoxib orally disintegrating tablets, which is different from Example 1 in that only fenugreek gum is used as the lubricant, and no micro-powdered silica gel is added.

[0038] Example 6: A process for preparing celecoxib orodisintegrating tablets, which is different from Example 1 in that an equal amount of microcrystalline cellulose is used as a lubricant instead of fenugreek gum.

[0039] Example 7: A process for preparing celecoxib orally disintegrating tablets, which is different from Example 1 in that the binder is pullulan and no hyaluronic acid is added.

[0040] Example 8: A process for preparing celecoxib orally disintegrating tablets, which is different from Example 1 in that an equal amount of gum arabic is used instead of hyaluronic acid.

[0041] Example 9: A process for preparing celecoxib orally disintegrating tablets, which is different from Example 1 in that glycine is not added to the filler, but only mannitol.

[0042] Example 10: A process for preparing celecoxib orally disintegrating tablets, which is different from Example 1 in that an equal amount of maltodextrin is used to replace glycine in the filler.

[0043] Example 11: A preparation process of celecoxib orally disintegrating tablets, which is different from Example 1 in that: In step S1, propylene glycol and soybean glyceride are added to the emulsion, and the mass ratio of propylene glycol, soybean lecithin and β-cyclodextrin is 0.2:0.4:1.

[0044] Example 12: A preparation process of celecoxib orally disintegrating tablets, which is different from Example 1 in that: In step S1, propylene glycol and soybean glyceride are added to the emulsion, and the mass ratio of propylene glycol, soybean lecithin and β-cyclodextrin is 0.1:0.2:1.

[0045] Example 13: A process for preparing celecoxib orally disintegrating tablets, which is different from Example 11 in that, in step S1, propylene glycol is not added to the emulsion, and only soy lecithin is added, and the mass ratio of soy lecithin to β-cyclodextrin is 0.4:1.

[0046] Example 14: A process for preparing celecoxib orally disintegrating tablets, which is different from Example 11 in that, in step S1, an equal amount of propylene glycol is used in the emulsion to replace soybean lecithin, and the mass ratio of propylene glycol to β-cyclodextrin is 0.6:1.

[0047] Comparative Example Comparative Example 1: A process for preparing celecoxib orally disintegrating tablets, comprising the following steps: S1. Prepare a base liquid: add 10 g of β-cyclodextrin to deionized water, stir and dissolve to obtain an emulsion, add 1.25 g of celecoxib to the emulsion, stir and uniformly obtain a base liquid, the mass ratio of β-cyclodextrin to celecoxib is 8:1, and the concentration of celecoxib in deionized water is 12 mg / ml; S2, preparation of inclusion compound: pre-freeze the base liquid at -60 ° C for 10 minutes, and then freeze-dry at -72 ° C for 48 hours to obtain the inclusion compound; S3, freeze-drying: 75.6 mg of the inclusion compound was mixed with 35.5 mg of the filler, 35.04 mg of the lubricant, 53.8 mg of the binder and 0.06 mg of the sweetener, 400 mg of pure water was added, and after stirring evenly, shearing and emulsifying at a speed of 2500 r / min for 5 minutes, vacuum degassing until there are no bubbles, and the liquid was injected into the blister with a pipette at a volume of 400 μL per tablet, and pre-frozen at -60 ° C for 30 minutes, freeze-dried, and packaged to obtain celecoxib orodisintegrating tablets. The freeze-drying process is specifically as follows: -3 The method comprises the steps of: entering the chamber at 0°C, keeping the temperature at -30°C for 10 minutes, evacuating to 200 μbar, then heating to -20°C at a speed of 1°C / min, keeping the temperature for 45 minutes, then heating to -5°C at a speed of 1°C / min, keeping the temperature for 50 minutes, then heating to 20°C at a speed of 1°C / min, keeping the temperature for 60 minutes; the filler comprises mannitol and glycine in a mass ratio of 1:2, the lubricant comprises micro-powder silica gel and fenugreek gum in a mass ratio of 1:1, the micro-powder silica gel is selected from Qingdao Yonghai Silica Gel, the sieve residue (45 μm) is ≤0.5%, the adhesive comprises pullulan and hyaluronic acid with a molecular weight of 800,000 Daltons in a mass ratio of 1:0.5, and the sweetener is stevioside.

[0048] Comparative Example 2: A preparation process of celecoxib orally disintegrating tablets, which is different from Example 1 in that ethyl orthosilicate is not added when preparing the carrier.

[0049] Comparative Example 3: A preparation process of celecoxib orally disintegrating tablets, which is different from Example 1 in that, when preparing the carrier, no ethyl orthosilicate and ammonium carbonate are added, 0.1 g of bacterial cellulose is added to deionized water, diluted to a concentration of 0.2 wt%, vacuum filtered to obtain a fiber cake, dried, and ground at 500 rpm for 1 h to obtain a carrier.

[0050] Comparative Example 4: A preparation process of celecoxib orally disintegrating tablets, which is different from Example 1 in that β-cyclodextrin is not used, celecoxib is added to deionized water and stirred evenly to prepare a base liquid with a concentration of 12 mg / ml.

[0051] Comparative Example 5: A preparation process of celecoxib orodisintegrating tablets, which is different from Example 1 in that freeze-drying is not used in step S4. Specifically, 75.6 mg of inclusion compound is evenly mixed with 35.5 mg of filler, 35.04 mg of lubricant, 53.8 mg of binder and 0.06 mg of sweetener, and tableted to obtain orodisintegrating tablets.

[0052] Performance testing Orally disintegrating tablets were prepared according to the methods in the examples and comparative examples, and the following tests were performed. The test results are recorded in Table 3.

[0053] 1. Disintegration time: Place the orodisintegrating tablet in distilled water (37±2° C.) and use a stopwatch to record the time from contact with water to complete disintegration of the orodisintegrating tablet. For each example or comparative example, 20 tablets were tested and the test results were averaged.

[0054] 2. Taste: 6 volunteers, 3 males and 3 females, were selected to place the orodisintegrating tablet on the same part of the tongue tip (middle of the tongue) without chewing or taking it with water until the orodisintegrating tablet was completely disintegrated. All suspended matter in the oral cavity was spit out. The taste of the orodisintegrating tablet was scored according to the evaluation criteria in Table 1, and the scoring results were averaged.

[0055] Table 1 Bitterness evaluation criteria for orally disintegrating tablets 3. Appearance: Six volunteers, three males and three females, were selected to observe the orodisintegrating tablets in a well-lit place to determine whether the color is uniform, whether the tablets are full, smooth, complete, and whether there are any cracks. The specific evaluation criteria are shown in Table 2, and the average score is taken.

[0056] Table 2 Appearance evaluation criteria for orally disintegrating tablets Table 3 Test results of celecoxib orodisintegrating tablets Combining the evaluation criteria in Tables 1-2 and the evaluation results in Table 3, it can be seen that in Examples 1-3, a specific method is used to prepare the carrier, and then an inclusion compound is prepared, which is mixed with a filler and freeze-dried. The orally disintegrating tablets prepared have a fast disintegration rate and can be completely disintegrated within 50 seconds. They are almost free of bitterness, and the tablets are uniform in color, full, and have no cracks on the edges. They are suitable for special groups such as the elderly and children with dysphagia.

[0057] In Example 4, micropowdered silica gel is used as a lubricant. As shown in Table 3, compared with Example 1, the dissolution rate of the orally disintegrating tablet prepared in Example 4 is significantly reduced, and the fragmentation phenomenon of the orally disintegrating tablet increases, and the integrity of the tablet deteriorates, indicating that fenugreek gum can enhance the disintegration time and integrity of the orally disintegrating tablet.

[0058] In Example 5, fenugreek gum was used as a lubricant. Compared with Example 1, the orally disintegrating tablet prepared in Example 5 had a faster disintegration rate, but the scores of fullness and fragmentation were lower.

[0059] In Example 6, microcrystalline cellulose was used instead of fenugreek gum. Compared with Example 1, the orally disintegrating tablets prepared in Example 6 had a longer disintegration time, a lower bitterness masking effect, and a lower sensory evaluation score.

[0060] Compared with Example 1, hyaluronic acid was not added to the adhesive in Example 7. The data in Table 3 showed that the disintegration rate of the orally disintegrating tablet prepared in Example 7 was slowed down, the amount of broken pieces was increased, and the scores of fullness and smoothness were reduced.

[0061] In Example 8, gum arabic was used instead of hyaluronic acid. Compared with Example 1, the scores of fullness and smoothness of the orally disintegrating tablets prepared in Example 8 were decreased, and the disintegration rate was slightly slowed down.

[0062] In Example 9, only mannitol was used as a filler, and in Example 10, maltodextrin was used instead of glycine. Compared with Example 1, the disintegration time of the orodisintegrating tablets prepared in Examples 9 and 10 did not change much, but the bitterness increased, and the sensory evaluation score decreased.

[0063] Compared with Example 1, Examples 11 and 12 further added propylene glycol and soybean glyceride to the emulsion formed by β-cyclodextrin. The orodisintegrating tablets prepared in Examples 11 and 12 had faster disintegration speed, little change in bitterness masking effect, and slightly increased various sensory evaluations.

[0064] Compared with Example 11, Example 13-14 does not add propylene glycol to the emulsion, and Example 14 uses propylene glycol instead of soy lecithin. It can be seen that the orally disintegrating tablets prepared in Examples 13 and 14 have a slightly lower evaluation than that in Example 11.

[0065] Comparative Example 1 Compared with Example 1, no carrier was used to encapsulate the base liquid containing celecoxib. It can be seen that the disintegration rate of the orally disintegrating tablet prepared in Comparative Example 1 was significantly reduced, the bitterness was also increased, and the sensory evaluation score was reduced.

[0066] Compared with Example 1, in Comparative Example 2, no ethyl orthosilicate was used when preparing the carrier, and in Comparative Example 3, no ethyl orthosilicate and ammonium carbonate were added when preparing the carrier. The disintegration time of the orodisintegrating tablets prepared in Comparative Examples 2 and 3 was significantly reduced, and the bitterness masking effect was reduced, and the scores of fullness and the like were reduced.

[0067] Compared with Example 1, in Comparative Example 4, no β-cyclodextrin was used, and the bitterness score of the orally disintegrating tablets prepared therefrom increased, the bitterness masking effect became worse, and the disintegration rate became slower.

[0068] In Comparative Example 5, the inclusion compound was not mixed and freeze-dried. Compared with Example 1, the disintegration rate of the orally disintegrating tablet was slower, the bitterness score effect did not change much, but the sensory evaluation was reduced.

[0069] This specific embodiment is merely an explanation of the present application and is not a limitation of the present application. After reading this specification, those skilled in the art may make modifications to the present embodiment without any creative contribution as needed, but such modifications are protected by the patent law as long as they are within the scope of the claims of the present application.

Claims

1. A process for preparing celecoxib orally disintegrating tablets, characterized in that: The following steps are involved: Preparation of base liquid: adding β-cyclodextrin to deionized water, stirring to dissolve, preparing an emulsion, adding celecoxib to the emulsion, stirring evenly, preparing a base liquid, wherein the mass ratio of β-cyclodextrin to celecoxib is 8-10:1, and the concentration of celecoxib is 10-12 mg / ml; Preparation of carrier: adding bacterial cellulose to deionized water, diluting to a concentration of 0.1-0.2wt%, adding ammonium carbonate, vacuum filtering, and obtaining a fiber cake; impregnating the fiber cake into an anhydrous ethanol solution of tetraethyl silicate, reacting at 50-60°C for 10-12h, washing, drying, and grinding to obtain a carrier; Preparation of inclusion complex: adding the carrier to the matrix liquid, stirring at room temperature for 2.5-2.7 hours and then centrifuging, freeze-drying the centrifuge to obtain the inclusion complex, the solid-liquid ratio of the carrier to the matrix liquid is 50:20-24; Freeze-drying: Evenly mix the inclusion compound with the filler, lubricant, binder and sweetener, add pure water, stir, emulsify, vacuum degas, pack into blisters, pre-freeze and freeze-dry, pack to obtain celecoxib orodisintegrating tablets.

2. The preparation process of celecoxib orally disintegrating tablets according to claim 1, characterized in that: The mass ratio of the ammonium carbonate, bacterial cellulose and tetraethyl orthosilicate is 1:0.1-0.2:0.1-0.

2.

3. The preparation process of celecoxib orally disintegrating tablets according to claim 1, characterized in that: In the freeze-drying step, the weight proportions of the raw materials are as follows: 74.8-75.6 parts of inclusion compound, 34.8-35.5 parts of filler, 35.04-37.85 parts of lubricant, 52.5-53.8 parts of binder, 0.05-0.06 parts of sweetener, and pure water is added to 400 parts.

4. The preparation process of celecoxib orally disintegrating tablets according to claim 1, characterized in that: Propylene glycol and soybean lecithin are also added to the emulsion, and the mass ratio of propylene glycol, soybean lecithin and beta-cyclodextrin is 0.1-0.2:0.2-0.4:

1.

5. The preparation process of celecoxib orally disintegrating tablets according to claim 1, characterized in that: The lubricant comprises micro powder silica gel and fenugreek gum in a mass ratio of 1:0.5-1.

6. The preparation process of celecoxib orally disintegrating tablets according to claim 1, characterized in that: The adhesive comprises pullulan and hyaluronic acid in a mass ratio of 1:0.3-0.

5.

7. The preparation process of celecoxib orally disintegrating tablets according to claim 1, characterized in that: The filler comprises mannitol and glycine in a mass ratio of 1:1-2.

8. The process for preparing the celecoxib orally disintegrating tablet according to claim 1, characterized in that: The sweetener is selected from at least one of neohesperidin dihydrochalcone, stevioside, trehalose and lactose.

9. The preparation process of celecoxib orally disintegrating tablets according to claim 1, characterized in that: In the step of preparing the inclusion compound, the freeze-drying method is to keep the temperature at - (30-35) ° C for 10 minutes, evacuate to 190-200 μbar, heat to - (20-25) ° C, keep the temperature for 45 minutes, heat to - (1-5) ° C, keep the temperature for 50 minutes, heat to 20-25 ° C, and keep the temperature for 60 minutes.

10. A celecoxib orodisintegrating tablet, characterized in that: The celecoxib orally disintegrating tablet is prepared by the preparation process of any one of claims 1 to 9.

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