A kind of celecoxib nanocrystalline tablet and preparation method thereof

Abstract

The present invention is a celecoxib nanocrystalline tablet for treating osteoarthritis and rheumatoid arthritis and a preparation method thereof. The present invention relates to the field of medical technology, and is a new preparation-nanocrystalline preparation and a preparation method of celecoxib for treating osteoarthritis and rheumatoid arthritis. The present invention adopts nanocrystallization technology to prepare drug nano powder. Excipients include disintegrants, fillers, and lubricants. The celecoxib tablet obtained by the present invention has good dissolution, and at 60min, the dissolution reaches more than 95%, and the dissolution is stable, without burst release phenomenon, and can maximize the efficacy of the drug and improve bioavailability.

Description

Background Art

[0001] Celecoxib chemical name 4-[5-(4-methylphenyl)-3-(trifluoromethyl)pyrazol-1-yl]benzenesulfonamide, molecular formula: C 17 H 14 F 3 N 3 O 2 S, molecular weight: 381.37g / mol. The molecular structure is as follows:

[0002] Celecoxib is a new generation of non-steroidal anti-inflammatory analgesic drugs, which inhibits the production of prostaglandins by selectively inhibiting cyclooxygenase-2 (COX-2), achieving anti-inflammatory and analgesic effects. It was successfully developed by GDSearle & Pfizer of the United States and launched on the market in 1999 under the trade name Celebrex. This product has significant analgesic and anti-inflammatory effects, and has the lowest incidence of upper gastrointestinal ulcers and other complications.

[0003] Celecoxib is clinically used to treat acute and chronic osteoarthritis and rheumatoid arthritis.

[0004] Celecoxib is a white or off-white powder with extremely poor water solubility, and its solubility at 25°C is only 7 mg / L. It is soluble in ethanol with a solubility of 33 mg / mL. It is a BCS Class II compound, a poorly soluble drug with low solubility and high permeability, and its rate-limiting step of absorption in the body is dissolution. Therefore, in order to improve the bioavailability of celecoxib, the main measure taken is to increase its dissolution rate.

[0005] Generally speaking, the common methods to improve the dissolution rate of BCS Class II drugs include: controlling the crystal form of the API, reducing the particle size, adding pH regulators, and amorphizing the crystal form.

[0006] Nanocrystals, also known as nanocrystals for short, are colloidal dispersion systems formed by dispersing nanoscale drug particles in water using surfactants or polymers as stabilizers. It is one of the ways to reduce particle size. The advantages of nanocrystals are: high saturated solubility, fast dissolution rate, high oral bioavailability; high drug loading, theoretical drug loading can reach 100%, and due to the presence of stabilizers, the actual drug loading can reach 30%~90% (w / w). Summary of the invention

[0007] The invention provides a celecoxib nano-crystalline sheet and a preparation method thereof.

[0008] An object of the present invention is to provide a celecoxib nanoparticle, characterized in that the average particle size of the celecoxib nanoparticle is less than 500nm, negatively charged, and the zata potential is between -25mV and 0mV. The weight percentage of celecoxib in the nanoparticle composition is 81.3%, the weight percentage of lecithin is 8.02%, and the weight percentage of sodium lauryl sulfate is 10.68%. This is achieved by the following steps: Solvent diffusion: Take celecoxib and lecithin, weigh them accurately, dissolve them in anhydrous ethanol, heat them in a water bath at 60°C if necessary to form an organic phase, dissolve sodium dodecyl sulfate in water as a nanoparticle protective agent to form an aqueous phase. Add the organic phase to the aqueous phase under mechanical stirring at room temperature and 600 rpm, and continue stirring for 10 minutes to form a drug dispersion.

[0009] High-pressure homogenization: Take the above drug dispersion, emulsify it under pressure using a high-pressure homogenizer, control the homogenizer pressure at 80-120 MPa, homogenize it 10 times, and then rotary evaporate to remove the organic solvent to obtain a drug nanoparticle suspension.

[0010] Take celecoxib nanoparticle suspension, add spray drying protective agent to dissolve, control the spray drying inlet temperature: 140°C, outlet temperature: 80°C, material flow rate: 5mL / min, air flow rate: 600L / min, and collect the drug nanoparticle powder.

[0011] The second object of the present invention is to provide a method for preparing a celecoxib nano crystal sheet. The celecoxib nano powder obtained by the above method is mixed evenly with a disintegrant and a filler, a binder is added to make a soft material, sieved, made into particles, dried, a lubricant is added to mix, and tabletted to obtain a celecoxib nano crystal sheet.

[0012] The invention is characterized in that the filler is mannitol, the disintegrant is low-substituted hydroxypropyl cellulose, the binder is hydroxypropyl cellulose which also has a disintegrant effect, and the lubricant is magnesium stearate.

[0013] After the drug is made into nano crystals, the nano powder has good redispersibility and high physical stability. The celecoxib tablets obtained by granulating and tableting celecoxib into nano crystals can maximize the efficacy of the drug and improve its bioavailability. DETAILED DESCRIPTION

[0014] Example 1: Preparation of Celecoxib Nanoparticles Solvent diffusion: Take 200g of celecoxib and 20g of lecithin, weigh accurately, dissolve in 2000mL of anhydrous ethanol, heat in a water bath at 60°C if necessary to form an organic phase, and use 1800mL of 0.5% sodium dodecyl sulfate aqueous solution as a nanoparticle protective agent to form an aqueous phase. Under mechanical stirring at room temperature and 600rpm, add the organic phase to the aqueous phase and continue stirring for 10 minutes to form a drug dispersion.

[0015] High-pressure homogenization: Take the above drug dispersion, emulsify it under pressure using a high-pressure homogenizer, control the pressure of the homogenizer to 100 MPa, homogenize it 10 times, and then rotary evaporate to remove the organic solvent to obtain a celecoxib nanoparticle suspension.

[0016] Example 2: Preparation of Celecoxib Nanoparticle Powder by Spray Drying Take the celecoxib nanoparticle suspension obtained in Example 1, add deionized water to dilute it to a celecoxib concentration of 5 mg / mL, add mannitol (5 g / 100 mL) as a protective agent for dissolution, control the spray drying inlet temperature: 140 ° C, outlet temperature: 80 ° C, material flow rate: 5 mL / min, air flow rate: 600 L / min, and collect the celecoxib nanoparticle powder.

[0017] Example 3: Preparation of Celecoxib Nanocrystalline Tablets Prescription: 1000 tablets, 500g of celecoxib nano powder (containing 100g of celecoxib), 20g of mannitol, 6g of low-substituted hydroxypropyl cellulose, 6g of hydroxypropyl cellulose, 5.5g of magnesium stearate. A total of 1000 tablets.

[0018] Preparation method: Take the prescribed amount of celecoxib nanopowder and mix it thoroughly with mannitol, add low-substituted hydroxypropyl cellulose, mix well, and pass through a 60-mesh sieve; add hydroxymethyl cellulose solution dissolved in anhydrous ethanol as a binder, granulate, pass through an 18-mesh sieve, dry in an oven at 55°C for 10 minutes, take out and pass through a 20-mesh sieve to obtain the whole granules; mix the granules with magnesium stearate and press into tablets to obtain the product.

[0019] Example 4: Dissolution test of celecoxib nanoparticles Take 500 mg of the uncompressed celecoxib nanocrystalline particles prepared in Example 2, 100 mg of celecoxib API, and 500 mg of physical mixture (celecoxib: mannitol = 1:4), and refer to the Chinese Pharmacopoeia 2020 Edition IV, 0931 Dissolution and Release Determination Method 2. Set the speed to 100 r / min, the temperature to (37 ± 0.5) ° C, the dissolution medium to pH 6.8 phosphate buffer containing 0.5% SDS (6.805 g of potassium dihydrogen phosphate and 0.944 g of sodium hydroxide per 1 L of water), sample an appropriate amount of solution at 5, 10, 20, 30, 45, and 60 min, and replenish an equal volume of dissolution medium, filter through a 0.22 μm filter membrane, take an appropriate amount of the filtrate, and detect the celecoxib content by UV method at a wavelength of 254 nm. The results are shown in the following table.

[0020]

[0021] It can be seen from the above table that the celecoxib nanocrystals have been basically dissolved completely in 10 minutes, which is much higher than the physical mixture and the raw material drug, and the dissolution performance is good.

[0022] Example 5: In vitro dissolution test of celecoxib nanocrystalline tablets Take the nanocrystalline tablets and Celebrex Celecoxib capsules prepared in Example 3. According to the Chinese Pharmacopoeia 2020 Edition Part IV, 0931 Dissolution and Release Determination Method, the dissolution medium is a hydrochloric acid solution with a pH of 1.0, the rotation speed is 50r / min, and an appropriate amount of solution is sampled at 5, 10, 20, 30, 45, and 60 minutes, and the same volume of dissolution medium is replenished, filtered through a 0.22μm filter membrane, and the test solution is prepared. The results are determined by high performance liquid chromatography, and the results are shown in the following table:

[0023] From the above table, we can know that the dissolution rate of celecoxib nanocrystalline tablets is basically complete at 60 minutes, greater than 95%, with good dissolution effect, stable dissolution, and no sudden release. The dissolution rate is better than that of Celebrex celecoxib capsules.

Claims

1. The present invention is a celecoxib nanocrystalline tablet for treating osteoarthritis and rheumatoid arthritis and a preparation method thereof. The present invention relates to the field of medical technology, and is a new preparation of celecoxib for treating osteoarthritis and rheumatoid arthritis - a nanocrystalline preparation and a preparation method thereof. The present invention adopts nanocrystallization technology to prepare drug nano powder. Excipients include disintegrants, fillers, and lubricants. The celecoxib tablet obtained by the present invention has good dissolution, and dissolution reaches more than 95% in 60 minutes, and the dissolution is stable, without burst release phenomenon, and can maximize the efficacy of the drug and improve bioavailability.

2. A celecoxib nanocrystalline tablet comprising the following ingredients: Celecoxib Nano Powder 10%-80% Filler 10%-20% Disintegrant 2%-8% Lubricant 0.5%-2% The celecoxib nanocrystalline tablet according to claim 1, characterized in that: The celecoxib nano powder contains 20% celecoxib nano particles, 70% mannitol and 10% sodium lauryl sulfate by weight. After being redispersed in water, the average particle size is less than 500nm.

3. Celecoxib nano-crystalline sheet according to claim 2, the preparation method of its nano powder is characterized in that The spray drying method is prepared by the following steps: Take the celecoxib nanoparticle suspension, add the spray drying protective agent to dissolve it, control the spray drying inlet temperature: 140°C, outlet temperature: 80°C, material flow rate: 5mL / min, air flow rate: 600L / min, and collect the celecoxib nanoparticle powder.

4. The celecoxib nanoparticles according to claim 3, characterized in that: The average particle size of celecoxib nanoparticles is less than 500 nm, with a negative charge and a zata potential of -25 mV-0 mV.

5. The celecoxib nanoparticles according to claim 4, characterized in that: The weight percentage of celecoxib in the nanoparticle composition is 81.3%, the weight percentage of lecithin is 8.02%, and the weight percentage of sodium dodecyl sulfate is 10.68%.

6. The method for preparing the celecoxib nanoparticles according to any one of claims 4 to 5, characterized in that This is accomplished by following these steps: Solvent diffusion: Take celecoxib and lecithin, weigh them accurately, dissolve them in anhydrous ethanol, heat them in a water bath at 60°C if necessary to form an organic phase, dissolve sodium dodecyl sulfate in water as a nanoparticle protective agent to form an aqueous phase. Add the organic phase to the aqueous phase under mechanical stirring at room temperature and 600 rpm, and continue stirring for 10 minutes to form a drug dispersion.

7. High-pressure homogenization: Take the above drug dispersion, emulsify it under pressure using a high-pressure homogenizer, control the homogenizer pressure at 80-120 MPa, homogenize it 10 times, and then rotary evaporate to remove the organic solvent to obtain a drug nanoparticle suspension.

8. The celecoxib nanocrystalline sheet according to claim 1, characterized in that: The filler is mannitol; the disintegrant is low-substituted hydroxypropyl cellulose; the binder is hydroxypropyl cellulose; the stabilizer is sodium lauryl sulfate; and the lubricant is magnesium stearate.

9. The method for preparing the celecoxib nano-crystalline sheet according to claim 1, wherein This is accomplished by following these steps: The celecoxib nano powder obtained by the above method is mixed evenly with a disintegrant and a filler, a binder is added to make a soft material, sieved, made into granules, dried, a lubricant is added to mix evenly, and tabletted to obtain celecoxib nano crystalline tablets.

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