CN104027319A - Celecoxib dispersible tablet and preparation method thereof - Google Patents

Abstract

The invention relates to a celecoxib dispersible tablet and a preparation method thereof. On the premise of guaranteeing good dispersion uniformity, the celecoxib dispersible tablet has high dissolution rate, can be used for overcoming the defect of inconvenience in taking due to large size of the tablet, can be rapidly dispersed in water so as to be taken, has good taste, and can be used for improving the compliance of patients.

Description

A kind of celecoxib dispersible tablet and preparation method thereof

Technical field

The invention belongs to technical field of pharmaceuticals, be specifically related to a kind of celecoxib dispersible tablet and preparation method thereof.

Background technology

U.S. FDA approved in 1998 celecoxib capsule (50mg, 100mg, 200mg, 400mg), and produced listing in 1999 by Pfizer, that one is treated osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, acute pain, also can be used for treating the medicine of primary dysmenorrhea and familial adenomatous polyp, import is called celecoxib, now this medicine is in the U.S., the listing of multiple countries such as Japan, within 2007, celecoxib is approved for again back pain, the treatment of scapulohumeral periarthritis and tenosynovitis, the expansion of indication, will bring undoubtedly larger market, larger demand.

Celecoxib is domesticly granted import first in August, 2000, and the indication of approval is osteoarthritis, rheumatoid arthritis and adult's acute pain, and ratify again for ankylosing spondylitis indication in October, 2012.Two of current granted imported materials medicine and capsule Jin You Pfizer and SearleL, the domestic producer of also not going on the market.

NSAID (non-steroidal anti-inflammatory drug) is widely used in the treatment of osteoarthritis and rheumatoid arthritis; celecoxib is a kind of NSAID (non-steroidal anti-inflammatory drug) of a new generation; there is unique mechanism of action and suppress specifically COX-2; owing to not acting on COX-1; do not affect PG12 synthetic that gastrointestinal tract and kidney is had to protective effect, gastrointestinal side effect and nephrotoxicity are all little than general NSAID (non-steroidal anti-inflammatory drug).

Within 1994, G.D Se Er company of the U.S. has applied for patent in China, and publication number is CN1141630, has reported compound 4-[5-(4-tolyl)-3-(trifluoromethyl)-1 hydrogen-1-pyrazol-1-yl in patent] benzsulfamide, i.e. celecoxib; And a claimed class 1, the method for 5-diaryl pyrrole and salt thereof and the described compound of preparation, the chemical constitution of celecoxib is as follows:

Celecoxib is the low dissolving that belongs to BCS II, high infiltration types of drug, and it is almost insoluble in water, is only 3.3mg/L, administration absorbs good on an empty stomach, within 2-3 hour, just reach the highest blood drug level, with clothes, can postpone to reach for 1-2 hour the highest blood drug level in high lipid food.

In world patent WO0142222, describe two kinds of crystal formations of crystalline form I and II, in WO2006051340, described crystal formation N, in the time preparing tablet, easily form the long acicular crystal crystalline state of viscosity, in the time mixing with adjuvant, easy coalescent in bulk, with adjuvant layering, cause uniformity of dosage units defective; WO0390731, the patent such as WO0309122 and WO2005014546 has disclosed DMF, DMSO and NMP cocrystallization thing, and these patents are all concentrated the physicochemical property of improving celecoxib, improves the bulk density of celecoxib, but make this crystal formation, when having increased technical process, also increased cost; World patent WO0032189(Chinese patent CN99802185.7) in described one and passed through powder material, controlling its optimum particle diameter is 5～7 microns, can the most effectively improve stripping, improve bioavailability, and find that particle diameter is less, absorb faster, but its caking property, while making to pulverize, easily adhere to or bond agglomeratingly, having increased micronized difficulty; In Chinese patent CN102000018A, having described one adopts fusion method to prepare solid dispersion crude drug and Polyethylene Glycol, overcome the difficult deficiency of pulverizing of crude drug, improve dissolution and bioavailability, but the method preparation temperature is high, the Polyethylene Glycol viscosity of melting is large, the melting of celecoxib crude drug is slow, is difficult for evenly mixing, and operation easier is larger.

Through constantly experiment, we are surprised to find that celecoxib raw material and specific adjuvant, be prepared into after corresponding preparations, can not only overcome the deficiency of crude drug character, and can also reduce kind and the consumption of adjuvant, by the simplest technique, reach higher bioavailability, good patient compliance, and preparation stabilization, easy and simple to handle, favorable reproducibility.

Summary of the invention

Celecoxib dispersible tablet involved in the present invention, is characterized in that overcoming the inconvenient difficulty of taking being caused more greatly by preparation specification, and said preparation can comparatively fast be scattered in wet suit use, and good mouthfeel can improve patient's compliance.

The present invention is mainly achieved through the following technical solutions, in being adopted, celecoxib crude drug adds the mode of silicon dioxide, be equipped with the specific adjuvants such as filler, disintegrating agent, wetting agent, fluidizer, lubricant, correctives, surfactant and be prepared into dispersion tablet form, effectively improve dispersing uniformity, overcome the deficiency of the existing physicochemical property of celecoxib, improve stripping and bioavailability, reduced cost.

The preparation of celecoxib dispersible tablet, its percentage by weight is composed as follows:

Celecoxib 40%～80%

Filler 10%～60%

Disintegrating agent 5%～20%

Fluidizer 0.5%～5%

Lubricant 1%～3%

Correctives 0.5%～3%

Surfactant 0.5%～3%

Wherein said filler is selected from a kind of and several in mannitol, lactose, microcrystalline Cellulose, calcium hydrogen phosphate, starch, sucrose, sorbitol, preferably lactose, one or more of mannitol, more preferably lactose.

Wherein said disintegrating agent is one or more in micropowder silica gel, low-substituted hydroxypropyl methylcellulose, cross-linking sodium carboxymethyl cellulose, sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, pregelatinized Starch, be preferably one or more in micropowder silica gel, low-substituted hydroxypropyl methylcellulose, polyvinylpolypyrrolidone, one or more in more preferably micropowder silica gel, low-substituted hydroxypropyl cellulose.

Wherein said fluidizer is one or more in silicon dioxide, differential silica gel, Pulvis Talci, is preferably one or more in micropowder silica gel, Pulvis Talci.

Wherein said lubricant is one or more in stearic acid, magnesium stearate, calcium stearate, hard paraffin, is preferably magnesium stearate.

Wherein said correctives is one or more in sucralose, acesulfame potassium, Mentholum, aspartame, saccharin sodium, xylitol, apple essence, flavoring orange essence, citric acid, be preferably one or more in sucralose, acesulfame potassium, Mentholum, aspartame, xylitol, more preferably one or more in sucralose, Mentholum.

Wherein said surfactant is one or more in sodium lauryl sulphate or tween 80 (polyoxyethylene sorbitan monooleate dehydration), is preferably sodium lauryl sulphate.

In addition, prescription adopts wet granulation, and wherein wetting agent used is one or more in purified water, 10%～40% alcohol water, glycerol, is preferably one or more in purified water, 20%～30% alcohol water.

In described wetting agent consumption accounts for, add 15%～50% of material total amount, be preferably 20%～40%, more preferably 25%～35%.

The present invention also provides the preparation method of above-mentioned celecoxib dispersible tablet:

1) by crude drug celecoxib and each adjuvant, cross respectively 80 mesh sieves, for subsequent use;

2) press recipe quantity weighting raw materials celecoxib and each adjuvant, be placed in wet mixing pelletizer, after mix homogeneously, add wetting agent to make soft material, use oscillating granulator 18～24 mesh sieves by soft material granulation, wet granular is placed in to 50 DEG C～70 DEG C baking ovens dry;

3), by the granule that obtains after drying, cross 30 mesh sieve granulate with oscillating granulator, and add fluidizer and lubricant to be mixed evenly;

4) will mix rear material, use rotary tablet machine tabletting, after two aluminum packagings, obtain celecoxib dispersible tablet.

Described higher compliance is because at present clinical preparation specification is larger, and the formulation characteristic of dispersible tablet can overcome because swallowing the difficulty of taking that inconvenience causes, and is scattered in water, and good mouthfeel, can improve patient's compliance preferably.

Described to overcome stripping low, and the not high deficiency of bioavailability, for to add specific adjuvant by screening, is aided with after technique preparation, can effectively improve and improve dispersing uniformity, and it is low to overcome stripping, the deficiency that bioavailability is not high.

Detailed description of the invention

By following object lesson, can more specifically understand the present invention, but the present invention is not limited to following embodiment.

embodiment:the existence form of this embodiment is tablet.(in every 1000 amounts)

embodiment 1:

embodiment 2:

embodiment 3:

embodiment 4:

embodiment 5:

embodiment 6:

embodiment 7:

preparation method:

1), by above-mentioned each prescription Raw medicine celecoxib and adjuvant, lactose, (micropowder silica gel), low-substituted hydroxypropyl cellulose, sodium lauryl sulphate, sucralose, Mentholum, Pulvis Talci, magnesium stearate are crossed respectively 80 mesh sieves, for subsequent use;

2) by above-mentioned each recipe quantity weighting raw materials celecoxib, lactose, (micropowder silica gel), low-substituted hydroxypropyl cellulose (inside adding), sodium lauryl sulphate, in wet mixing pelletizer, stirring and evenly mixing, add after pure water soft material processed, with oscillating granulator 24 mesh sieves granulations, the wet granular making is placed in to 60 DEG C of baking ovens, and being dried to moisture is 2% and following, with oscillating granulator 30 mesh sieve granulate;

3) take low-substituted hydroxypropyl cellulose (additional), sucralose, Mentholum, Pulvis Talci, magnesium stearate by above-mentioned each recipe quantity and be placed in three-dimensional mixer, mix homogeneously together with granule after arrangement;

4) get the material after mixing, with rotary tablet machine φ 11 flat stampings, and packaging.

Make respectively 1,2,3,4,5,6,7 by above-mentioned prescription.

dispersing uniformity experiment

Investigate foundation: " Chinese Pharmacopoeia " version annex I rules of preparations dispersing uniformity experiment in 2010.

Concrete grammar: get 6 of test samples, put in 250ml beaker, add the water 100ml of 15 DEG C～25 DEG C, jolting 3 minutes, all disintegrate is also by No. two sieves.

Specific experiment data see the following form:

Test	1	2	3	4	5	6	7
								Time	3min10s	1min27s	1min30s	2min	1min54s	2min10s	2min

2-7 dispersing uniformity all meets the relevant regulations in " Chinese Pharmacopoeia " as seen from the above table, and dispersing uniformity is qualified, and 1 dispersing uniformity is defective.

Therefore can reach a conclusion, inside add the dispersing uniformity that a part of silicon dioxide contributes to improve said preparation.

stripping experiment

1-7 sample and listing product (the celecoxib 200mg specification of Pfizer Inc.) contrast are carried out to In Vitro Dissolution experiment, and specific operation process is as follows:

Stripping investigation method: two annex XD of " Chinese Pharmacopoeia " version in 2010, bis-method slurry methods

Dissolution medium: 0.04M tertiary sodium phosphate and 1.0% sodium lauryl sulphate

Stripping volume: 1000ML

Rotating speed: 50 turn/min

Temperature: 37 DEG C

Sampling time point: 10min, 20min, 30min, 45min, 60min

Assay method: ultraviolet spectrophotometer

Measure wavelength: 250nm

External contrast stripping experimental result:

As seen from the above table, the stripping of embodiment of the present invention 2-6 is all better than the product capsule preparations that goes on the market, and 1(adds micropowder silica gel without interior) stripping, slightly lower than listing product capsule.

Therefore reach a conclusion, celecoxib dispersible tablet prepared by celecoxib principal agent and specific adjuvant, dispersing uniformity is qualified, and tool is compared with high-dissolution.

Claims (10)

1. a celecoxib dispersible tablet, it is characterized in that containing the dosage unit that one or more can oral release, the celecoxib crude drug that each dosage unit contains 20mg-500mg, in employing, add the mode of silicon dioxide, be equipped with filler, disintegrating agent, wetting agent, fluidizer, lubricant, correctives, surfactant and be prepared from.

2. celecoxib dispersible tablet as claimed in claim 1, is characterized in that, adds dioxide-containing silica in described to account for 1%～8% of recipe quantity preferably 2%～7%, more preferably 3%～5%.

3. celecoxib dispersible tablet as claimed in claim 1, is characterized in that wherein:

1) consumption of filler accounts for 10%～60% of recipe quantity;

2) consumption of disintegrating agent accounts for 5%～20% of recipe quantity;

3) consumption of fluidizer accounts for 0.5%～5% of recipe quantity;

4) consumption of lubricant accounts for 1%～3% of recipe quantity;

5) consumption of correctives accounts for 0.5%～3% of recipe quantity;

6) consumption of surfactant accounts for 0.5%～3% of recipe quantity;

7) consumption of celecoxib accounts for 40%～80% of recipe quantity.

4. celecoxib dispersible tablet as claimed in claim 1, it is characterized in that described filler is selected from one or more in mannitol, lactose, microcrystalline Cellulose, calcium hydrogen phosphate, starch, sucrose, sorbitol, preferably one or both in lactose, mannitol.

5. celecoxib dispersible tablet as claimed in claim 1, it is characterized in that described disintegrating agent is one or more in micropowder silica gel, low-substituted hydroxypropyl methylcellulose, cross-linking sodium carboxymethyl cellulose, sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, pregelatinized Starch, one or more in preferably micropowder silica gel, low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone.

6. celecoxib dispersible tablet as claimed in claim 1, is characterized in that described wetting agent is the alcohol water of purified water or 10%～40%.

7. the celecoxib dispersible tablet as described in claim 1,6, is characterized in that wetting agent wherein used is one or more in purified water, 10%～40% alcohol water, glycerol, is preferably one or more in purified water, 20%～30% alcohol water.

8. celecoxib dispersible tablet as claimed in claim 1, is characterized in that described fluidizer is one or more in silicon dioxide, micropowder silica gel, Pulvis Talci, is preferably one or both in micropowder silica gel, Pulvis Talci; Described lubricant is one or more in stearic acid, magnesium stearate, calcium stearate, hard paraffin, preferably magnesium stearate.

9. celecoxib dispersible tablet as claimed in claim 1, it is characterized in that described correctives is one or more in sucralose, acesulfame potassium, Mentholum, aspartame, saccharin sodium, xylitol, apple essence, flavoring orange essence, citric acid, preferably one or more in sucralose, acesulfame potassium, Mentholum; Described surfactant is one or more in sodium lauryl sulphate or tween 80 (polyoxyethylene sorbitan monooleate dehydration), is preferably sodium lauryl sulphate.

10. the celecoxib dispersible tablet as described in arbitrary claim in claim 1～10, is characterized in that its preparation method is:

1) by celecoxib and each adjuvant, all cross 80 mesh sieves, for subsequent use;

2) by principal agent and each adjuvant, mix homogeneously, adds wetting agent to make soft material, crosses 18～24 mesh sieve granulations, and wet granular is dry in 50 DEG C～70 DEG C baking ovens;

3) granule obtaining after drying is crossed to 30 mesh sieve granulate, add fluidizer and lubricant to mix;

4) will mix rear material, tabletting, packaging, obtains celecoxib dispersible tablet.