CN102949403A - Celecoxib composition, and preparation method and application thereof - Google Patents
Celecoxib composition, and preparation method and application thereof Download PDFInfo
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- CN102949403A CN102949403A CN2011102437461A CN201110243746A CN102949403A CN 102949403 A CN102949403 A CN 102949403A CN 2011102437461 A CN2011102437461 A CN 2011102437461A CN 201110243746 A CN201110243746 A CN 201110243746A CN 102949403 A CN102949403 A CN 102949403A
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Abstract
The invention provides a celecoxib composition which contains one or a plurality of dose units releasable through oral administration. Each dose unit contains 50 to 500 mg of a mixture of a celecoxib D97 particle and one or a plurality of medicinal excipients. The composition can be used for treating or preventing diseases caused by COX-2.
Description
Technical field
The invention belongs to medical technical field, be specifically related to contain active component celecoxib (Celecoxib, trade name celecoxib) can oral release pharmaceutical composition and its production and use.
Background technology
U.S. G.D Se Er company had applied for patent in China in 1994; publication number is CN1141630; reported chemical compound 4-[5-(4-aminomethyl phenyl-3-(Trifluoromethyl-1 H-pyrazol-1-yl) benzsulfamide (celecoxib) in the patent; and a claimed class 1, the method for 5-diaryl pyrazole and salt thereof and the described chemical compound of preparation.Celecoxib has lower array structure:
Patent report this chemical compound can be used for treating inflammation and with the disease of inflammation-related.Preparation is oral dosage form such as Tablet and Capsula agent.
The people such as Simon were at Arthritis and Rheumatism in 1998, the 41st volume, numbering 9, in JIUYUE, 1998 delivered " celecoxib; a kind of safety of new cox 2 inhibitor and the preliminary study of effectiveness ", described the research of celecoxib effectiveness and safety in treatment osteoarthritis and rheumatic arthritis in the article.
Up to now, the effective oral Preparation of celecoxib because the physics and chemistry character of described chemical compound uniqueness, particularly its low solubility and the factor relevant with its crystalline texture comprise caking property, low bulk density and low compressibility complicated.Celecoxib is insoluble in the water-bearing media unusually.For example, when with the Capsule form oral administration, the celecoxib of preparation is not easy to dissolve and disperse, thereby can not absorb rapidly in gastrointestinal tract.
In addition, when tabletting on the tablet machine drift film, the not preparation celecoxib with easy formation viscosity minute hand shape crystallization crystalline state easily is fused into monoblock.Even when mixing with other material, the celecoxib crystallization or easily and other separating substances and in described compositions mixed process coalescent in bulk, produce the large polymeric compositions of comprising of inhomogeneous mixing of unwanted celecoxib.Therefore, preparation has required mixing homogeneity, the pharmaceutical composition that comprises celecoxib is difficult.And, comprise in the pharmaceutical composition of celecoxib in preparation, also can run into the processing problem.For example, the low bulk density of celecoxib so that in compounding pharmaceutical compositions process the difficult treatment of desired small amounts of material.Therefore, need to solve with preparation and comprise the particularly relevant a large amount of problems of oral dosage units of the pharmaceutical composition that suits of celecoxib and dosage form.
Especially, compare with celecoxib or other celecoxib compositions of not preparation, oral celecoxib preparation need to have one or more following properties:
(1), dissolubility improves;
(2), disintegration time shortens;
(3), dissolution time shortens;
(4), the fragility of tablet reduces;
(5), the hardness of tablet increases;
(6), wettability is improved;
(7), compressibility is improved;
(8), the flowability of liquid and granulated solid composition is improved;
(9), the physically stable property improvement of final product composition having;
(10), the size of tablet or capsule reduces;
(11), mixing homogeneity improves;
(12), dose uniformity improves;
(13), in encapsulated or tabletting process, the control and improvement of weight differential;
(14), the grain density of wet granulation increases;
(15), the needed water of wet granulation reduces;
(16), the time decreased of wet granulation;
(17), reduce the drying time of wet granulation mixture.
Summary of the invention
In order to solve above-mentioned technical problem, the present invention now provides a kind of pharmaceutical composition, said composition comprises one or more dosage units that can oral release, and each dosage unit comprises about 50mg to the celecoxib granule that closely mixes with one or more pharmaceutically acceptable excipient of 500mg.
In one embodiment, compositions has granule maximum magnitude D
97(90% sample particle is less than D to be lower than 200 μ m
97Value) the main particle size distribution of celecoxib.
The dosage unit that contains said composition can be the solid form that separates such as tablet, pill, hard or Perle, lozenge, sachet or fragrant ingot; In addition, compositions can be the basic uniformly form of flowable mass, and such as granule or granular solid or liquid suspension body, wherein single dosage unit is therefrom to shift out with the degree that can measure.Also provide a kind of in need to be with the patient of cox 2 inhibitor treatment the method for medical condition or disease, comprise once a day or orally give compositions of the present invention twice.
Pharmaceutical composition of the present invention is release composition immediately preferably, during the patient of the disease that causes at the oral COX-2 of suffering from described disease is alleviated.
Compositions of the present invention contains the celecoxib of particle form.As by grinding or grind or primary granule by Precipitation from solution can being agglomerated into the secondary flocculated particle, unless otherwise indicated herein, term as used herein " granule footpath " refers to the maximum magnitude of primary granule size.Believe that granular size is the important parameter that affects the celecoxib clinical effectiveness.Therefore, in the embodiment, the celecoxib particle size distribution of the present composition is the D of its maximum magnitude granule
97Less than 200 μ m, preferably less than 50 μ m, be more preferably less than 30 μ m, most preferably less than 20 μ m.According to embodiment of the present invention, the minimizing in celecoxib granule footpath improves its bioavailability usually.
Having been found that and be with the water for ball milling celecoxib before forming compositions of the present invention with mixed with excipients in ball mill, is that effectively but also for overcoming the problem relevant with celecoxib crystal adhesion characteristic also is favourable during mixing or fusion for improving bioavailability not only.The celecoxib that does not grind or the celecoxib that can grinder grinds with the grinder of other type such as liquid are more bonding than using celecoxib with water for ball milling to be easier to, and the latter during mixing is not easy to condense the secondary condensation product that forms the celecoxib granule.Reduce to condense and can improve the uniformity that rod closes, this is particular importance for the preparation unit dosage form such as capsule and tablet.This result is very unexpected with comparing in the practicality of the liquid energy grinder shown in the preparation of preparation other medicines chemical compound such as aerojet grinder.Be not subjected to the constraint of particular theory, suppose with water for ball milling the celecoxib crystal formation of minute hand shape to be become the more uniform crystal form that is more suitable for mixing purpose, and minute hand shape crystal be easier to keep in the aerojet process of lapping.
Also have been found that by coming pharmaceutical compositions can further improve the uniformity of mixing with the carrier material wet granulation celecoxib.It is all the more so when particularly employed celecoxib parent material is by the band water for ball milling.Band water for ball milling celecoxib parent material is so that granular size reaches requirement mentioned above, and then wet granulation is desirable especially.
In the embodiment, the new pharmaceutical composition of the present invention contains celecoxib and one or more are selected from carrier material or the excipient of diluent, disintegrating agent, binding agent, wetting agent and lubricant.Preferably, at least a carrier material is water miscible diluent or wetting agent.This water-soluble diluent or wetting agent help dispersion and the stripping of celecoxib when pharmaceutical composition is taken in.Preferably, water-soluble diluent and wetting agent exist simultaneously.But the present composition can be material such as granule or granular solids or the liquid of basically Uniform Flow, perhaps can be the form of disperseing, such as capsule or the tablet that all contains single dose unit.
But in the compositions of Uniform Flow basically, single dose unit can take out with suitable volume measurement device such as spoon or cup with measuring.Suitable flowable mass includes but not limited to powder and granule.In addition, flowable mass is that the celecoxib of solid particle phase form is dispersed in the suspension that liquid phase is preferably aqueous phase.When this suspension of preparation, use wetting agent seemingly favourable such as polysorbate vinegar 80.Suspension can be dispersed in liquid phase by the celecoxib that will grind and prepare; In addition, celecoxib can from solvent such as alcohol, be precipitated out in the solution in the preferred alcohol.Water preferably contains agreeable to the taste carrier such as water, syrup or fruit juice (for example Sucus Mali pumilae).
The practicality of the present composition
The present composition can be used for treating and prevents the various diseases that caused by COX-2.Described compositions can be used for but the inflammation that is not limited to treat the patient, for example treats pain and headache and as antipyretic treatment fever as analgesics.For example, said composition can be used for the treatment of arthritis disease include but not limited to rheumatoid arthritis, vertebral arthropathy, gout ossa articularia arthritis, systemic lupus erythematosus (sle) and childhood arthritis.Said composition also can be used for treating asthma, bronchitis, dysmenorrhea, premature labor, key inflammation, bursitis, anaphylaxis neuritis, cytomegalovirus infection, lumbago, hepatopathy and comprises that hepatitis, the disease relevant with skin such as psoriasis, eczema, seat skin ulcer, ultraviolet injury, burn and dermatitis and post-operation inflammatory comprise inflammation behind ophthalmologic operation such as cataract operation or the refractive surgery.The present composition can be used for treating gastrointestinal disease such as enteritis, Crohn disease, gastritis, zest bowel syndrome and ulcerative colitis.Described compositions can be used for treating inflammation, and these diseases such as migraine, polyarteritis nodosa, thyroiditis, aplastic anemia, hodgkin's disease, scleroderma, rheumatic fever, type i diabetes, neuromuscular junction disease comprise that myasthenia gravis, white matter disease comprise multiple sclerosis, sarcoidosis, the nephrotic syndrome, Behcets disease, polymyositis, heel inflammation.The swelling that nephritis, allergy, damage occur afterwards comprises cerebral edema, myocardial ischaemia etc.Described compositions can be used for treating ophthalmic diseases, such as retinitis, conjunctivitis, retinopathy, uveitis, eye light dread and ocular tissue's acute injury.Described compositions can be used for treating pneumonia, such as the pneumonia relevant with viral infection and wing muscle fiber pathological changes, and can be used for treating bone resorption disease such as the bone resorption relevant with osteoporosis.Described compositions can be used for treating the central nervous system injury that some central nervous system disease such as cortex dementia comprise presenile dementia, neurodegenerative disease and cause because of apoplexy, ischemia and wound.Term herein " treatment " comprises dull-witted part or all of inhibition, and dementia comprises Alzheimer’s disease, vascular dementia, presenile dementia, alcoholic dementia and senile dementia.
The present composition is useful as anti-inflammatory agents particularly, such as treatment of arthritis, and additional advantage is arranged, and NSAID (non-steroidal anti-inflammatory drug) (NSAIDs) compositions than routine has obviously low harmful side effect exactly.Described compositions can be used for treatment of allergic rhinitis, respiratory distress syndrome, endotoxin shock syndrome and hepatopathy.Described compositions can be used for treating pain, includes but not limited to postoperative pain, toothache, myalgia and the pain that is caused by cancer.
Described compositions can be used for but is not limited to treat and the patient of the cardiomyopathy of prevention and inflammation-related.Described compositions can be used for treatment and prevents angiopathy, coronary artery disease, aneurysm, blood vessel repulsion, arteriosclerosis, atherosclerosis.
Compositions of the present invention has being similar to or is better than the antiinflammatory of conventional NSAIDs compositions, analgesic and analgesic properties.Described compositions is the inhibitory hormone uterine contraction of inducing and have potential antitumaous effect also, but reduces the ability of some mechanism side effect that conventional NSAIDs induces.Particularly, compare with conventional NSAIDs compositions, the present composition has the gastrointestinal toxicity of reducing and the irritating ability of gastrointestinal, comprise upper stomach intestinal ulcer and hemorrhage, reduce the renal hypofunction of ability as causing liquid detention and hypertension to increase the weight of of kidney side effect, reduce the impact in bleeding time is comprised the hematoblastic function of inhibition, and may reduce to induce in the aspirin sensitivity asthmatic patient energy of asthma attack.
The preferred effectiveness of pharmaceutical composition of the present invention is to be used for the treatment of rheumatoid arthritis and osteoporosis, be used for alleviation, the treatment of presenile dementia and the chemoprophylaxis of colon cancer of pain (particularly postoperation of oral cavity pain, general surgical postoperative pain, orthopedics's postoperative pain and acute burst osteoarthritis).
The form of the present composition
Pharmaceutical composition of the present invention comprises celecoxib and one or more and is applicable to oral administration, preferred nontoxic pharmaceutically useful carrier, excipient and auxiliary agent (this paper is referred to as " carrier mass " or " excipient ").Carrier mass must be acceptable aspect the compatibility of other component of the present composition and must be harmless to the user.The present composition can be by selecting suitable carrier mass and to the effective celecoxib dosage of described treatment, suiting by any suitable oral administration.Therefore, employed any carrier mass can be that solid or liquid or the two have concurrently, and described compositions preferably comprises about 1-95%, preferably approximately 10-90%, more preferably about 25-85%, the further celecoxib of 30-80% weight preferably approximately.Described pharmaceutical composition of the present invention can comprise that the blending ingredients technology prepares by any known pharmaceutical technology.
The every dosage unit of the present composition comprises requirement Celecoxib and can be following dosage form, for example tablet, pill, hard or soft capsule, dragee, cachet, the powder that can adjust, granule, suspension, the agent of indulging in, liquid or be applicable to any other form of oral administration.Preferably, described compositions can be prepared into the discrete doses unit form that respectively contains the amount of pre-determining Celecoxib, such as tablet or capsule.For example, these oral dosage unit form can further comprise buffer agent.In addition, tablet, pill etc. can with or do not prepare with coating materials.
Carrier mass or excipient
As mentioned above, every dosage unit of pharmaceutical composition of the present invention comprises treatment or prevents effective dose celecoxib and one or more to be applicable to pharmaceutically suitable carrier material of oral administration.The present composition preferably comprises celecoxib and one or more carrier mass of requirement, and described carrier mass is selected from pharmaceutically acceptable diluent, disintegrating agent, binding agent, sticker, wetting agent, lubricant and antitack agent.More preferably, with capsule or the tablet form tabletting or encapsulated for use in conventional administration of described compositions to discharge immediately.
Diluent
Pharmaceutical composition of the present invention can not comprise or comprise one or more pharmaceutically acceptable diluents as carrier mass.Suitable diluent comprises alone or in combination lactose, Lactis Anhydrous, spray-dired lactose, starch, the starch of directly compressible, mannitol, Sorbitol, Dextrose monohydrate, microcrystalline Cellulose, alkali calcium phosphate, polyethylene and adjoins pyrrolidone etc.Described diluent accounts for about 5-99% of composition total weight, preferred 10-85%, selected diluent have suitable mobile and, if tablet also requires to have compressibility.
Disintegrating agent
Pharmaceutical composition of the present invention comprises one or more pharmaceutically acceptable disintegrating agents as carrier mass, particularly for tablet.Suitable disintegrating agent comprises the corn starch of alone or in combination starch, sodium starch glycollate, cellulose (such as pure cellulose, methylcellulose, sodium carboxymethyl cellulose and carboxymethyl cellulose), alginate, pregelatinized, crosslinked polyvidone and natural gum (such as agar, guar gum, locust bean gum, karaya, pectin and Calculus Bovis from Northwest of China Cao glue).
Disintegrating agent can in any step of preparation pharmaceutical composition of the present invention, particularly add in the lubricated step before granulation or before tabletting.Described disintegrating agent accounts for about 0.2-30% of composition total weight, 0.2-10% preferably approximately, and more preferably about 0.2-5%.
Binding agent and sticker
Pharmaceutical composition of the present invention can not comprise or comprise one or more pharmaceutically acceptable binding agents or sticker as carrier mass, particularly for tablet.Preferably, described binding agent and sticker provide enough viscosity to the tabletting powder, allowing normal operation as adjusting size, lubricated, tabletting and packing, and when further when taking in, make described tablet energy disintegrate and described compositions can be absorbed.Suitable binding agent and sticker comprise the alone or in combination arabic gum, Calculus Bovis from Northwest of China Cao glue, sucrose, gelatin, glucose, starch, cellulosic material is as including, but are not limited to methylcellulose and sodium carboxymethylcellulose (as: Tylose), alginic acid and alginate thereof, Magnesiumaluminumsilicate, Polyethylene Glycol, guar gum, polysaccharide acid, bentonite, polyethylene adjoins pyrrolidone, the polyisobutylene ester, hydroxypropyl emthylcellulose (HPMC), propyl cellulose (Klucel), ethyl cellulose (Ethocel), the starch of pregelatinized (such as National 1551 and National 1550).If exist, described binding agent accounts for about 0.5-25% of composition total weight, 0.75-15% preferably approximately, and more preferably about 1-10%.
Wetting agent
In the extremely water insoluble solution of celecoxib.Therefore, pharmaceutical composition of the present invention preferably comprises one or more pharmaceutically acceptable wetting agent as carrier mass, to improve pharmaceutical composition relative bioavailability of the present invention.Suitable wetting agent comprises alone or in combination oleic acid; Glyceryl monostearate; Dehydrated sorbitol mono-fatty acid ester; Sorbitan monolaurate; Emulphor FM; Polysorbate 80; Tween 20; Enuatrol; Sucrose fatty acid ester and sodium lauryl sulphate.Anion surfactant type wetting agent is preferred.If exist, described wetting agent accounts for about 0.25-15% of composition total weight, 0.4-10% preferably approximately, and more preferably about 0.5-5%.
Sodium lauryl sulphate is preferred wetting agent.If exist, described sodium lauryl sulphate accounts for about 0.25-7% of composition total weight, more preferably about 0.4-6%, and further 0.5-5% preferably approximately.
Lubricant
Pharmaceutical composition of the present invention can not comprise or comprise one or more pharmaceutically acceptable lubricants and/or fluidizer as carrier mass.Suitable lubricant and/or fluidizer comprise alone or in combination stearate (magnesium stearate, calcium and sodium); Stearic acid; Hydrogenated vegetable oil (for example Sterotex); Pulvis Talci; Wax; Stearowet; Boric acid; Sodium benzoate; Sodium acetate; Fumaric acid sodium; Sodium chloride; DL one leucine; Polyethylene Glycol (for example Macrogol 4000 and polyethylene glycol 6000); Enuatrol; Sodium lauryl sulphate and Stepanol MG.If exist, described lubricant accounts for about 0.1-10% of composition total weight, 0.2-8% preferably approximately, and more preferably about 0.25-5%.
For example, magnesium stearate is preferred, is used for the lubricant that rubs between minimizing equipment and the granulation mixture in the tabletting process.
The capsule release conditions
Capsule of the present invention and tablet composition be release composition immediately preferably, and when external test, afterwards in about 45 minutes, described compositions discharges about at least 60% celecoxib in absorption.More preferably, they discharge about at least 70% celecoxib in about 45 minutes afterwards in absorption.Further preferably, they discharge about at least 85% celecoxib in about 45 minutes afterwards in absorption.
The method for preparing the celecoxib compositions is as follows
The present invention also relates to the micronized method of celecoxib, in the preparation process of compositions, at first that celecoxib (if necessary, with water) is levigate or micronize arrives desired granularity.Although can use grinder or the lapping machine of various routines, compare with the grinding of other type, can make final microgranule obtain desirable particle diameter with the acicular crystal of water for ball milling celecoxib.Essential and do not need to utilize the cooled with liquid nitrogen celecoxib may in process of lapping, be heated to unwanted temperature.As mentioned above, in this grinding steps, the D97 granularity reduced to be lower than about 200 μ m, preferably be lower than about 100 μ m, more preferably less than about 75 μ m, further more preferably less than about 40 μ m, and most preferably be lower than the bioavailability that about 20 μ m can increase celecoxib greatly.
The present invention also relates to prepare the method for the pharmaceutical composition that comprises celecoxib.Especially, the present invention relates to comprise the method for the pharmaceutical composition of particulate form celecoxib.Especially, the present invention relates to prepare the method for celecoxib compositions, described compositions exists with discrete unit dose tablet or Capsule form, wherein comprises approximately 12-24 hour therapeutical effect amount celecoxib of enough generations in each tablet or the capsule.For example, each dosage unit preferably comprises the celecoxib of about 100mg-200mg.According to the present invention, can prepare tablet of the present invention or capsule compositions with wet granulation, dry granulation or direct compression or encapsulated method.
Description of drawings
Fig. 1 is the flow chart that the representational method of the pharmaceutical composition of the present invention for preparing capsule form is described,
Fig. 2 is the flow chart that the method for the pharmaceutical composition of the present invention for preparing tablet form is described.
The specific embodiment
The following example is used for explanation the present invention and the present invention is not construed as limiting.Hereinafter discussed in more detail for generation of shown in the experimental technique of data.The symbol that uses in these embodiments is consistent with convention with employed those of pharmacy literature in the same period.If not special explanation, (i) all percent by weight of narrating in these embodiments are based on the percentage by weight that general composition weight meter is calculated so, (ii) total composition weight of capsule is total capsule-filling weight and the weight that does not comprise used capsule shells itself, and (iii) coated tablet is about 3% of coated tablet gross weight with the weight of conventional material such as OpadryWhite YS-1-18027A coating and coating material.
Provided the preparation example of the many gelatine capsules in the scope of the invention in the following example.Described embodiment makes the reader can be clearer: gelatine capsule agent of the present invention, tablet and their preparation method; Radio-opaque distal marking in the scope of the invention is apparent for the pharmaceutical science worker, and their preparation also to be pharmaceutical science worker's ability can reach.
In each embodiment, given first the inventory of used material, it is to prepare single dose 100mg, 200mg, represents by the form of the amount of every kind of used component of 1000 (sheet) preparation amounts.After providing used BOM, according to given device description preparation process.
Embodiment 1
The capsule that preparation has following compositions:
Embodiment 2
The capsule that preparation has following compositions:
Embodiment 3
The capsule that preparation has following compositions:
Embodiment 4
The capsule that preparation has following compositions:
Embodiment 5
The capsule that preparation has following compositions:
Embodiment 6
The capsule that preparation has following compositions:
Embodiment 7
The capsule that preparation has following compositions:
Embodiment 8
The capsule that preparation has following compositions:
Embodiment 9
The capsule that preparation has following compositions:
Embodiment 10
The capsule that preparation has following compositions:
Embodiment 1-10 is applicable: feed intake by 5000 amounts of formula preparation in batches for the wet granulator with high shear force of 1kg, place wet granulator to add successively sodium lauryl sulphate, polyvinylpyrrolidone, cross-linking sodium carboxymethyl cellulose, add or do not add sucrose fatty acid ester micronized celecoxib and stirred 30 minutes; Add lactose, add or do not add 2 minutes mix homogeneously of microcrystalline Cellulose continuation stirring with identical method.Water soft material processed is granulated in oscillating granulator 24 mesh sieves, and with the wet granular that makes in 60 ℃ of baking ovens dry 4 hours, with adding magnesium stearate mix homogeneously behind the 30 orders concussion sieve granulate.Then with in particle packing to 1 gelatine capsule of mixing or be processed into special-shaped tablets.
Prepare the tablet coating suspension with following method: press solid content 12%, weightening finish 3%.Take by weighing coating powder, slowly add in the pure water in stirring (liquid level has just had whirlpool), dispersed with stirring is even, continues to stir 45 minutes, and 100 eye mesh screens filter, and get final product.Coating pan is with 35 rev/mins of rotating speeds, and temperature 45-50 ℃ adds label preheating 5-10 minute; Regulate compressed air ejection liquid is well atomized, beginning coating, the complete continuation of coating dry 30-40 minute.
Embodiment 11
D
97The bioavailability of raw material (particle diameter＜5 μ m)
Select 12 of the healthy Beagle dogs of 9～10.5kg, each 6 of male and female, animal is divided into following three groups at random: the celecoxib of (1) intravenous injection 0.5mg/kg body weight, then the celecoxib of intravenous injection 5.0mg/kg body weight for the second time, (2) celecoxib of the 5.0mg/kg body weight of oral administration solution form, (3) oral not D of preparation
97The celecoxib of the 5.0mg/kg body weight of raw material capsule form.The used solvent of intravenous injection and oral administration solution is the mixture of PEG400 (PEG-400) and water, and ratio is 2: 1 (v/v).The intravenous time of injecting is 15min, double injection interval 15min.Respectively at after 0h before the administration and the administration 0.25,0.5,1,1.5,2,3,4,6,8,12, the 24h venipuncture gets blood, blood sample collection in heparinization in vitro, separated plasma.Measure the concentration of celecoxib in the blood plasma by HPLC, the gained pharmacokinetic parameter sees Table 1.
Result of study shows, the celecoxib of Beagle dog oral administration solution form is compared with the intravenous injection celecoxib, and its absolute bioavailability is higher, and lower without its absolute bioavailability of celecoxib raw material of any processing.
The pharmacokinetic parameter of table 1. celecoxib in the Beagle body
Embodiment 12
D
97The relative bioavailability of raw material (particle diameter＜5 μ m) preparation
Use the Beagle dog to D
97The preparation of (particle diameter＜5 μ m) celecoxib raw material carries out the pharmacokinetics evaluation, investigates feed particles footpath, pharmaceutical formulation with respect to the relative bioavailability of celecoxib oral administration solution.12 Beagle dogs are divided into three groups, 4 every group, male and female half and half, each group is respectively: oral celecoxib D without grinding
97Raw material capsule 5.0mg/kg body weight (compositions A), oral micronized celecoxib D
97Raw material capsule 5.0mg/kg body weight (compositions B), (3) oral celecoxib D
97The preparation 50mg/ grain (compositions C) of raw material, the prescription of preparation sees Table 2-1.Respectively at after 0h before the administration and the administration 0.25,0.5,1,1.5,2,3,4,6,8,12, the 24h venipuncture gets blood, blood sample collection in heparinization in vitro, separated plasma.Measure the concentration of celecoxib in the blood plasma by HPLC, the gained pharmacokinetic parameter sees Table 2-2.
The pharmaceutical formulation of table 2-1 celecoxib
Result of study shows, compares with the celecoxib of the oral administration solution form shown in the embodiment 1, and the relative bioavailability of micronization (compositions B) or celecoxib preparation (compositions C) is apparently higher than celecoxib D
97Raw material capsule (compositions A) is seen lower tabulation 2-2.Means (solid composite of wet granulation) by preparation prove absolutely, the wettability (by add sodium lauryl sulphate etc. in granulation liquid) and the raising dispersibility (adding cross-linking sodium carboxymethyl cellulose in the granulation) that the celecoxib granule are directly reduced (grind by grinder and reduce the granule footpath) or increase celecoxib can obviously increase bioavailability.
The pharmacokinetic parameter of table 2-2 celecoxib preparation in the Beagle body
Claims (14)
1. pharmaceutical composition, it is characterized in that, comprise one or more separation solid form can oral release dosage unit, each dosage unit comprises the celecoxib granule of 100mg～500mg and the dense mixture of one or more pharmaceutically acceptable excipient, and the distribution of celecoxib granularity is so that the D of described granule maximum magnitude
97Be lower than 200 μ m, wherein the celecoxib structure is:
2. compositions according to claim 1 is characterized in that, the D of described celecoxib granule maximum magnitude
97Be lower than 100 μ m.
3. compositions according to claim 2 is characterized in that, the D of described celecoxib granule maximum magnitude
97Be lower than 30 μ m.
4. compositions according to claim 3 is characterized in that, the D of described celecoxib granule maximum magnitude
97Be lower than 20 μ m.
5. each compositions is characterized in that according to claim 1-4, and described dosage unit is selected from tablet, pill, hard or soft capsule, lozenge, sachet or fragrant ingot.
6. compositions according to claim 5 is characterized in that, excipient is selected from pharmaceutically useful diluent, disintegrating agent, binding agent, wetting agent and lubricant described in the capsule of unit dose or the tablet form.
7. compositions according to claim 6 is characterized in that, contains
(a) total amount is one or more pharmaceutically acceptable diluents of composition weight 10%～85%;
(b) total amount is one or more pharmaceutically acceptable disintegrating agents of composition weight 0.2%～10%;
(c) total amount is one or more pharmaceutically acceptable binding agents of composition weight 0.75%～15%.
8. compositions according to claim 7, also further containing total amount is one or more pharmaceutically acceptable wetting agents of composition weight 0.4～10%.
9. compositions according to claim 7, also further containing total amount is one or more pharmaceutically acceptable lubricants of composition weight 0.2～8%.
10. compositions according to claim 7, wherein diluent comprises lactose described in (a); (b) disintegrating agent described in comprises crosslinked sodium carboxymethyl cellulose; Binding agent comprises polyvinylpyrrolidone (c).
11. compositions according to claim 8 is characterized in that wetting agent comprises sodium lauryl sulphate.
12. compositions according to claim 9 is characterized in that lubricant comprises magnesium stearate.
13. each described compositions among the claim 1-12 is characterized in that for the preparation of the purposes in the medicine that treats and/or prevents of the internal disease that is fit to treat with cyclooxygenase-2 inhibitor.
14. purposes according to claim 13, wherein said disease are rheumatoid arthritis, osteoarthritis or pain.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105343030A (en) * | 2015-12-16 | 2016-02-24 | 钟柏根 | Celecoxib capsule and preparation method thereof |
| CN112933085A (en) * | 2020-12-28 | 2021-06-11 | 中以海德人工智能药物研发股份有限公司 | Application of compound in preparation of medicine for treating or preventing viral hepatitis |
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| CN1288378A (en) * | 1998-11-30 | 2001-03-21 | G·D·西尔公司 | Celecoxib compositions |
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| CN1594296A (en) * | 2004-06-24 | 2005-03-16 | 华东理工大学 | Process for preparing 4-[3-trifluoromethyl-5-(p-tolyl)-1H-pyrazolyl] benzene sulfonamide |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105343030A (en) * | 2015-12-16 | 2016-02-24 | 钟柏根 | Celecoxib capsule and preparation method thereof |
| CN112933085A (en) * | 2020-12-28 | 2021-06-11 | 中以海德人工智能药物研发股份有限公司 | Application of compound in preparation of medicine for treating or preventing viral hepatitis |
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