CN103372216B - Solid medical composition containing celecoxib - Google Patents

Solid medical composition containing celecoxib Download PDF

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CN103372216B
CN103372216B CN201210124793.9A CN201210124793A CN103372216B CN 103372216 B CN103372216 B CN 103372216B CN 201210124793 A CN201210124793 A CN 201210124793A CN 103372216 B CN103372216 B CN 103372216B
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celecoxib
solid
liquid solvent
liquid
polyethylene glycol
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CN103372216A (en
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李鹏飞
曹宇
戚强龙
张严源
张盈盈
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BEIJING JINGWEI YANKANG PHARMACEUTICAL RESEARCH INSTITUTE Co Ltd
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BEIJING JINGWEI YANKANG PHARMACEUTICAL RESEARCH INSTITUTE Co Ltd
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Abstract

The invention provides a solid medical composition containing celecoxib, wherein the composition further contains a pharmaceutical liquid solvent and other auxiliary materials. The composition exists in form of solid.

Description

A kind of solid composite medicament containing celecoxib
Technical field
The present invention relates to the pharmaceutical composition adopting preferred liquid solvent and drugs of low aqueous solubility celecoxib.Relate more specifically to this based composition that wherein celecoxib mainly exists in solid form, and obviously can improve the stripping of celecoxib in pharmaceutical composition, and prepare the method for this based composition.
Background of invention
Compound celecoxib has following chemical constitution:
This compound dissolves hardly in water, and its consumption in pharmaceutical preparation is 50 ~ 400mg.The CELEBREX of Pfizer's listing tMspecification comprises 50mg, 100mg, 200mg, 400mg.Consider celecoxib insoluble,practically characteristic in water, how being discharged from medicine by so many celecoxib is exactly wherein vital technical threshold.In addition, this material also has some other obvious character feature, and as its caking property, low bulk density and low compressibility etc., these all determine the mobility that pulverous celecoxib is difficult to, also higher relative to its difficulty pulverized of general material.
Patent CN1154490, CN1299683 disclose a kind of compositions, and it is mainly manifested in the mixture of 10mg to 1000mg celecoxib and adjuvant, and wherein celecoxib particle diameter must be D 90≤ 200 μm.The medicine celecoxib that in this scheme, water-soluble is low is the mode by controlling its particle diameter, make raw material be as much as possible small-particle state to reach the effect of smooth stripping.In fact, by the capsule of this explained hereafter, the improvement of dissolution is limited, and owing to too increasing the complexity of technique to the micronized high requirement of celecoxib.Find in the operating process of reality, celecoxib has higher toughness and certain caking property, and rigidity is bad, and this makes its pulverizing have larger difficulty, is unfavorable for industrialization.
Patent CN1230167 mentions the raw material (celecoxib) in pharmaceutical preparation, is divided into two parts, and Part I medicine is the solution form be dissolved in solvent, or is D 50the microgranule that < is 5 μm, Part II is D 90the particulate forms of>=25 μm exists, and make sustained-release preparation, wherein the solvent of Part I dissolved substance is Polyethylene Glycol.Obviously, this technical scheme, with solution state celecoxib or small particle diameter (D 50< 5 μm) as the very fast component discharging medicine, and D 90>=25 μm of these schemes are used to delay drug release, and reach the object of Co ntrolled release speed with this two component.
Patent CN100335136 discloses a kind of combination of oral medication.This pharmaceutical composition is by celecoxib, and glycol or glycol ethers (comprising Polyethylene Glycol), hydroxypropyl methylcellulose cellulose forms.Wherein the suitable major part of celecoxib is dissolved in Polyethylene Glycol, and remaining part suspends in drug solution.The object of this technical scheme is the precipitation after preventing drug-eluting.In this technology, Polyethylene Glycol consumption requires very high, and there is very large industrialization difficulty with liquid or semi-solid state form fill hard capsule, and the poorly sealed liquid of such as hard capsule oozes out, high viscosity liquid or semi-solid little loading amount fill are forbidden, and are difficult to fill etc. even.
Comprise the many of these technical schemes above to provide in celecoxib oral administration solid medicine related art scheme, all there is drawback clearly.Such as the celecoxib being difficult to fine powder to be carried out fine powder, or celecoxib is dissolved, is suspended in the middle of liquid by celecoxib.In the research process of reality, we are surprised to find that, do not carry out deliberately fine-powdered with by celecoxib, only need the particular liquid solvent adding relatively seldom amount just can reach preparation effect more better than prior art.
Summary of the invention
The present invention relates to a kind of Celecoxib solid composition, wherein with the addition of a small amount of liquid solvent, this liquid solvent can promote the stripping of celecoxib in stripping environment.In the composition, celecoxib exists with the form of expression of solid.Compositions can be prepared into solid particle, also can be conveniently used in filled capsules or tabletting.
The present invention relates to a kind of solid composite medicament containing celecoxib, it also comprises liquid solvent and other can be used for medicinal adjunct ingredient, and wherein said liquid solvent is adsorbed by described celecoxib and adjunct ingredient, and compositions presents solid forms.
In the solid composite medicament containing celecoxib of the present invention, wherein said liquid solvent is the mixture of liquid polyethylene glycol or these liquid polyethylene glycols, or solid-state poly-L glycol is the mixture of liquid condition with liquid polyethylene glycol upon mixing.
Of the present invention containing in the solid composite medicament of celecoxib, wherein said liquid polyethylene glycol is the Polyethylene Glycol that molecular weight is less than or equal to 600.
Of the present invention containing in the solid composite medicament of celecoxib, wherein said liquid polyethylene glycol is Polyethylene Glycol 100, Macrogol 200, PEG400, Macrogol 600.
Of the present invention containing in the solid composite medicament of celecoxib, wherein said liquid polyethylene glycol is Macrogol 200.
Of the present invention containing in the solid composite medicament of celecoxib, wherein said solid polyethylene glycol is the Polyethylene Glycol that molecular weight is more than or equal to 1000.
Of the present invention containing in the solid composite medicament of celecoxib, the particle diameter of wherein said celecoxib is D 90be greater than 200 μm.
Of the present invention containing in the solid composite medicament of celecoxib, wherein said liquid solvent amount ranges is in the composition 1 % by weight ~ 20 % by weight.
Of the present invention containing in the solid composite medicament of celecoxib, wherein said liquid solvent amount ranges is in the composition 2 % by weight ~ 10 % by weight.
Of the present invention containing in the solid composite medicament of celecoxib, be finally made into oral solid formulation, comprise granule, capsule or tablet.
Accompanying drawing explanation
Fig. 1 is the comparison of different liquids additive technique stripping curve.
Fig. 2 is technological process Fig. 1.
Fig. 3 is technological process Fig. 2.
Fig. 4 is that celecoxib to add after liquid solvent preparation and controls raw material particle size technique and do not carry out special handling preparation dissolved corrosion comparison diagram.
Fig. 5 is the stripping curve of prescription A preparing product.
Fig. 6 is the stripping curve of prescription H preparing product.
Detailed description of the invention
In the present invention to the particle diameter of celecoxib without particular/special requirement, relative to must by the technique of raw material fine powder, have better industrialization operability, technique be more succinct.In the present invention's research, celecoxib is all without special pulverizing or milled processed, and the particle diameter of celecoxib is D 90be greater than 200 μm, by the adjustment including liquid solvent consumption and kind, can accomplish that the product dissolved corrosion obtained to fine-powdered technique is similar, also can accomplish than fine powder technique obtain the stripping of product sooner, more complete.
In the present invention, celecoxib accounts for composition components major part, and liquid solvent only accounts for fraction, and in whole compositions, liquid solvent is adsorbed by celecoxib and other a small amount of adjuvant, and compositions presents solid forms.After making granule, good mobility can be had.The mass percent < 25% of liquid solvent in compositions gross mass, preferably, the mass percent of liquid solvent in compositions gross mass even < 10%.Not using too much liquid solvent, be that too much liquid solvent will affect the curing molding of compositions, will there is the situation that character is not good in obtained product, the solid extremely low in hardness, semisolid or or even liquid, and this is completely unnecessary.
Liquid solvent used in this application refers to the nonaqueous solvent in liquid condition, can be selected from the mixture of liquid polyethylene glycol and these liquid polyethylene glycols, solid polyethylene glycol and liquid polyethylene glycol be the mixture of liquid condition, or other liquid diol kind solvent such as propylene glycol.These solvents, except preparation excellent effect, also have stable in properties, safety are pharmaceutically acceptable, have the features such as clear and definite method of quality control.
Liquid polyethylene glycol can be small-molecular-weight Polyethylene Glycol, and namely Macrogol 600 and molecular weight are lower than the Polyethylene Glycol of Macrogol 600, such as Polyethylene Glycol 100,200 and 400.
Solid polyethylene glycol can be macromolecule Polyethylene Glycol (>=1000).
Preferably, liquid solvent used in this application is the mixture of liquid polyethylene glycol or these liquid polyethylene glycols, such as use independent Polyethylene Glycol 100, Macrogol 200, PEG400, Macrogol 600, or two or more mixed solvent among them.
Unless specified otherwise herein, " liquid state ", " liquid " mentioned in this application refers to and to be in a liquid state in room temperature and an atmospheric pressure.
Unless specified otherwise herein, " solid-state " mentioned in this application refers to that in room temperature and an atmospheric pressure be solid-state.
In preparation process in the past, once someone attempted the surfactant Polysorbate of main flow to be used in the middle of oral solid formulation, such as added Tween 80 in atorvastatin.And test display other liquid solvent except Polyethylene Glycol, be all difficult to make celecoxib obtain the result of extraction identical with using relative small-molecular-weight Polyethylene Glycol.Attempt using liquid Polysorbate, liquid polyoxyethylene castor oil etc., all can not obtain and make celecoxib preparation obtain similar or close result of extraction, see Fig. 1.
Dosage form as finally selected is capsule, selected liquid solvent should have the good compatibility with gelatine capsule shell, its compatibility performance affects except these normal study of pharmacy requirements except not having medicine quality, can't have the potential threat causing gelatine capsule shell deformation.Experiment confirms, be immersed in respectively in Polyethylene Glycol 100,200,400 by commercially available medicinal gelatin capsule shell, all do not find that there is any deformation in 4 months, capsule shells form trait is complete, elasticity, the tight degree of capsule cap capping, with virgin rubber softgel shell no significant difference.And under same experimental condition, propylene glycol just causes the expansion of gelatine capsule shell within a couple of days, melt.So in practical operation, although add the effect that propylene glycol also can obtain certain promotion stripping, be but difficult to be applicable in capsule.
The Adding Way employing of liquid solvent directly mixes rear granulation with pressed powder or soluble in water being sprayed in pressed powder is granulated.Consider, liquid parts adds the mobility that have impact on powder in compositions significantly, even it is also influenced powder dispersion to be obtained very uniform flow, so compositions preparation should be granulated.Through granulating, adding lubricant after drying, improve the mobility of compositions with this, and for pack or filled capsules or tabletting.Obtained granule is comparatively loose, can be the granule of any particle diameter within the scope of 14 order ~ 40 orders, also can in thinner Powdered granule.Add lubricant as stearic acid, magnesium stearate, micropowder silica gel, Pulvis Talci, polyethylene glycol 6000, castor oil hydrogenated etc. after, can obtain good mobility with meet preparation produce demand.Such as mobility describes≤35 ° with angle of repose.The preparation scheme of these compositionss is all applicable to the preparation of granule and capsule, but only having minority can carry out tabletting prepares tablet.This is the overall character in most cases rigidity deficiency due to compositions, this depends primarily on the properties and characteristics of the celecoxib accounting for higher proportion, when celecoxib is in compositions during mass percent > 70%, composition grain hardness is low, be difficult to tabletting, the existence of liquid solvent can strengthen this character.
Also need to add other appropriate adjuvant in this programme, such as, to regulate character and other related preparations performance, the microcrystalline Cellulose, starch, lactose, sucrose, mannitol, sorbitol, glucose, dextrose etc. of celecoxib granule.And the performance of stripping is more outstanding when wherein using with water solublity inborn nature adjuvants such as lactose, sucrose, mannitol, sorbitol, glucose, dextroses, and the hardness being conducive to granule is improved.For improving the loose situation of granule, adding water solublity and binding composition, such as polyvidone, methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, arabic gum, alginic acid and salt etc. thereof.In addition, collapsing of can also adding that cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, polyvinylpolypyrrolidone, low-substituted hydroxypropyl cellulose etc. promote granule in aqueous dissolution medium is loose.Adjuvant conventional in some other tablet technique, also can be applied in the preparation of this compositions.
Before the present invention occurs, in the production decision of celecoxib, sodium lauryl sulphate is a kind of adjuvant of key.Sodium lauryl sulphate is classical surfactant, through being commonly used in the aspect such as solubilising, moistening to medicine.And after employing technical scheme provided by the invention prepares Celebret, whether sodium lauryl sulphate adds the final mass that obviously can't affect product.
This programme typical process flow has two kinds of forms, sees Fig. 2 and Fig. 3.
Although solved the problem of celecoxib formulation products stripping difficulty by this programme, extraly particular/special requirement is not proposed to the links of technological design, does not require more specifically process equipment yet.Decrease the technical process of fine-powdered, dissolving, these complexity that suspend on the contrary.Final manufactured goods are made to show stability that is more excellent, product quality also better.
The product that this programme is made finally evaluates the effect of technique with stripping.Stripping method for measuring is: according to dissolution method (Chinese Pharmacopoeia version in 2010 two XC second methods), with 0.04M sodium radio-phosphate,P-32 solution (regulating pH 12.0 ± 0.1 with phosphoric acid or the sodium hydroxide test solution) 1000ml containing 1% sodium lauryl sulphate for solvent, rotating speed is 50 turns per minute, operate in accordance with the law, choose suitable sampling time point and get solution, through 0.45 μm of membrane filtration, it is appropriate that precision measures subsequent filtrate, adds that giving an account of matter quantitatively dilutes the solution making 0.10mg/ml; It is appropriate that another precision takes reference substance, uses and give an account of the solution that matter makes 0.10mg/ml, in contrast product solution, measures according to (Chinese Pharmacopoeia two annex VD in 2010).Stripping sampling time point is 10 minutes, 20 minutes, 30 minutes, 45 minutes and 60 minutes.This dissolving-out method, consistent with the Celebret that U.S. FDA (US Food and Drug Administration) is announced.
Fig. 4 is that celecoxib to add after liquid solvent preparation and controls raw material particle size technique and do not carry out special handling preparation dissolved corrosion comparison diagram.
Its stripping of the capsule prepared by this programme performance can stablize to continue within the longer time, can't separate out rapidly.The lasting tracing detection of solution 24h after to the stripping in 45 minutes of obtained product, finds that dissolution fluid there is no to separate out and finds, and it measures dissolution that different time points of measuring liquid measures also and no significant difference.
Stripping in 45 minutes 0 hour 4 hours 12 hours 24 hours
Stripping (%) 94.7 94.3 95.2 94.5
Embodiment
Embodiment 1
Component A(mg) B(mg) C(mg) D(mg) F(mg)
Celecoxib 200 200 200 200 200
Macrogol 200 30 10 20 25 13
Lactose monohydrate 25 47 41 37 39
Polyvidone (K30) 15 15 15 15 15
Cross-linking sodium carboxymethyl cellulose 10 5 0 5 3
Sodium lauryl sulphate 3 6 9 3 3
Silicon dioxide 4 4 4 4 4
Magnesium stearate 3 3 3 3 3
Gross weight (every) 290 290 290 290 280
The adding of sodium lauryl sulphate in these materials is not necessary.Wherein celecoxib particle diameter is D 90be greater than 200 μm, mixing of materials evenly after, add water or other moistening ingredients that can use in pharmacy, make granule, dry, after adding lubricant mixing, filled capsules and get final product.Macrogol 200 can participate in mixing directly, also can be added to the water and add.
The stripping measurement result of prescription A product:
Stripping % 0min 10min 20min 30min 45min 60min
1 0 54.69 79.03 89.26 91.92 94.59
2 0 51.26 82.68 94.04 97.20 98.03
3 0 54.35 86.53 90.05 94.42 95.56
4 0 40.85 78.36 89.1 93.97 96.35
5 0 41.97 76.17 89.77 94.59 97.82
6 0 55.72 85.45 93.29 97.26 98.24
Average % 0 49.81 81.37 90.92 94.89 96.77
Stripping curve figure is shown in Fig. 5.
Embodiment 2
Component G(mg) H(mg) I(mg)
Celecoxib 200 200 200
PEG400 30 10 20
Microcrystalline Cellulose 35 25 38
Polyvidone (K30) 15 15 15
Lactose monohydrate 0 22 0
Carboxymethyl starch sodium 10 5 10
Sodium lauryl sulphate 3 6 0
Silicon dioxide 4 4 4
Magnesium stearate 3 3 3
Gross weight 290 290 290
Basic process prepared by the present embodiment is with embodiment 1, and wherein celecoxib particle diameter is D 90be greater than 200
μm。Because celecoxib consumption is in the formulation relatively very large, so obtained finished product content uniformity substantially need not be too careful.
The stripping measurement result of prescription H:
stripping % 0min 10min 20min 30min 45min 60min
1 0 55.59 74.24 82.56 87.27 94.10
2 0 37.32 59.27 72.95 81.70 88.02
3 0 44.16 62.43 75.46 85.37 87.68
4 0 50.44 65.98 80.71 84.39 90.22
5 0 52.07 69.32 81.57 86.24 91.18
6 0 42.16 62.33 78.42 83.21 89.32
average % 0 46.96 65.59 78.61 84.70 90.09
Stripping curve figure is shown in Fig. 6.
Embodiment 3
Component J(mg) K(mg) L(mg) M(mg)
Celecoxib 100 100 100 400
Macrogol 200 8 10 12 25
Polyvidone (K30) 8 6 5 11
Lactose monohydrate 45.3 48.3 25.3 39.1
Cross-linking sodium carboxymethyl cellulose 2 2 2 3
Sodium lauryl sulphate 3 0 2 4
Silicon dioxide 2 2 2 4.2
Magnesium stearate 1.7 1.7 1.7 4.7
Gross weight 170 170 150 491
Basic process prepared by the present embodiment is with embodiment 1,2, and wherein celecoxib particle diameter is that D90 is greater than 200 μm.This process program also can obtain good effect in the formulation products lower than 200mg specification.And when preparation specification is more than or equal to 400mg time, although also can play the effect improving stripping, because explosive payload is excessive, can there is certain difficulty when filled capsules, and the large capsule shell chosen is unfavorable for swallowing.

Claims (5)

1. containing the solid composite medicament of celecoxib, comprise celecoxib, liquid solvent and other pharmaceutic adjuvant, wherein said liquid solvent is adsorbed by described celecoxib and adjunct ingredient, and compositions presents solid forms; Described liquid solvent is selected from one or more in Polyethylene Glycol 100, Macrogol 200, PEG400, Macrogol 600, described liquid solvent amount ranges is in the composition 2 % by weight ~ 10 % by weight, and the technique preparing described solid composite medicament comprises granulation step.
2. solid composite medicament as claimed in claim 1, wherein said liquid solvent is Macrogol 200.
3. solid composite medicament as claimed in claim 1, the particle diameter of wherein said celecoxib is that D90 is greater than 200 μm.
4. solid composite medicament as claimed in claim 1, it is finally made into oral solid formulation.
5. solid composite medicament as claimed in claim 4, described oral solid formulation comprises granule, capsule, tablet.
CN201210124793.9A 2012-04-26 2012-04-26 Solid medical composition containing celecoxib Active CN103372216B (en)

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Publication number Priority date Publication date Assignee Title
CN105232494A (en) * 2015-11-11 2016-01-13 青岛百洋制药有限公司 Celecoxib capsules and production technology thereof

Citations (4)

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Publication number Priority date Publication date Assignee Title
CN1516581A (en) * 2001-04-17 2004-07-28 Amino-sulfonyl-containing active compound (COX-2 inhibitors), polyethylene glycol and removing free radical antioxidate and liquid
CN101217939A (en) * 2005-05-27 2008-07-09 灵药生物技术有限公司 Injectable compositions and process of preparation thereof
CN102000018A (en) * 2010-02-09 2011-04-06 浙江大学宁波理工学院 Solid dispersion containing celecoxib as well as preparation method and application thereof
CN102238941A (en) * 2008-09-17 2011-11-09 迈兰实验室公司 Granulates, process for preparing them and pharmaceutical products containing them

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004047752A2 (en) * 2002-11-26 2004-06-10 Transform Pharmaceuticals, Inc. Pharmaceutical formulations of celcoxib

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1516581A (en) * 2001-04-17 2004-07-28 Amino-sulfonyl-containing active compound (COX-2 inhibitors), polyethylene glycol and removing free radical antioxidate and liquid
CN101217939A (en) * 2005-05-27 2008-07-09 灵药生物技术有限公司 Injectable compositions and process of preparation thereof
CN102238941A (en) * 2008-09-17 2011-11-09 迈兰实验室公司 Granulates, process for preparing them and pharmaceutical products containing them
CN102000018A (en) * 2010-02-09 2011-04-06 浙江大学宁波理工学院 Solid dispersion containing celecoxib as well as preparation method and application thereof

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