CN1216869C - Polymorphic crystalline forms of celecoxib - Google Patents

Polymorphic crystalline forms of celecoxib Download PDF

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Publication number
CN1216869C
CN1216869C CN008060835A CN00806083A CN1216869C CN 1216869 C CN1216869 C CN 1216869C CN 008060835 A CN008060835 A CN 008060835A CN 00806083 A CN00806083 A CN 00806083A CN 1216869 C CN1216869 C CN 1216869C
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type
composition
crystal formation
disease
cyclooxygenase
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CN1411447A (en
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莱昂纳多·J·菲罗
巴特里夏·J·米亚科
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Pharmacia LLC
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Pharmacia LLC
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    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4

Abstract

Pharmaceutical compositions are provided comprising one or more orally deliverable dose units, each comprising a selective cyclooxygenase-2 inhibitory compound of low water solubility in a therapeutically effective amount, wherein the compound is present in the form of solid particles, about 25 % to 100 % by weight of which are smaller than 1 mm. The compositions are useful in treatment or prophylaxis of cyclooxygenase-2 mediated conditions and disorders and have particular advantages where rapid onset of therapeutic effect is desired. The novel Form I and Form II crystalline forms of celecoxib are described. The crystalline forms have unique chemical and physical properties relative to other solid state forms of celecoxib and are characterized by their powder x-ray diffraction (PXRD) patterns, differential scanning calorimetric (DSC) thermograms, and other physical characterizations.

Description

The polymorphic crystal formation of YM 177
The related application reference
Present patent application requires the right of priority of U.S. Provisional Patent Application the 60/169856th series number of submission on December 9th, 1999.
Invention field
The present invention relates to contain the cyclooxygenase-2 inhibitor medicine as active ingredient can oral release pharmaceutical composition, prepare the method for the disease of this method for compositions, the mediation of treatment cyclooxygenase-2, described method comprises this composition of orally give curee, and the application of this composition in the preparation medicine.
The invention belongs to cyclooxygenase-2 and suppress the medicament field, and be specifically related to the new I type and the II type crystal formation of YM 177 (celecoxib), prepare these YM 177 crystal formations method, contain the pharmaceutical composition of these YM 177 crystal formations and treat and/or prevent the illness of cyclooxygenase-2 mediation and/or the method for disease (comprising illness and disease).
Background of invention
Reported multiple have to treat and/or prevent be used for the inhibiting compound of selective cyclooxygenase-2, disclose these compounds treatment prevent the disease of specific cyclooxygenase-2 mediation or common this type of disease in the effect that has.Among such compound, people such as Talley are at U.S. Patent number 5,760, the excessive pyrazolyl benzsulfamide of measuring generation of report in 068, for example comprise compound 4-[5-(4-aminomethyl phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzsulfamide, this paper is also referred to as YM 177 (celecoxib), and compound 4-[5-(3-fluoro-4-p-methoxy-phenyl)-3-difluoromethyl]-the 1H-pyrazol-1-yl] benzsulfamide, this paper is also referred to as moral and draws gratifying (deracoxib).YM 177 has following structure:
Moral is drawn the gratifying following structure that has:
Report has and treats and/or prevents that to be used for inhibiting other compound of selective cyclooxygenase-2 be to replace De isoxazolyl benzsulfamide, as people such as Talley at U.S. Patent number 5,633,272 reports, for example comprise compound 4-[5-methyl-3-phenyl-isoxazole azoles-4-yl] benzsulfamide, this paper is also referred to as watt moral gratifying (valdecoxib), and it has following structure:
Also have report to have to treat and/or prevent that to be used for inhibiting other compound of selective cyclooxygenase-2 be at U.S. Patent number 5 as people such as Ducharme; 474; (methylsulfonyl) benzofurane ketone of the replacement of 995 reports; for example comprise compound 3-phenyl-4-[4-(methylsulfonyl) phenyl]-5-H-furans-2-ketone; this paper is also referred to as sieve not gratifying (rofecoxib), and it has following structure:
Figure C0080608300061
People such as Balley are at U.S. Patent number 5; 981; 576 disclose described more (methylsulfonyl) benzofurane ketone that can be used as cyclooxygenase-2-inhibitor; comprise 3-(1-cyclo propyl methoxy)-5; 5-dimethyl-4-[4-(methylsulfonyl) phenyl]-5-H-furans-2-ketone and 3-(1-cyclopropyl oxyethyl group)-5,5-dimethyl-4-[4-(methylsulfonyl) phenyl]-5-H-furans-2-ketone.
European Patent Application No. 0863134 discloses compound 2-(3, the 5-difluorophenyl)-3-[4-(methylsulfonyl) phenyl that can be used as cyclooxygenase-2 inhibitor]-2-cyclopentamethylene-1-ketone.
In international publication number WO99/55380, especially disclose the cyclooxygenase-2 that can be used as and suppressed compound with following structure:
Many selective cyclooxygenase-2s suppress compounds comprise YM 177, moral draw gratifying, watt moral is gratifying and sieve is not gratifying, it is hydrophobic and has low solubility in water.When being mixed with oral administration, such compound has actual difficulty, and all the more so under the situation of hope or generation therapeutic action fast especially.
Illustrative ground, because the physics and the chemical property of YM 177 uniqueness, particularly its low solubility and the factor relevant with its crystalline texture comprise cohesiveness, low bulk density and low compressibility, it is mixed with the preparation that is used for the effective oral administration of curee becomes complicated and make.YM 177 is insoluble in the water-bearing media unusually.For example, when with the capsule form oral administration, Pei Zhi YM 177 is not to be not easy dissolving and dispersive, thereby is unfavorable for rapid absorption in gi tract.In addition, when compressing tablet on the tabletting machine punch die, the not YM 177 of preparation with the long needles crystalline of easy formation viscosity crystalline state fuses into the monoblock material easily.Even when mixing with other material, easy and other separating substances of YM 177 xln, and in described composition mixing process, be agglomerated into piece, produce the composition that inhomogeneous blended contains the big aggregate of unwanted YM 177.Therefore, preparation has required mixing uniformity, the pharmaceutical composition that contains YM 177 is difficult.And, contain in the pharmaceutical composition of YM 177 in preparation, also can run into handling problem.For example, the low bulk density of YM 177 makes and be difficult to handle needed small amounts of material in compounding pharmaceutical composition process.Therefore, contain the appropriate drug composition and the dosage form of YM 177, during particularly oral release dose unit, have a large amount of relevant problems to need to solve in preparation.
Especially, for for the YM 177 or other YM 177 composition of not preparation, the oral delivery formulations that the cyclooxygenase-2 that contains the low water solubility of YM 177 suppresses medicine need have one or more following properties:
(1) improves solubleness;
(2) shorten disintegration time;
(3) shorten dissolution time;
(4) reduce the tablet fragility;
(5) increase tablet hardness;
(6) improve wettability;
(7) improve compressibility;
(8) flowability of improvement liquid and granulated solid composition;
(9) physical stability of improvement final product composition having;
(10) size of reduction tablet or capsule;
(11) improve mixture homogeneity;
(12) improve dose uniformity;
(13) in encapsulation capsule and/or compressing tablet process, improve the control of weight differential;
(14) pellet density of increase wet granulation composition;
(15) the water requirement of minimizing wet granulation;
(16) time of minimizing wet granulation; With
(17) time of drying of minimizing wet granulation mixture.
Further, need especially to suppress the oral delivery formulations of medicine than the cyclooxygenase-2 of the low water solubility that contains YM 177 of the known formulations onset quickly of corresponding not compounding pharmaceutical or these medicines.Reach the maximum serum concentration (C of the degree of quick begin treatment effect and for example medicine Max) and oral administration after reach the shortest time (T of maximum serum concentration Max) pharmacokinetic parameter relevant, need the cyclooxygenase-2 of such low water solubility that contains YM 177 to suppress the oral delivery formulations of medicine especially, it can provide the bigger C of known formulations than corresponding not compounding pharmaceutical or these medicines MaxAnd/or T more early Max
As pointing out below this paper, in the illness of the cyclooxygenase-2 mediation of very wide scope and disease, pointed out or pointed out potentially treatment with the selective cyclooxygenase-2 inhibitor that comprises YM 177.It is useful that the preparation that shows the pharmacokinetics consistent with performance therapeutic action fast is provided, special for hope need ease the pain early or the treatment of the acute illness of other symptom all the more so.
Such preparation can show obvious improvement in illness for the treatment of the cyclooxygenase-2 mediation and disease.
The cyclooxygenase-2 of low-solubility in water that comprises YM 177 suppresses that medicine is the most common to be prepared into the solia particle agent.Medicine independent or primary particle can be dispersed in the liquid medium, as in suspension formulation, perhaps can assemble secondary particle or particle that formation can be coated, so that capsule formulation to be provided, perhaps through compressing tablet or mold pressing so that Tabules to be provided.
Preparation has the primary particle size of required scope, or has required mean particle size size, or has size-grade distribution and be characterised in that as D 90The whole bag of tricks of pharmaceutical preparation of parameter be known and commonly used in the art.This paper D 90Be defined as the linear measurement to diameter, account for the volume cost that the particle of volume 90% has in the preparation, on the longest dimension of particle, it is worth less than such diameter.For practical purpose, based on the D of 90% weight measurement 90More suitable usually than what by volume measure.
For with preferential openly text is consistent, the term " particulate " of this paper definition and people such as " nanoparticle (nanoparticle) " and Courteille are at U.S. Patent number 5,384, the unanimities of 124 definition, refer to respectively have between 1mm and 2000mm diameter and less than the particle of 1mm (1000nm) diameter.According to U.S. Patent number 5,384,124, the preparation of particulate and nanoparticle, " being mainly used in the dissolving that postpones active principle ".Yet people such as Liversidge are at U.S. Patent number 5,145, and 684 disclose described nanoparticle composition so that medicine " unexpected high bioavailability " to be provided, and particularly have low solubility drugs in as liquid mediums such as water.The pharmacokinetic data that international publication number WO93/25190 provides rat studies to obtain, it shows that nanoparticle (mean particle size 240-300nm) oral administration has apparently higher than the performance speed of the absorption of particulate (mean particle size 20-30mm) administration.
Many methods of the nanoparticle composition of preparation therapeutical agent are known.Usually these methods adopt mechanical systems, for example grind or mill, reducing granularity to millimicro level (less than 1mm) scope, or from solution the particle of precipitation millimicro level.Can illustrational method be disclosed in the following independently document: Violanto ﹠amp; The U.S. Patent number 4,826,689 of Fischer, the above-mentioned people's such as Liversidge that quote U.S. Patent number 5,145,684, Na ﹠amp; The U.S. Patent number 5,298,262 of Rajagopalan, people's such as Liversidge U.S. Patent number 5,302,401, Na ﹠amp; The U.S. Patent number 5,336,507 of Rajagopalan, Illig ﹠amp; The U.S. Patent number 5,340,564 of Sarpotdar, Na ﹠amp; The U.S. Patent number 5,346,702 of Rajagopalan, people's such as Hollister U.S. Patent number 5,352,459, the U.S. Patent number 5,354 of Lovrecich, 560, the above-mentioned people's such as Courteille that quote U.S. Patent number 5,384,124, the U.S. Patent number 5,429,824 of June, people's such as Bosch U.S. Patent number 5,510,118, people's such as Eickhoff U.S. Patent number 5,518,738, Ruddy﹠amp; The U.S. Patent number 5,503,723 of Eickhoff, the U.S. Patent number 5,534,270 of De Castro, people's such as Canal U.S. Patent number 5,536,508, people's such as Liversidge U.S. Patent number 5,552,160, people's such as Eickhoff U.S. Patent number 5,560,931, people's such as Bagchi U.S. Patent number 5,560,932, people's such as wong U.S. Patent number 5,565,188, people's such as wong U.S. Patent number 5,569,448, people's such as Eickhoff U.S. Patent number 5,571,536, Desieno ﹠amp; The U.S. Patent number 5,573,783 of Stetsko, people's such as Ruddy U.S. Patent number 5,580,579, people's such as Ruddy U.S. Patent number 5,585,108, the U.S. Patent number 5,587,143 of Wong, Franson ﹠amp; The U.S. Patent number 5,591,456 of Snyder, people's such as Bagchi U.S. Patent number 5,662,883, people's such as Bagchi U.S. Patent number 5,665,331, Ruddy ﹠amp; The U.S. Patent number 5,718,919 of Roberts, people's such as Wiedmann U.S. Patent number 5,747,001, International Patent Publication No. W WO93/25190, International Patent Publication No. W WO96/24336, International Patent Publication No. W WO98/35666.
Summary of the invention
According to the present invention, very poor water miscible selective cyclooxygenase-2 suppresses compound, for example YM 177, moral draw gratifying, watt moral is gratifying or sieve is not gratifying, if the following pharmacokinetic property of this compound exhibits promptly causes bigger maximum serum-concentration (C Max) and/or administration after reach the shorter time (T of maximum serum-concentration Max), when containing this compound compositions, just provide initial treatment effect faster oral so.The granularity that contains the solid particulate of this compound by minimizing obtains described big C MaxAnd/or shorter T Max, like this so that this particle major part by weight diameter and on the particulate longest dimension less than 1mm.Do not having under the situation of theory constraint, when granularity is reduced to less than 1mm, just thinking bigger C MaxAnd/or short T MaxCause the faster dissolving of this compound.
Therefore, provide a kind of pharmaceutical composition that comprises one or more oral release dose units now, each comprises that the selective cyclooxygenase-2 of the low water solubility for the treatment of significant quantity suppresses compound, and wherein this compound is to have about D of 0.01 to about 200mm 90The solid particulate of granularity exists, and particle is most of by weight less than 1mm, with other wherein basically all particles compare greater than the similar compositions of 1mm, fully high C can be provided MaxAnd/or fully short T Max
A kind of pharmaceutical composition that comprises one or more oral release dose units also is provided, and each comprises that the selective cyclooxygenase-2 of the low water solubility for the treatment of significant quantity suppresses compound, and wherein this compound is to have about D of 0.01 to about 200mm 90The solid particulate of granularity exists, and wherein about by weight particle of 25% to 100% is less than 1mm.
The dose unit that said composition comprises can be the dispersed solids article form, for example tablet, pill, hard or soft capsule, lozenge, sachet or pastille; In addition, but the form of the fluid that said composition can be full and uniform exist, for example particle or granulating solid or liquid suspension, wherein single dose unit is that appropriateness can be taken out.
The method of a kind of curee's of treatment medical conditions or disease also is provided, refers to here comprise the composition of the present invention of one or more dose units of orally give, once a day or twice with cyclooxygenase-2 inhibitor treatment.Such method is specially adapted to follow the medical conditions or the disease of acute pain.
The present invention also comprises a kind of new solid-state version YM 177, I type YM 177.The present invention further comprises another solid-state version YM 177, II type YM 177.In these new solid-state versions each comprises solvation crystal formation, non-solventization and non-hydrated crystal formation.
These novel YM 177 that the application describes have above-mentioned one or more and useful chemistry and/or physical properties described herein or that disclosed other solid-state version of document is relevant.
Another embodiment of the present invention comprises a kind of new crystal of YM 177.For example, a kind of embodiment of the present invention comprises the I type crystal formation of YM 177, preferably has the X-ray powder diffraction spectrographic crystal formation that the peak is arranged at 5.5,5.7,7.2 and 16.6 degree, 2 θ places.
In another embodiment, the invention provides the I type crystal formation that contains the YM 177 for the treatment of significant quantity and the pharmaceutical composition of at least a pharmaceutically acceptable carrier, auxiliary agent or thinner.
In another embodiment, the invention provides a kind of treatment or the illness of prevention cyclooxygenase-2 mediation or the method for disease, wherein this method comprises and gives the I type YM 177 that the curee treats significant quantity.
In another embodiment, the invention provides a kind of method of the I of preparation type YM 177, it comprises crystallization YM 177 from the mixture that contains YM 177 and solvent, wherein carries out crystallization under the mapping sex reversal temperature of I type YM 177, thereby produces I type YM 177.
In another embodiment, the invention provides a kind of method for preparing the YM 177 crystal formation, wherein this method comprises the solvate that heats YM 177, thereby produces I type YM 177.
In another embodiment, the invention provides a kind of method of the I of preparation type YM 177, wherein this method comprises the III type YM 177 that grinds or mill, thereby produces I type YM 177.
In another embodiment, the invention provides a kind of method of the I of preparation type YM 177, wherein this method comprises and grinding or the solvate of the YM 177 of milling, thereby produces I type YM 177.
In another embodiment, the invention provides a kind of method of the I of preparation type YM 177, wherein this method comprises fusing II type YM 177 and cools off this melt, thereby produces I type YM 177.
In another embodiment, the invention provides a kind of method of the I of preparation type YM 177, wherein this method comprises fusing III type YM 177 and cools off this melt, thereby produces I type YM 177.
In another embodiment, the invention provides a kind of method of the I of preparation type YM 177, wherein this method comprises evaporating solvent from YM 177 solution, thereby produces I type YM 177.
Another embodiment of the present invention comprises a kind of new crystal of YM 177, for example, a kind of embodiment of the present invention comprises the II type crystal formation of YM 177, preferably has the crystal formation that the X-ray powder diffraction at peak is arranged at about 10.3,13.8 or 17.7 degree 2 θ places.
Another embodiment of the present invention provides a kind of this crystallization for the treatment of significant quantity and pharmaceutical composition of at least a pharmaceutically acceptable carrier, auxiliary agent or thinner of containing.
It is a kind of to curee treatment or the illness of prevention cyclooxygenase-2-mediation or the method for disease that another kind of embodiment of the present invention provides, and this method comprises and gives the II type YM 177 that the curee treats significant quantity.
Another embodiment of the present invention provides a kind of method of the II of preparation type YM 177, it comprises crystallization YM 177 from the mixture that contains YM 177 and solvent, wherein under the mapping sex reversal temperature of II type YM 177, carry out crystallization, thereby produce II type YM 177.
Another embodiment of the present invention provides the method for a kind of YM 177 crystal formation of preparation, and wherein this method comprises heating YM 177 solvate, thereby produces II type YM 177.
Another embodiment of the present invention provides a kind of method of the II of preparation type YM 177, and wherein this method comprises the III type YM 177 that grinds or mill, thereby produces II type YM 177.
Another embodiment of the present invention provides a kind of method of the II of preparation type YM 177, and wherein this method comprises the YM 177 solvate that grinds or mill, thereby produces II type YM 177.
Another embodiment of the present invention provides a kind of method of the II of preparation type YM 177, and wherein this method comprises fusing I type YM 177 and cools off this melt, thereby produces II type YM 177.
Another embodiment of the present invention provides a kind of method of the II of preparation type YM 177, and wherein this method comprises fusing III type YM 177 and cools off this melt, thereby produces II type YM 177.
Another embodiment of the present invention provides the solid-state version YM 177 of a kind of I of comprising type YM 177 and II type YM 177.
Another embodiment of the present invention provides the solid-state version YM 177 of a kind of I of comprising type YM 177 and III type YM 177.
Another embodiment of the present invention provides the solid-state version YM 177 of a kind of II of comprising type YM 177 and III type YM 177.
Another embodiment of the present invention provides the solid-state version YM 177 of a kind of I of comprising type YM 177, II type YM 177 and III type YM 177.
Further feature of the present invention partly is significantly, and part is pointed out hereinafter.
Brief Description Of Drawings
Fig. 1 describe I type YM 177 (Fig. 1 a), II type YM 177 and the mixture (Fig. 1 b) of III type YM 177 and the contrast of the experiment PXRD collection of illustrative plates between the III type YM 177 (Fig. 1 c);
Fig. 2 describes the contrast between the IR spectrum of the mixture of I type YM 177, II type YM 177 and III type YM 177 and III type YM 177;
Fig. 3 describes each and has the contrast of the YM 177 crystal formation of covering (endotherm is following) with the DSC differential thermogram of 0.5 ℃ of/minute scanning.
The explanation of preferred embodiment
The term of this paper " selective cyclooxygenase-2 inhibitor " or " selective cyclooxygenase-2 inhibition compound " mean treatment degree of functioning ground and suppress cyclooxygenase-2, and cause that the nonsteroidal antiinflammatory drug (NSAIDs) than routine suppresses the compound that cyclo-oxygenase-1 significantly reduces.
Mean about the term of selective cyclooxygenase-2 inhibitor " difference water-soluble " or " low water solubility " this paper that the solubleness in 25 ℃ is lower than about 10g/l in distilled water, preferably be lower than about 1g/l.
Term " oral administration " this paper comprises therapeutical agent or its composition any releasing pattern to the curee, and therapeutical agent wherein or composition are inserted in curee's mouth, and no matter whether therapeutical agent or composition are swallowed.Therefore " oral administration " comprises oral cavity and hypogloeeis and esophagus administration.The absorption of therapeutical agent can be found to comprise oral cavity, esophagus, stomach, duodenum, ileum and colon at GI any part or some parts.
Term " oral release " this paper means and is suitable for oral administration.
" curee " this paper means the object that therapeutical agent or its composition can give, and comprises the patient at arbitrary sex and any age, also comprises any non-human animal, particularly domestic animal or (companion) animal in pairs, is illustrated as cat, dog or horse.
Term " dosage " unit " this paper means under the situation that selective cyclooxygenase-2 inhibitor exists, and contains the pharmaceutical composition of a certain amount of therapeutical agent part, is suitable for the single oral administration so that therapeutic action to be provided.A common dosage unit, perhaps small part (about at the most 4) dose unit repeatedly, the therapeutical agent that q.s is provided is to produce required effect.
This paper is applied to term that selective cyclooxygenase-2 suppresses compound and " is present in the solid particulate " and comprises such composition, wherein solid particulate mainly is made up of this compound, and wherein solid particulate contains this compound that forms intimate mixture with one or more other compositions.These other composition comprises one or more therapeutical agents and/or one or more the pharmaceutically acceptable vehicle except that selective cyclooxygenase-2 suppresses compound.
The term of this paper " vehicle " refers to it self is not therapeutical agent, but as therapeutical agent being discharged to patient or adding in the pharmaceutical composition any carrier or auxiliary material with the dispersion goods that improve its operability or storage property or permission or help said composition with a dosage unit to be mixed with the capsule that for example is suitable for oral administration or tablet.Vehicle comprises the material of (but being not limited to this) thinner, disintegrating agent, tackiness agent, tackiness agent, wetting agent, lubricant, glidant, the material of covering or offsetting undesirable taste or smell, correctives, dyestuff, flavouring agent and improvement composition outward appearance.
Term " even substantially " about the pharmaceutical composition that comprises several compositions means these composition thorough mixing, so that each composition does not exist with dispersion layer, and does not form concentration gradient in composition like this.
Term " purity " means the chemical purity of the YM 177 that obtains according to conventional H PLC analytical method.
Term " phase purity " means when measuring with infrared spectroscopy described herein, the solid-state purity of specific crystal formation that relates to YM 177 that obtains or armorphous YM 177.
Term " mapping sex reversal temperature " means polymorphic form stable on the thermodynamics becomes another kind of form from a kind of formal transformation temperature.For example, for two polymorphic forms, crystal form A and crystal form B, under mapping sex reversal temperature, crystal form A can be a crystal formation stable on the thermodynamics, but crystal form B is a crystal formation stable on the thermodynamics on this temperature.
The dose unit that comprises one or more oral releases according to new pharmaceutical composition of the present invention.Each dose unit comprises the selective cyclooxygenase-2 inhibitor for the treatment of significant quantity, is example with the YM 177, and preferably treating significant quantity is that about 10mg is to about 1000mg.
Be understandable that, depend on curee's body weight for the treatment significant quantity of curee's selective cyclooxygenase-2 inhibitor especially.Illustrate, at cyclooxygenase-2 inhibitor is that YM 177 and curee are under the situation of children or animalcule (for example dog), is suitable for the serum-concentration that provides consistent with result of treatment in about 10mg low relatively YM 177 of measuring to the preferable range of about 1000mg.The curee is that (for example, horse under) the situation, the such YM 177 serum-concentration that obtains probably need contain the dose unit of relatively large amount YM 177 for grownup or large animal.
With the YM 177 is example, and common dose unit contains about 10,20,25,37.5,50,75,100,125,150,175,200,250,300,350 or cyclooxygenase-2-inhibitor of 400mg in composition of the present invention.For the grownup, the normally about 50mg of YM 177 every dose unit in composition of the present invention of treatment significant quantity is to about 400mg.The every dose unit of YM 177 of special preferred amounts is that about 100mg is to about 200mg, for example about 100mg or about 200mg.
The present invention contains for example composition of YM 177 of selective cyclooxygenase-2 inhibitor, form intimate mixture separately or with one or more vehicle, exist with the nanoparticle form, promptly the form of this solids in its diameter of longest dimension of particle less than 1mm.
It is normally unpredictable for the influence of the pharmacokinetic property of the medicine of the medicine of any granularity or any kind of to the nanoparticle scope to reduce granularity from particulate scope (greater than the 1mm diameter).According to the present invention, for the selective cyclooxygenase-2 inhibitor of low water solubility, the C that the nanoparticle composition exhibiting is higher than microparticle compositions MaxAnd/or shorter T MaxTherefore, with wherein all particles are greater than the reference composition comparison of 1mm basically, In one embodiment of the present invention, the weight percent of nanoparticle can enough provide higher basically C in the particle MaxAnd/or short basically T MaxPreferred composition has enough nanoparticle weight percents so that short basically T to be provided in this embodiment Max, and more preferably enough nanoparticle weight percents are to provide comparison according to the high more basically C of composition MaxShorter T Max
When to fasting adult oral administration, the dose unit of 100mg preferably shows less than about 90 minutes T Max, more preferably be less than about 60 minutes with less than about 45 minutes T Max, C MaxBe at least about 100ng/ml, more preferably at least about 200ng/ml.Usually within oral administration 30 minutes, composition of the present invention provides the serum-concentration of selective cyclooxygenase-2 inhibitor to be at least about 50ng/ml; Preferred compositions just reaches such concentration in lacking to 15 minutes.The early stage rising of be sure oing serum-concentration is relevant with the quick acting of the present composition.
In another embodiment of the invention, selective cyclooxygenase-2 inhibitor, for example YM 177 exists with solid particulate, and it has about D of 0.01 to about 200mm 90Granularity, wherein about by weight particle of 25% to 100% is a nanoparticle.When the nanoparticle weight percent was relatively low, for example about 25% to about 50%, D 90Granularity preferably about 0.01 is to about 100mm, and more preferably from about 0.01 to about 75mm, more more preferably from about 0.01 to about 40mm, even more preferably from about 0.01 to about 25mm.Granularity can change continuously along nanoparticle and particulate scope, and perhaps said composition has the size-grade distribution of bimodal or multimodal, and one group of particle has the D less than 1mm 90Granularity, another group particle has basic D greater than 1mm 90Granularity.Usually preferred nanoparticle at least about 50 weight % in the particle is especially preferably at least about 75 weight %.In one embodiment, all particles are less than 1mm basically, that is, the weight percent of nanoparticle is 100% or near 100%.
Primary particle for example by grinding or milling, perhaps by precipitating, can assemble forming the secondary aggregated particles in solution.Unless point out other implication in the context, the term " granularity " that this paper adopts refers to the size of primary particles on longest dimension.
Only consider the nanoparticle composition of composition of the present invention, mean particle size preferably about 0.1 to about 0.8mm (about 100 to about 800nm), more preferably from about 0.15 to about 0.6mm (about 150 to about 600nm), preferably about 0.2 to about 0.4mm (about 200 to about 400nm).Selective cyclooxygenase-2 inhibitor, for example YM 177 can be crystal formation or armorphous in nanoparticle.Comprise that the method for preparing nanoparticle that grinds and mill provides the medicine of crystalline forms usually, and comprise the medicine that armorphous form generally is provided from the method for solution precipitation.
The selective cyclooxygenase-2 inhibitor that contains low water solubility of the present invention, for example the composition of YM 177 contains the vehicle that one or more are selected from thinner, disintegrating agent, tackiness agent, wetting agent and lubricant alternatively.In one embodiment, the nanoparticle that contains selective cyclooxygenase-2 inhibitor has and is adsorbed on its surperficial surface-modifying agent.In another embodiment, the nanoparticle of selective cyclooxygenase-2 inhibitor is comprised in the matrix of polymer formation.At least a vehicle is preferably water-soluble diluent or wetting agent.When picked-up composition of the present invention, such water-soluble diluent or wetting agent promote the dispersion and the dissolving of cyclooxygenase-2 inhibitor.Preferably there are water-soluble diluent and wetting agent simultaneously.
But composition of the present invention can be for example particle or granular solids or a liquid of basic fluid uniformly, and perhaps it can be to disperse the thing form, and for example each contains the capsule or the tablet of single dosage unit.
But a kind of be in the composition of basic fluid uniformly, adopt the volumetric measuring device that is fit to for example when teaspoon or cup single dose unit can take out with measuring.But the fluid that is fit to comprises (but being not limited thereto) pulvis and granule.In addition, but fluid can be have a cyclooxygenase-2 inhibitor be scattered in the suspension of the preferred water of liquid phase mutually with solid particulate.Particle to small part is nanoparticle mutually.When the such suspension of preparation, for example Spheron MD 30/70 or analogue are likely useful to adopt wetting agent.Can come prepare suspension by the nanoparticle cyclooxygenase-2 inhibitor that in liquid phase, disperses nanoparticle or part; Another kind method is, cyclooxygenase-2 inhibitor, and YM 177 for example can be from for example being to be precipitated out the solution of solvent with alcohol, preferred alcohols is an ethanol.Water preferably contains good to eat carrier for example water, syrup or as fruit juice such as Sucus Mali pumilaes.
Composition of the present invention is used for the treatment of and prevents the disease of the cyclooxygenase-2 mediation of unusual wide region.Present described composition is used for (not being formed on this but do not limit to) treatment curee's inflammation, as is used in pain killer and the febrifuge in the fever treatment in pain and the headache treating.For example, such composition can be used for the treatment of arthritis disease, comprises (but being not limited thereto) rheumatic arthritis, vertebral arthropathy, gouty arthritis, osteoarthritis, systemic lupus erythematous and adolescent arthritis.Such composition also can be used for treating asthma, bronchitis, dysmenorrhoea, premature labor, tendonitis, bursitis, supersensitivity neuritis, cytomegalovirus infection, the apoptosis that comprises HIV-inductive apoptosis, pain in the back, comprises the hepatopathy of hepatitis, the disease relevant with skin for example psoriasis, eczema, acne, ultraviolet injury, burn and dermatitis, and the post-operation inflammatory that comprises inflammation behind ophthalmologic operation such as cataract operation or the refractive surgery.Composition of the present invention can be used for treating gastrointestinal illness such as enteritis, Crohn disease, gastritis, pungency bowel syndrome and ulcerative colitis.Described composition can be used for treating the inflammation in the following disease, and these diseases such as migraine, polyarteritis nodosa, thyroiditis, aplastic anemia, lymphogranulomatosis, scleroderma, rheumatic fever, type i diabetes, neuromuscular junction disease comprise that myasthenia gravis, white matter disease comprise that the swelling that takes place after multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet, polymyositis, Gum disease, ephritis, allergy, the damage comprises cerebral edema, myocardial ischaemia etc.Described composition can be used for treating ophthalmic diseases, as the retinitis, conjunctivitis, retinopathy, uveitis, eye photophobia and ocular tissue's acute injury.Described composition can be used for treating pneumonia, as pneumonia relevant with virus infection and bladder fiber pathology, and can be used for treating bone absorpting disease as the bone absorpting disease relevant with osteoporosis.Described composition can be used for treating the central nervous system injury that some central nervous system disease such as cortex dementia comprise presenile dementia, neurodegenerative disorders and cause because of apoplexy, local asphyxia and wound.Term herein " treatment " comprises that part or all of inhibition is dull-witted, and dementia comprises Alzheimer's, vascular dementia, many infraction dementias, presenile dementia, alcoholic dementia and senile dementia.
Composition of the present invention is useful as anti-inflammatory agents particularly, as treatment of arthritis, and additional advantage is arranged, and is exactly that its toxic side effect is starkly lower than conventional NSAID (non-steroidal anti-inflammatory drug) (NSAIDs) composition.
Described composition can be used for treatment of allergic rhinitis, respiratory distress syndrome, endotoxin shock syndromes and hepatopathy.Described composition can be used for treating pain, comprises (but being not limited thereto) post-operative pain, toothache, myalgia and the pain that is caused by cancer.
Described composition can be used for the cardiomyopathy of (but being not limited thereto) treatment and prevention curee and inflammation-related.Described composition can be used for treatment and prevention vascular disease, coronary artery disease, aneurysma, blood vessel repels, arteriosclerosis, comprise the atherosclerotic atherosclerosis of heart transplantation, myocardial infarction, embolism, apoplexy, the thrombosis that comprises venous thrombosis, the angina that comprises unstable angina, the coronary pluques inflammation, the inflammation of bacteria-induction comprises clothing bacterium inductive inflammation, the inflammation of virus induction comprises the vascular transplantation of coronary artery bypass surgery with the inflammation relevant with surgical procedure, these surgical procedures, the revascularization process that comprises revascularization, place stent, endarterectomy or other relate to artery, the invasion procedure of vein and capillary vessel.Said composition can be used for the curee of (but being not limited thereto) treatment and associated angiogenesis disease.Composition of the present invention can need to suppress the curee of vasculogenesis.Said composition can be used for treating the formation of tumour, comprises metastases; Ophthalmic diseases for example corneal graft rejection, eye neovascularization, retina neovascularization comprises damage or infects back neovascularization, diabetic retinal diseases, macula lutea variation, retrolental fibroplasia and neovascular glaucoma; Ulcer disease is stomach ulcer for example; Morbid state but nonmalignant disease such as vascular tumor comprise baby's vascular tumor, nasopharyngeal fibrohemangioma and bone does not have angionecrosis; And disease in the female sexual system such as endometriosis.
Described composition can be used for prevention or treats optimum or malignant tumour/tumorigenesis, comprise cancer altogether, as colorectal carcinoma, the cancer of the brain, osteocarcinoma, come from epithelial tumour as rodent cancer, gland cancer etc. and form (epithelial cancer), as lip cancer, mouthful cancer, the esophageal carcinoma, carcinoma of small intestine and gastrointestinal system carcinomas such as cancer of the stomach, colorectal carcinoma, liver cancer, bladder cancer, carcinoma of the pancreas, ovarian cancer, cervical cancer, lung cancer, breast cancer and skin carcinoma are as the epithelial cancer of squamous cell and the low cell carcinoma of base, prostate cancer, renal cell carcinoma and the whole health of other known influence.Composition of the present invention especially effectively tumour is gastrointestinal cancer, Barret ' s esophagus cancer, liver cancer, bladder cancer, carcinoma of the pancreas, ovarian cancer, prostate cancer, cervical cancer, lung cancer, breast cancer and skin carcinoma such as squamous cell and rodent cancer.The present composition also can be used for the fibrosis that the radiotherapy treatment produces.Said composition can be used for treating the adenoma polyposis, comprises the curee of the adenoma polyposis (FAP) of familial.In addition, said composition can be used for preventing to form polyp in the patient that FAP danger is arranged.
Composition of the present invention has being similar to or is better than the anti-inflammatory of conventional non-steroidal anti-inflammatory drug composition, analgesic and analgesic properties.Described composition is inhibitory hormone inductive uterine contraction and have the potential antitumous effect also, but causes that the ability of the mechanism side effect of some common NSAIDs reduces.Particularly, compare with the NSAIDs composition of routine, composition of the present invention has potential reduce to comprise upper stomach intestinal ulcer and the hemorrhage gastrointestinal toxicity and the ability of gastrointestinal irritation, the ability that the side effect of potential minimizing kidney is gone down as the renal function that causes fluid retention and hypertension to increase the weight of, potential minimizing comprises the hematoblastic function of inhibition to the influence in bleeding time, and may reduce Asprin susceptibility asthmatic patient is induced the ability of asthma attack.
Described composition is used to alleviate pain, fever and the inflammation that various diseases causes, described disease comprises rheumatic fever, symptom, common cold, back and cervical pain, dysmenorrhoea, headache, the toothache relevant with influenza or other viral infection, dampens and sprain, myositis, neurodynia, synovitis, sacroiliitis comprise the damage that rheumatic arthritis, degenerative joint disease (osteoarthritis), gout and ankylosing spondylitis, bursitis, burn and surgical operation and tooth treatment cause.In addition, described composition suppresses the transfer of tumour cell and therefore the growth of metastatic tumor also can be used in for example colorectal carcinoma of treatment cancer.Described composition also is used for the treatment of and/or prevents the proliferative disease of cyclo-oxygenase mediation, and disease can occur in diabetic retinopathy and the tumor-blood-vessel growth disease as described.
Described composition by the synthetic inhibition prostaglandin(PG) inductive smooth muscle contraction of prevention shrinkability prostanoid and therefore can be used in treatment dysmenorrhoea, premature labor, asthma and with the eosinophil diseases associated.They also can be used in the treatment presenile dementia, are used to reduce particularly postmenopausal women's bone loss (promptly treating osteoporosis) and be used for the treatment of glaucoma of bone loss.
Because surpassing, the specificity of their high cyclooxygenase-2 (COX-2) inhibitor activity and/or their inhibition cyclooxygenase-2 suppresses cyclo-oxygenase-1 (COX-1), therefore, composition of the present invention can be used as the surrogate of conventional NSAIDs, especially when described NSAIDs is disabled, for example suffers from the patient of peptide ulceration, gastritis, regional enteritis, ulcerative conjunctivitis, diverticulitis or have the patient that history takes place gastrointestinal damage again; Gastrointestinal hemorrhage, hemopexis disease comprise anaemia, as hypoprothrombinemia, hemophilia or other bleeding problems; Ephrosis; Or patient before operation or the patient who takes antithrombotics.At John Vane, nature (Nature), Vol.367.pp.215-216,1994 and in medicine news and perspective (Drug News and perspectives), Vol.7, pp.501-512 provides the potential utility of simple description cyclooxygenase-2 inhibitor in 1994 the document.
The preferred effectiveness of pharmaceutical composition of the present invention is to be used for the treatment of rheumatoid arthritis and osteoarthritis, be used for alleviation, the treatment of presenile dementia and the chemoprophylaxis of colorectal carcinoma of pain (particularly oral cavity post-operative pain, general surgical postoperative pain, orthopedics's post-operative pain and acute attack osteoarthritis).
Because the advantage of the quick acting effect that pharmaceutical composition of the present invention shows, these compositions have than the disease that was used for the treatment of acute cyclooxygenase-2 mediation in the past, suppress the special advantage of compound formulation especially for lenitive cyclooxygenase-2.
Composition of the present invention can be used in combination treatment with opioid and other analgesic agent, and described analgesic agent comprises opioid analgesics, Mu receptor antagonist, Kappa receptor antagonist, non-narcotic (being habituation) analgesic agent, monoamine uptake inhibitor, adenosine conditioning agent, hemp chemical ingredients derivative, P substance antagonist, antagonists of neurokinine-1 receptor and sodium channel blockers etc.Preferred combined treatment comprises the use present composition and is selected from following compounds: morphine, pethidine, morphine monomethyl ether, pentazocine; buprenorphine; butorphanol; Wy-16225; meptazinol; hydrocodone; oxycodone; methadone; DuP-747; dynorphin (Dynorphine) A, enadoline; RP-60180; HN-11608; E-2078; ICI-204448; paracetamol (Paracetamol); Propoxyphene; nalbuphine; E-4018; filenadol; OHM 3508; amitriptyline; DuP-631; GP-531; Acadesine; AKI-1; AKI-2; GP-1683; GP-3269; 4030W92; tramadol raceme and isolating (+) and (-) enantiomer; AXC-3742; SNX-111; ADL2-1294; CT-3 and CP-99994.
The cyclooxygenase-2 inhibitor that can select to contain specified quantitative is the dose unit of YM 177 for example, to provide any adopted required administration frequency to reach required dosage every day.Every day, dosage and administration frequency reached the suitable dose unit of selecting thus, depended on many factors, comprised curee's age, body weight, sex and the medical conditions and the essence and the seriousness of illness or disease, thereby can extensively change.
Under the situation of YM 177, for composition of the present invention, provide YM 177 required every day dosage once a day or every day secondary oral administration method demonstrate than the improved effect of other medication.Thereby, in order to suppress the disease of cyclooxygenase-2 mediation on the therapeutics or on the prophylactic effectively, preferably with composition of the present invention once a day or every day the secondary oral administration.
For the treatment of rheumatic arthritis, can use composition of the present invention to provide the about 50mg of YM 177 dosage every day to about 1000mg, preferably about 100mg is to about 600mg, and more preferably from about 150mg is to about 500mg, and further preferred about 175mg is to about 400mg, for example about 200mg.Dosage can be once a day, every day secondary, every day three times, or more.For example, dosage can be 200mg, every day secondary.When giving composition of the present invention, usually suitable YM 177 dosage every day is about 0.67 to about 13.3mg/kg body weight, preferred about 1.33 to about 8.00mg/kg body weight, 2.00-6.67mg/kg body weight more preferably from about, and further preferred about 2.33-5.33mg/kg body weight, for example about 2.67mg/kg body weight.Every day, dosage can divide every day 1-4 dosage, preferred every day 1 or 2 administrations.For Most patients, preferably with every next 100mg dose unit, twice speed administration every day, but for some patient, with every next 200mg dose unit or two 100mg dose units, every day, twice speed administration was favourable.
Treatment for osteoarthritis, can use composition of the present invention to provide the about 50mg of YM 177 dosage every day to about 1000mg, preferably about 100mg is to about 600mg, and more preferably from about 150mg is to about 500mg, and further preferred about 175mg is to about 400mg, for example about 200mg.When giving composition of the present invention, usually suitable YM 177 dosage every day is about 0.67 to about 13.3mg/kg body weight, preferred about 1.33 to about 8.00mg/kg body weight, 2.00-6.67mg/kg body weight more preferably from about, and further preferred about 2.33-5.33mg/kg body weight, for example about 2.67mg/kg body weight.Every day, dosage can be by 1-4 dosage every day, preferred every day 1 or 2 dosage.Preferably with every day a 100mg dose unit, every day twice, perhaps every next 200mg dose unit or two 100mg dose units, speed once a day gives composition of the present invention.
For Alzheimer, can use composition of the present invention to provide the about 50mg of YM 177 dosage every day to about 1000mg, preferably about 100mg is to about 800mg, and more preferably from about 150mg is to about 600mg, and further preferred about 175mg is to about 400mg, for example about 400mg.When giving composition of the present invention, usually suitable YM 177 dosage every day is about 0.67 to about 13.3mg/kg body weight, preferred about 1.33 to about 10.67mg/kg body weight, 2.00-8.00mg/kg body weight more preferably from about, and further preferred about 2.33 to about 5.33mg/kg body weight, for example about 5.33mg/kg body weight.Every day, dosage can be by 1-4 dosage every day, preferred every day 1 or 2 dosage.For Most patients, preferably with every next 200mg dose unit or two 100mg dose units, every day twice speed give composition of the present invention.
For treatment for cancer, can use composition of the present invention to provide the about 50mg of YM 177 dosage every day to about 1000mg, preferably about 100mg is to about 800mg, and more preferably from about 150mg is to about 600mg, and further preferred about 175mg is to about 400mg, for example about 400mg.When giving composition of the present invention, usually suitable YM 177 dosage every day is about 0.67 to about 13.3mg/kg body weight, preferred about 1.33 to about 10.67mg/kg body weight, 2.00-8.00mg/kg body weight more preferably from about, and further preferred about 2.33-5.33mg/kg body weight, for example about 5.33mg/kg body weight.Every day, dosage can be by 1-4 dosage every day, preferred every day 2 dosage.For Most patients, preferably with every next 200mg dose unit or two 100mg dose units, every day twice speed give composition of the present invention.
For treatment of pain, can use composition of the present invention to provide the about 50mg of YM 177 dosage every day to about 1000mg, preferably about 100mg is to about 600mg, and more preferably from about 150mg is to about 500mg, and further preferred about 175mg is to about 400mg, for example about 200mg.When giving composition of the present invention, usually suitable YM 177 dosage every day is about 0.67 to about 13.3mg/kg body weight, preferred about 1.33 to about 8.00mg/kg body weight, more preferably from about 2.00 to about 6.67mg/kg body weight, and further preferred about 2.33 to about 5.33mg/kg body weight, for example about 2.67mg/kg body weight.Every day, dosage can be by 1-4 dosage every day.Preferably with every next 50mg dose unit, four times a day, perhaps every next 100mg dose unit, perhaps each two 50mg dose units, every day twice, perhaps every next 200mg dose unit or two 100mg dose units or four 50mg dose units, speed once a day give composition of the present invention.
In a word, preferably give the present composition, during after the administration about 24 hours, make curee's YM 177 average serum concentration be at least about 100ng/ml so that described dosage to be provided with appropriate dosage and frequency.
YM 177 content in the present composition preferably in scope disclosed herein in, said composition also can be used for the administration of YM 177 dosage outside open dosage range.For other selective cyclooxygenase-2 inhibitor, by selecting suitable dosage with reference to the patent documentation of above quoting.
Contain or suppress compound by the selective cyclooxygenase-2 of low water solubility, for example YM 177, moral draw gratifying, watt moral is gratifying or sieve nanoparticle of gratifying composition not, can prepare according to the method for the preparation of in the past any poor water soluble drug that is applied to other nanoparticle form.For the appropriate methodology of such other medicines, be disclosed in to illustrative the above United States Patent (USP) of quoting as proof 4,826,689,5,145,684,5,298,262,5,302,401,5,336,507,5,340,564,5,346,702,5,352,459,5,354,560,5,384,124,5,429,824,5,510,118,5,518,738,5,503,723,5,534,270,5,536,508,5,552,160,5,560,931,5,560,932,5,565,188,5,569,448,5,571,536,5,573,783,5,580,579,5,585,108,5,587,143,5,591,456,5,662,883,5,665,331,5,718,919 and 5,747,001, and international publication WO93/25190 cited above, WO96/24336 and WO98/35666, but be not limited only to this, more than all disclosed texts in the lump as a reference.Those of ordinary skill in the art can easily adopt wherein the method for describing, and is used to prepare the selective cyclooxygenase-2 inhibitor of the nanoparticle form of poorly water-soluble, for example YM 177, moral draw gratifying, watt moral is gratifying or sieve is not gratifying.
Any vehicle that composition of the present invention uses can be that solid or liquid or both all can.Said composition preferably contains, and in selective cyclooxygenase-2 inhibitor weight, about 1% to about 95%, and preferred about 10 to about 90%, and more preferably from about 25% to about 85%, and further preferred about 30% to about 80%, for example YM 177.The composition of the present invention that contains vehicle can any usually known pharmacopedics technology prepare, it comprises mixes vehicle with medicine or therapeutical agent, except under the situation that has medicine or therapeutical agent, promptly prepare selective cyclooxygenase-2 inhibitor to small part, with one or more vehicle, exist alternatively with the nanoparticle form of above pointing out.
The every dose unit of composition of the present invention contains the cyclooxygenase-2 inhibitor of aequum, YM 177 for example, and can be tablet for example, pill, hard or soft capsule, lozenge, cartridge bag, dispersion powder, granule, suspension, elixir, liquid, or any other oral administration may adopt suitable formulation.Such composition preferred preparation becomes the dispersion dose unit of each cyclooxygenase-2 inhibitor that contains predetermined amount, for example tablet or capsule.These oral dosage forms can further comprise, for example, and buffer reagent.Tablet, pill and other formulations can dressings or dressing not.
For example, the composition of the present invention that is applicable to oral cavity or sublingual administration is included in lozenge that contains YM 177 in flavoring matrix such as sucrose and gum arabic or the tragakanta and the pastille that contains YM 177 in inert base such as gelatin and glycerine or sucrose and gum arabic.
The liquid dosage form of oral administration comprises pharmaceutically acceptable suspension, syrup and the elixir that contains normally used inert diluent in this area such as water.Described composition also can comprise for example wetting agent, emulsifying agent and suspension agent, sweeting agent, correctives and spices.
As mentioned above, can prepare the present composition that contains vehicle by any suitable pharmaceutical methods, described pharmaceutical methods comprises makes cyclooxygenase-2 inhibitor (at least partially with the nanoparticle form) and vehicle bonded step.In a word; described preparation of compositions is cyclooxygenase-2 to be suppressed the thinner of compound (hereinafter referring to " nanoparticle compound " sometimes) and liquid or pulverizing or the two evenly and fully mixes; then, if desired or wish, encapsulation capsule or with formed product.For example, tablet can prepare with one or more vehicle compressing tablets or mold pressing by powder or the particle with the nanoparticle compound.The preparation compressed tablets can be in suitable machine, will contain the nanoparticle compound and selectively mix free-pouring composition such as the powder or the particle compressing tablet of one or more tackiness agents, lubricant, inert diluent, wetting agent and/or dispersion agent.The mold pressing tablet can will prepare with the wetting nanoparticle compound mold pressing of inert liquid diluent by in suitable machine.
As mentioned above, the partly or wholly nanoparticle selective cyclooxygenase-2 that every dose unit of the present composition comprises treatment or prevention significant quantity suppresses compound, YM 177 for example, and one or more are applicable to the pharmaceutically acceptable vehicle of oral administration.Composition of the present invention preferably includes the nanoparticle compound of aequum and one or more mixed with excipients, and described vehicle is selected from pharmaceutically acceptable thinner, disintegrating agent, tackiness agent, tackiness agent, wetting agent, lubricant and antitack agent.In addition, nanoparticle itself selectively contains just like disclosed one or more matrix polymers and/or surface-modifying agent in several documents cited above.More preferably, with such composition with immediate release capsule or tablet form compressing tablet or encapsulation capsule, for use in conventional administration.
By the suitable selection and the combination of vehicle, compatibility, security, solubilized form, disintegration form and/or other pharmacokinetics, chemistry and/or the physical properties aspect that can be provided at other character, effect, biological utilisation, elimination time, stability, YM 177 and carrier substance show the composition that improves performance.Preferred vehicle is water-soluble or water-dispersible and has wettability, can offset the low water solubility and the hydrophobicity of cyclooxygenase-2 inhibitor thus.When described preparation of compositions was become tablet, the combination of selected vehicle provided except that other character, improved tablet aspect dissolving and disintegration form, hardness, shatter strength and/or friability.
Composition of the present invention comprises that selectively one or more pharmaceutically acceptable thinners are as vehicle.Suitable thinner comprises lactose USP independent or combination; Lactose hydrous USP; Spray-dired lactose USP; Starch USP; The starch of directly compressible; Mannitol USP; Sorbitol Powder; Glucose monohydrate; Microcrystalline Cellulose NF; Bibasic calcium phosphate dihydrate NF; Thinner based on sucrose; Commercially available sugar; One alkali valency calcium sulfate monohydrate; Calcium sulfate dihydrate NF; Calcium lactate trihydrate particle NF; DextratesNF (for example, Emedx); Celutab; Glucose (for example cerelose); Inositol; The cereal solid of hydrolysis is Maitrons and Mor-Rex for example; Amylose starch; Rexcel; Powdery cellulose (for example Elcema); Lime carbonate; Glycine; Wilkinite; Polyvinylpyrrolidone, or the like.If exist, such thinner account for composition total weight about 5% to about 99%, preferred about 10 to about 85%, more preferably from about 20% to 80%.Preferably, selected thinner has suitable flowability properties, and when the needs tablet, also requires to have compressibility.
Lactose and Microcrystalline Cellulose independent or combination are effective thinners.Two kinds of thinners and YM 177 are that chemistry is compatible.Use the outer Microcrystalline Cellulose of particle (that is, after drying step, add in the wet granulation composition Microcrystalline Cellulose) to can be used for improving hardness (for tablet) and/or disintegration time.Lactose, particularly Spherolac 100 are particularly preferred.Typically, lactose is with low relatively thinner cost, provide have suitable cyclooxygenase-2 inhibitor rate of release, the composition of flowable and/or drying property before the stability, compressing tablet.It provides a kind of high-density matter, and this (if using wet granulation) process that helps granulating makes composition density increase and therefore improve the flowability of mixture.
Composition of the present invention selectively contains one or more pharmaceutically acceptable disintegrating agents as vehicle, particularly for tablet.The disintegrating agent that is fit to comprises, starch independent or combination, sodium starch glycollate, clay (for example Veegum HV), Mierocrystalline cellulose (as pure cellulose, methylcellulose gum, Xylo-Mucine and carboxymethyl cellulose), alginate, the W-Gum (as National 1551 and National 1550) of pre-gelledization, crosslinked polyvinyl pyrrolidone USP NF and natural gum (as agar, guar gum, Viscogum BE, kuteera gum, pectin and tragakanta).Disintegrating agent can be in any suitable step of preparation said composition, and particularly the lubricated step before granulation or before compressing tablet adds.If exist, such disintegrating agent account for composition total weight about 0.20% to about 30%, preferred about 0.20% to about 10%, and more preferably from about 0.2% to about 5%.
Croscarmellose sodium is the disintegrating agent that preferably is used for tablet or capsule disintegration, and if exist, preferably account for composition total weight about 0.2% to about 10%, more preferably from about 0.2% to about 6%, and further preferred about 0.2% to about 5%.Croscarmellose sodium makes the present composition have disintegration ability in the bigger particle.
Composition of the present invention selectively contains one or more pharmaceutically acceptable tackiness agents or tackiness agent as vehicle, particularly for tablet.Such tackiness agent and tackiness agent are preferably given and are provided enough viscosity by the compressing tablet powder, allowing normal technological operation as adjusting size, lubricated, compressing tablet and packing, and when taking in, make described tablet energy disintegration and said composition is absorbed.Tackiness agent that is fit to and tackiness agent comprise gum arabic independent or combination, tragakanta, sucrose, gelatin, glucose, starch, for example (but being not restricted to this) methylcellulose gum and Xylo-Mucine be (for example, Tylose) for cellulosic material, alginic acid and alginate thereof, magnesium aluminum silicate, polyoxyethylene glycol, guar gum, polysaccharide acid, wilkinite, polyvinylpyrrolidone, polymethacrylate, Vltra tears (HPMC), hydroxypropylcellulose (Klucel), ethyl cellulose (Ethocel), the starch of pre-gelledization (as National 1551 and starch 1550).If exist, this tackiness agent and/or tackiness agent account for composition total weight about 0.5% to about 25%, preferred about 0.75% to about 15%, and more preferably from about 1% to about 10%.
Polyvinylpyrrolidone is the preferred adhesive that is used for providing for cyclooxygenase-2 inhibitor and other excipient powders mixture in granulation viscosity.If exist, polyvinylpyrrolidone accounts for composition total weight preferably about 0.5% to about 10%, and more preferably from about 0.5% to about 7%, and further preferred about 0.5% to 5%.Although the viscosity of preferably polyethylene pyrrolidone is approximately 6cPs or lower, particularly about 3cPs or lower also can use the polyvinylpyrrolidone of viscosity up to about 20cPs.Polyvinylpyrrolidone provides powdered mixture cohesiveness and promotes essential combination so that form particle in wet granulation.
The cyclooxygenase-2 that the present invention adopts suppresses compound, particularly YM 177, in the extremely water insoluble solution.Therefore, composition alternative of the present invention comprises but preferably comprises one or more pharmaceutically acceptable wetting agents as vehicle.Preferably, the selective wetting agent is so that keep cyclooxygenase-2 inhibitor and water to combine closely, and this has thought to improve the condition of the relative biological utilisation of pharmaceutical composition of the present invention.The wetting agent that is fit to comprises oleic acid, Zerol, dehydrated sorbitol mono-fatty acid ester, sorbitan monolaurate, Emulphor FM, polyoxyethylene sorbitan monoleate, polyoxyethylene sorbitan mono-laurate, sodium oleate and sodium lauryl sulphate independent or combination.Anion surfactant as wetting be preferred.If exist, described wetting agent account for composition total weight about 0.25% to about 15%, preferred about 0.4 to about 10%, more preferably from about 0.5% to about 5%.
Sodium lauryl sulphate is preferred wetting agent.If exist, sodium lauryl sulphate account for composition total weight about 0.25% to about 7%, more preferably from about 0.4% to about 6%, and further preferred about 0.5% to about 5%.
Composition of the present invention selectively comprises one or more pharmaceutically acceptable lubricants and/or glidant as vehicle.Lubricant that is fit to and/or glidant comprise glyceryl behapate (Compritol 888) independent or combination; Stearate (Magnesium Stearate, calcium and sodium), stearic acid, hydrogenated vegetable oil (for example complete hydrogenated vegetable oil), talcum powder, wax, Stearowet, boric acid, Sodium Benzoate, sodium acetate, sodium fumarate, sodium-chlor, DL-leucine, polyoxyethylene glycol (for example wax shape polyoxyethylene glycol and methoxy poly (ethylene glycol) mixture 4000 and 6000), sodium oleate, sodium lauryl sulphate and Stepanol MG.If exist, such lubricant account for composition total weight about 0.1% to about 10%, preferred about 0.2% to about 8%, and more preferably from about 0.25% to about 5%.
For example, Magnesium Stearate is to be used for the preferred emollient that rubs between minimizing equipment and the granulation mixture in the compressing tablet process.
Other vehicle (for example antitack agent, tinting material, correctives, sweeting agent and sanitas) is that pharmacy field is known and can be included in the present composition.For example ferric oxide can be added in the described composition so that form yellow.
In one embodiment of the present invention, composition with capsule or tablet as unitary dose and comprise aequum, be granular selective cyclooxygenase-2 inhibitor of millimicro (for example YM 177) and tackiness agent partly or entirely.Preferably, said composition further comprises one or more vehicle, and this vehicle is selected from pharmaceutically acceptable thinner, disintegrating agent, tackiness agent, wetting agent and lubricant.More preferably, said composition comprises that one or more are selected from the vehicle of lactose, sodium lauryl sulphate, polyvinylpyrrolidone, croscarmellose sodium, Magnesium Stearate and Microcrystalline Cellulose.Further preferred described composition comprises lactose-hydrate and croscarmellose sodium.Further more preferably, described composition further comprises one or more carrier substance sodium lauryl sulphate, Magnesium Stearate and Microcrystalline Cellulose.
Although can prepare dose unit capsule of the present invention and tablet composition by for example directly encapsulating capsule or direct compression, they are wet granulation before the encapsulation capsule and before the compressing tablet preferably.Except that other influence, wet granulation can make the levigated composition density increase, thereby improves flowable, improves the weight distribution that compressing tablet and easier metering or improvement are used to encapsulate capsule or compositions for tableting.The secondary granularity that granulation obtains (being granular size) not merely is crucial, its only in preferred average particle size so that handle and processing aspect be important, and for tablet, but allow to form the mixture of the direct compressing tablet of the pharmaceutically acceptable tablet of preparation.
Bulk density that particle is required and tap density are generally about 0.3g/ml to about 1.0g/ml.
The vehicle that is used for capsule of the present invention and tablet composition preferably selects to provide the disintegration time less than about 30 minutes, and preferred about 25 minutes or still less, more preferably from about 20 minutes or still less, more preferably 15 minutes or still less.
For tablet formulation, will be enough to make homogeneous whole mixtures compressing tablet in the preparative scale tabletting machine of routine of the quantity of tablet in batches, use normal pressure (as, in a typical compressing tablet punch die, use the extremely pressure of about 50kN of about 1kN).Can adopt any tablet hardness of operating, produce, store, taking in of being suitable for.For the 100mg tablet, hardness preferably is at least 4kP, more preferably is at least about 5kP, further preferably is at least about 6kP.For the 200mg tablet, hardness preferably is at least 7kP, more preferably is at least about 9kP, further preferably is at least about 11kP.Yet, mixture is not pressed onto so degree, otherwise when being exposed to gastric juice along with meeting generation hydration difficulty.
For tablet formulation, in standard test, preferred tablet fragility is more preferably less than 0.8%, further preferably less than about 0.5% less than about 1.0%.
The present invention also relates to a kind of method for the treatment of illness or disease, wherein use cyclooxygenase-2 inhibitor to treat, present method comprises to the present composition that needs oral one or more dose units of curee.For preventative, alleviate the state of an illness, or improve illness or the used dosage of disease preferably be equivalent to above-mentioned once a day or treat for twice every day, but can change according to various factors.These factors comprise type, age, body weight, sex, diet, and curee's the state of an illness and the character and the severity of disease.Therefore, the actual dosage that adopts can have bigger change, and can depart from the above preferred dosage regimen that provides.
The use cyclooxygenase-2 inhibitor can be from above-mentioned dosage to the initial treatment of the curee who suffers from illness or disease.Usually lasting several weeks to several months of necessary treatment or several years are until illness or disease is controlled or elimination.Can carry out the routine monitoring to measure result of treatment to the patient who stands present composition treatment with any method well known in the art.These data of successive analysis make can improve this treatment plan in therapeutic process, thereby a time point in office can take the optimum significant quantity of cyclooxygenase-2 inhibitor, and thereby can also determine to treat the time length.In this way, in therapeutic process, can rationally change treatment plan/dosage arrangement, thereby can be by the minimum quantity administration of the cyclooxygenase-2 inhibitor that shows satisfactory effect, and administration only continue successfully to treat disease in case of necessity between.
The present invention also relates to prepare the weak water miscible cyclooxygenase-2 inhibitor that contains of the present invention, YM 177 for example is partly or entirely with the method for compositions of nanoparticle form.More particularly, the present invention relates to prepare method with this based composition of the tablet of isolating unitary dose or capsule form, therefore each tablet or capsule contain the cyclooxygenase-2 inhibitor of q.s, so that above-mentioned quick initial treatment effect to be provided, and preferred about 12 to 24 hours continued treatment effect.Each tablet or capsule preferably contain the 50mg that has an appointment to about 200mg, 50mg according to appointment, and about 100mg or about 200mg cyclooxygenase-2 inhibitor are as YM 177.The present invention can use wet granulation, dry granulation or directly suppress or encapsulate tablet or the capsule that the capsule legal system is equipped with composition of the present invention.
Wet granulation is the preferred method of preparation pharmaceutical composition of the present invention.In wet-granulation process, with the cyclooxygenase-2 inhibitor (when needing, can use) that is not included in any part of nanoparticle form with one or more carrier substance at first levigate or micronize to required size range greater than 1mm.Though can use the runner milling or the granulator of various routines, medicine is impacted to mill mills (pin milling) as the bolt formula, with other modes mill mutually that specific energy provides the improved final composition blended homogeneity that reaches.In mill processes, with the material cooling of milling, may be necessary as using liquid nitrogen to cool off, can avoid cyclooxygenase-2 inhibitor is heated to unwanted temperature.In this mills step, D 90Granularity preferably is reduced to less than about 25mm.
To mill then or micronized cyclooxygenase-2 inhibitor (even having also seldom); mix with the cyclooxygenase-2 inhibitor of the nanoparticle form of the above-mentioned any means known in the art preparation of the usefulness of aequum, so that the granular cyclooxygenase-2 inhibitor compound of part or all of millimicro (" nanoparticle compound ") to be provided.
Simultaneously or subsequently; with the nanoparticle compound; as at one high-shear mixer/nodulizer; planetary-type mixer; in double-walled mixing tank or the crank throw formula mixing tank; comprise the vehicle of milling with one or more vehicle, or the vehicle of nanoparticle form forms powder mixture together with YM 177.Usually, in this step, nanoparticle compound and one or more thinners, disintegrating agent and/or tackiness agent; and selectively; mix with one or more wetting agents, but another kind of spendable method is to add one or more excipient of all or part in step subsequently.For example, in using the tablet formulation of croscarmellose sodium as disintegrating agent, found in mixing step (intragranular croscarmellose sodium is provided), to add partial cross-linked Xylo-Mucine, and add remainder afterwards at drying step discussed below (particle external crosslinking Xylo-Mucine is provided), can promote the disintegration of prepared tablet.In the case, preferably in particle, add about 60%, outside particle, add about 25% to about 40% croscarmellose sodium to about 70% croscarmellose sodium.Similarly, for tablet formulation, found behind following drying step, to add that Microcrystalline Cellulose (Microcrystalline Cellulose outside the particle) can improve the particulate compressibility and with the hardness of the tablet of this granules preparation.
The mixing step of present method preferably includes nanoparticle compound, lactose, polyvinylpyrrolidone and croscarmellose sodium is mixed.Found that mixing time is as short as the enough uniform powder mixture of the distribution that cyclooxygenase-2 inhibitor can be provided in 3 minutes.
With water, preferred purified water adds in the powder mixture then, mixture is further mixed for some time, to form wet grain mixture.A kind of wetting agent of preferred use, and preferably elder generation adds it in entry and mixed at least 15 minutes, preferably mixing is at least 20 minutes, water is added in the powder mixture again.Water can add in the mixture at once, progressively add in for some time, or is divided into several parts of addings in for some time.Preferably water was progressively added in for some time.Another kind of spendable method is, wetting agent can be added in the powder mixture, then water added in the formed mixture.The preferred homogeneity of additionally mixed for some time to guarantee that water distributes in mixture again after adding entry.
A mixture that preferably will wet then carries out wet-milling, as with screening shredder, forms the condensed matter of byproduct with elimination in the wet granulation operation.If can not remove, these condensation products will prolong fluidised bed drying operation subsequently and increase the variation of humidity control.
To wet then grain or wet-milling mixture drying for example, are carried out in a baking oven or fluidized bed dryer, and fluid bed drier is to form dried particles.If desired, a mixture that can will wet before dry pushes or a nodularization (spheronize).For drying process, can regulate operational condition such as inlet air temperature and time of drying so that the required water content that dried particles reaches.For this drying step and processing step subsequently, 2 or a plurality of granulation process are combined and will be ideal.
For reaching the degree that needs, then the particle size reduction of dried particles is suppressed and encapsulates capsule to prepare so that be.Can use the conventional equipment that granularity is reduced such as vibrator or impact mill (as Fitz mills).
Along with the increase of the mixing time of the low mixture of water content can be observed granularity reduction is arranged slightly.Supposing that water content is crossed low can not fully activate employed tackiness agent, and the cohesive force deficiency in particle between the primary particle be so that particle can not bear the shearing force that blender blade produces, thereby granularity wearing and tearing rather than increase.Normally, increase water content and make the cohesive force between primary particle can bear the shearing force that blender blade produces, and make grain growth but not wear and tear along with the increase of mixing time and/or amount of water with abundant activated adhesive.Change wet grinding device screen sizes and can produce bigger impact to granularity than changing input speed and/or grinding rate.
Then dry powder particle is placed in the mixing tank that suits, as the double-walled mixing tank, can select to add lubricant (as Magnesium Stearate) and any other carrier substance (as in a certain tablet formulation, adding Microcrystalline Cellulose outside the particle and/or the croscarmellose sodium outside the particle) to form finally through the blended mixture.Comprise Microcrystalline Cellulose at this thinner, having found to add in addition in this step a part of Microcrystalline Cellulose can increase particulate compressibility and tablet hardness.Yet the quantity that increases Magnesium Stearate surpasses the hardness that about 1%-2% can reduce tablet, and increases fragility and dissolution time.
Then will be finally through the encapsulation of blended mixture (, mixture being pressed into the tablet of required weight and hardness with the instrument of suitable size) perhaps if the preparation tablet.Can adopt known conventional compacting of those of ordinary skills and encapsulation technology.For capsule, by using the height of bed of about 20mm to about 60mm, about compression set of 0 to about 5mm reaches per hour about 60,000 capsules to about 130,000 capsular speed, the result that can obtain suiting.By using the compression set of the minimum that can control capsules weight, can reduce or eliminate the formation of block.When the need of coating tablet, can adopt the known conventional packaging technique of those of ordinary skills.
Combination results cyclo-oxygenase 2 inhibitor such as the YM 177 homogeneous granules of operating unit, its content is in unit dosage level, disintegration promptly, then discharge fully, thereby in filled capsules or compressing tablet process, can control changes in weight reliably, and enough density is arranged, thereby in selected equipment, can produce in batches, and be suitable for particular capsule or the molded single dose of tablet.
The present invention also relates to the present composition and treat and/or prevent by the application in the medicine of the illness of cyclooxygenase-2 mediation and disease, in these illnesss and disease, need or wish to obtain the quick acting of curative effect especially in preparation.
The present invention also comprises a kind of new solid-state version of YM 177, I type YM 177.The present invention further comprises another solid-state version of YM 177, II type YM 177.Every kind of these new solid-state version comprises the crystal formation of solvation, the crystal formation of non-solventization and non-hydrated.With described in this paper document or in addition disclosed other solid-state versions compare, described these the novel YM 177 of the application have one or more above-mentioned superior chemistry and/or physical propertiess.
In one embodiment of the present invention, solid-state version comprises I type YM 177.Do not limit the present invention, think that I type YM 177 has high solvability and dissolution rate faster than III type YM 177, because the III type has better thermodynamic stability than I type, and because the III type has lower free energy than I type.Fast dissolution rate is a kind of useful properties, can increase its bioavailability usually because increase the dissolution rate of medicine.
I type YM 177 is the crystal formation of YM 177, and its X-ray powder diffraction spectrogram has the peak at about 5.5,5.7,7.2 and 16.6 degree 2 θ places.I type YM 177 X-ray powder diffraction spectrogram is basic as being shown in the top figure of Fig. 1 a.The fusing point of I type YM 177 is about 162.5 ℃ to about 163 ℃, is preferably about 162.8 ℃.When as shown in Figure 3, when with 0.5 ℃ of/minute scanning, I type YM 177 has differential scanning calorimetric heat absorption maximum value in about 163.3 ℃.The infrared spectra of I type YM 177 is shown in Fig. 2, it is characterized by at about 3250cm -1And 3260cm -1The peak is arranged, and another peak is at 3350cm -1And 3360cm -1Between, preferably this peak is respectively at 3256cm -1And 3356cm -1Solid-state version of the present invention has phase purity and is at least about 5%I type YM 177, preferably at least about 10%I type YM 177, more preferably at least about 25%I type YM 177, further preferably at least about 50%I type YM 177, again further preferably at least about 75%I type YM 177, also further preferably at least about 90%I type YM 177, and most preferably has the basic I type YM 177 phase purity that is.
In another embodiment of the invention, a kind of pharmaceutical composition is provided, it comprises the solid-state version YM 177 and at least a pharmaceutically acceptable carrier for the treatment of significant quantity, auxiliary agent or thinner, wherein the solid-state version YM 177 contains 2%I type YM 177 at least, and preferred 10%I type YM 177, or more preferably 50%I type YM 177, further preferred 98%I type YM 177.In a kind of preferred embodiment, the solid-state version YM 177 mainly is an I type YM 177.
In another embodiment of the invention, described the curee is treated or prevents the illness of cyclooxygenase-2 mediation or the method for disease, present method comprises the I type YM 177 to curee's administering therapeutic significant quantity.Preferably, treat or prevent illness or disease by the cyclooxygenase-2 mediation is pain, infection, sacroiliitis, tumor growth, transfer, or the familial adenomatous polyposis disease.
Another embodiment of the present invention is the method for preparing I type YM 177, wherein this method comprises and makes the crystallization from the mixture that contains YM 177 and solvent of I type YM 177, wherein is to carry out crystalline under the temperature of the mapping sex reversal temperature that is higher than I type YM 177.Before the crystallization of I type YM 177, can in solvent, come seeding by the crystal seed with I type YM 177, cause producing I type YM 177, it has at least about 5 weight % phase purity, preferably at least about 10 weight % phase purity, more preferably at least about 25 weight % phase purity, more preferably at least about 50 weight % phase purity, also further preferably at least about 90 weight % phase purity.
The present invention also relates to prepare the crystal formation of YM 177, wherein this method comprises the solvate that heats YM 177, thereby produces I type YM 177.For example this solvate can be heated to about 50 ℃ to about 160 ℃ temperature, preferred about 60 ℃ to about 150 ℃, more preferably from about 70 ℃ to about 140 ℃, also preferred about 80 ℃ to about 130 ℃, also more preferably from about 85 ℃ to about 120 ℃, further preferred about 90 ℃ to about 110 ℃, most preferably from about 100 ℃.Can carry out the heating of any conventional time, surpass about 1 minute, preferably surpass about 5 minutes, more excellently surpass about 60 minutes as heating, also more preferably from about 2 hours, also further preferred about 4 hours or longer.In addition, can under any pressure, carry out this method, be preferably lower than normal atmosphere.The used solvate of the present invention contains YM 177 and solvent.For example solvent can be an amide solvent.Useful amide solvent comprises N, dinethylformamide, N,N-dimethylacetamide, 1-Methyl-2-Pyrrolidone, 1,3-dimethyl-3,4,5,6-tetrahydrochysene-2 (1H)-pyrimidone and 1,1,3,3-tetramethyl-urea, or any mixture of these solvents.Preferred solvent is 1,1,3, the 3-tetramethyl-urea.Another preferred solvent is 1,3-dimethyl-3,4,5,6-tetrahydrochysene-2 (1H)-pyrimidone.It is 1-Methyl-2-Pyrrolidone that another preferred solvent is arranged again.Also having another preferred solvent is N, dinethylformamide.Also having another preferred solvent is N,N-dimethylacetamide.
The method for preparing solvate comprise with YM 177 be selected from following amide solvent and mix: N, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, 1-Methyl-2-Pyrrolidone, 1,3-dimethyl-3,4,5,6-tetrahydrochysene-2 (1H)-pyrimidone and 1,1,3,3-tetramethyl-urea, or any mixture of these solvents.Preferred solvent is 1,1,3, the 3-tetramethyl-urea.Another preferred solvent is 1,3-dimethyl-3,4,5,6-tetrahydrochysene-2 (1H)-pyrimidone.Also having another preferred solvent is 1-Methyl-2-Pyrrolidone.It is N that another preferred solvent is arranged again, dinethylformamide.Also having another preferred solvent is N,N-dimethylacetamide.
The present invention also relates to prepare the method for I type YM 177, wherein this method comprises the III type YM 177 that grinds or mill.The useful step that grinds for example comprises wet-milling or ball milling.The useful step of milling can comprise as grinding or shaking.
The present invention also relates to prepare the method for I type YM 177, wherein this method comprises the YM 177 solvate that grinds or mill.Useful grind step and for example can comprise wet-milling or ball milling.The useful step of milling can comprise as grinding or shaking.
Another embodiment of the present invention is the method for preparing I type YM 177, and wherein this method comprises fusing II type YM 177 and cold this this melt, thereby produces I type YM 177.
Another embodiment of the present invention is the method for preparing I type YM 177, and wherein this method comprises fusing III YM 177 and cools off this melt, thereby produces I type YM 177.
The present invention also relates to prepare the method for I type YM 177, wherein this method comprises evaporating solvent from YM 177 solution.For example solvent can be ether or hydrocarbon, or the mixture of ether and hydrocarbon.Preferred solvent comprises ethyl acetate and heptane, and preferred proportion is 15: 85.Can under any pressure, carry out present method, preferably be lower than normal atmosphere.Can under the temperature of a wide region, carry out this method, preferably at about 35 ℃.
In another embodiment of the invention, solid-state version comprises II type YM 177.Do not limiting under the situation of the present invention, think that II type YM 177 has high solvability and dissolution rate faster than III type YM 177, because III type YM 177 has better thermodynamic stability than II type YM 177, and because III type YM 177 has lower free energy than II type YM 177.Fast dissolution rate is useful, can increase its bioavailability usually because increase the dissolution rate of medicine.
II type YM 177 has X-ray powder diffraction spectrogram and at about 10.3,13.8,17.7 degree 2 θ places the peak is arranged.The peak of the mixture of YM 177 I type and II type is shown in the figure at the top of Fig. 1 b.The fusing point of II type YM 177 is about 161 ℃ to about 162 ℃, preferred about 161.5 ℃.When with 0.5 ℃ of/minute scanning, II type YM 177 has differential scanning calorimetric heat absorption maximum value in about 162.0 ℃.Estimate that II type YM 177 has higher solvability and dissolution rate faster than III type YM 177.Solid-state version of the present invention has phase purity and is at least about 5% II type YM 177, preferably at least about 10%II type YM 177, more preferably at least about 25%II type YM 177, further preferably at least about 50%II type YM 177, also further preferably at least about 75%II type YM 177, further preferably at least about 90%, most preferably be II type YM 177 substantially again.
In another embodiment of the invention, a kind of pharmaceutical composition is provided, it comprises solid-state version YM 177 and at least a pharmaceutically acceptable carrier, auxiliary agent or the thinner of significant quantity, wherein this solid-state version YM 177 contains 2%II type YM 177 at least, and preferred 10%II YM 177, or more preferably 50%II YM 177, further preferred 98%II YM 177.In a kind of embodiment preferred, the solid-state version YM 177 mainly is an II type YM 177.
In another embodiment of the invention, described the curee is treated or prevents by the illness of cyclooxygenase-2 mediation or the method for disease, this method comprises the II type YM 177 to curee's administering therapeutic significant quantity.Preferably, treat or prevent illness or disease by the cyclooxygenase-2 mediation is pain, infection, sacroiliitis, tumor growth, transfer, or the familial adenomatous polyposis disease.
Another embodiment of the present invention is the method for preparing the II YM 177 from the mixture that contains YM 177 and solvent, wherein is to carry out crystalline under the temperature of the mapping sex reversal temperature that is higher than II type YM 177, thereby produces II type YM 177.Before the crystallization of II type YM 177, can cause producing II type YM 177 with the crystal seed seeding solvent of II type YM 177, it has at least about 5 weight % phase purity, preferably at least about 10 weight % phase purity, more preferably at least about 25 weight % phase purity.
The present invention also relates to prepare the method for YM 177 crystal formation, wherein this method comprises the solvate that heats YM 177, thereby produces II type YM 177.This solvate can be heated to for example about 50 ℃ to about 160 ℃ temperature, preferred about 60 ℃ to about 145 ℃, more preferably from about 70 ℃ to about 140 ℃, also preferred about 80 ℃ to about 140 ℃, further preferred about 90 ℃ to about 140 ℃, further preferred about 100 ℃ to about 140 ℃, further more preferred about 110 ℃ to about 140 ℃, further in addition preferred about 120 ℃ to about 140 ℃, further in addition preferred about 125 ℃ to about 135 ℃ again, most preferably from about 130 ℃.Can carry out the heating of any conventional time, surpass about 1 minute, preferably surpass about 5 minutes, more preferably surpass about 60 minutes as heating, further preferred about 2 hours, preferred about 4 hours or longer.In addition, can under any pressure, carry out this method, preferably be lower than normal atmosphere.The used solvate of the present invention contains YM 177 and solvent.For example solvent can be an amide solvent.Useful amide solvent comprises N, dinethylformamide, N,N-dimethylacetamide, 1-Methyl-2-Pyrrolidone, 1,3-dimethyl-3,4,5,6-tetrahydrochysene-2 (1H)-pyrimidone and 1,1,3,3-tetramethyl-urea, or any mixture of these solvents.Preferred solvent is 1,1,3, the 3-tetramethyl-urea.Another preferred solvent is 1,3-dimethyl-3,4,5,6-tetrahydrochysene-2 (1H)-pyrimidone.Further preferred solvent is a 1-Methyl-2-Pyrrolidone.Further preferred again solvent is N, dinethylformamide.Further preferred in addition solvent is a N,N-dimethylacetamide.
In another embodiment of the invention, wherein prepare II type YM 177 by heating YM 177 solvate, the method for preparing this solvate comprise with YM 177 be selected from following amide solvent and mix: N, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, 1-Methyl-2-Pyrrolidone, 1,3-dimethyl-3,4,5,6-tetrahydrochysene-2 (1H)-pyrimidone and 1,1,3,3-tetramethyl-urea, or any mixture of these solvents.Preferred 1,1,3,3-tetramethyl-urea, more preferably 1,3-dimethyl-3,4,5,6-tetrahydrochysene-2 (1H)-pyrimidone, further preferred 1-Methyl-2-Pyrrolidone, further preferred again N, dinethylformamide, and further preferred in addition N,N-dimethylacetamide.
Another embodiment of the present invention is the solid-state version YM 177 that contains I type and II type YM 177.
The present invention's another embodiment again is the solid-state version YM 177 that contains I type and II type YM 177.
The present invention's another embodiment again is the solid-state version YM 177 that contains I I type and I I I type YM 177.
The present invention's another embodiment again is the solid-state version YM 177 that contains I type, II type and III type YM 177.
The present invention also relates to prepare the method for II type YM 177, wherein this method comprises the III type YM 177 that grinds or mill.The useful step that grinds for example comprises wet-milling or ball milling.The useful step of milling can comprise as grinding or shaking.
The present invention also relates to prepare the method for I type YM 177, wherein this method comprises the YM 177 solvate that grinds or mill.The useful step that grinds for example comprises wet-milling or ball milling.The useful step of milling can comprise as grinding or shaking.
Another embodiment of the present invention is the method for preparing II type YM 177, and wherein this method comprises fusing I type YM 177 and cools off this melt, thereby produces II type YM 177.
Another embodiment of the present invention is the method for preparing II type YM 177, and wherein this method comprises fusing III type YM 177 and cools off this melt, thereby produces II type YM 177.
From the solvent that contains Virahol and water, make the YM 177 crystallization and prepare III type YM 177 (referring to as U.S.5,910,597).
III type YM 177 has complicated differential scanning calorimetric melting transition.When scanning with 0.5 ℃/min, observe the fusing of III type YM 177 at about 160.8 ℃, recrystallization becomes II type YM 177 subsequently, observes the fusing of II type YM 177 at about 162.0 ℃ subsequently.III type YM 177 is the thermal steady state of YM 177.
Characterize the polymorphic crystal formation of YM 177
Use X-ray powder diffraction (PXRD), infrared absorption spectrum (IR), dsc (DSC) and Raman (Raman) spectral characterization I type and II type YM 177.
X-ray powder diffraction (PXRD)
Can use the multi-functional diffractometer of siemens (Siemens) D5000 powdery diffractometry meter or Inel to analyze the various crystal formations of YM 177.For siemens D5000 powdery diffractometry meter, can measure the raw data of 2 ° to 5 ° 2-θ value, gradient is 0.02 °, the gradient cycle is 2 seconds.For the multi-functional diffractometer of Inel, sample places aluminium quality sample container, collects the raw data of 30 minutes all 2 θ values simultaneously.
As described in Figure 1, can easily distinguish the YM 177 of three kinds of crystal formations by PXRD.Use CuX-gamma ray source (1.54nm), I type YM 177 is about 5.5 °, 5.7 °, 7.2 ° and 16.6 ° in 2-θ value and locates to observe the feature diffraction, and II type YM 177 is then observed the feature diffraction at about 10.3 °, 13.8 ° and 17.7 °.
Fusing/decomposition temperature
Measure the fusing and/or the decomposition temperature of non-solvent YM 177 crystal formation with TA instrument 2920 Differential Scanning Calorimeters.Each sample (1-2mg) is placed a sealing or a untight aluminum container, and heat by 0.5 ℃/minute speed.Fusing/decomposition range is defined as starting point from extrapolation to the maximum value of fusing/minute heat of desorption.
Three kinds of polymorphic crystal formations of YM 177 have been discerned.The I type YM 177 of polymorphic crystal formation is in about 162.8 ℃ of fusings; II type YM 177 is in about 161.5 ℃ of fusings; And III type YM 177 is in about 160.8 ℃ of fusings.During fusing, observing III type YM 177 part recrystallization becomes II type YM 177 or I type YM 177.
N,N-dimethylacetamide (DMA) and N have been discerned, three kinds of polymorphic crystal formations of dinethylformamide (DMF) and solvate.The physical properties and the diagnostic characteristics of new polymorphic crystal formation are shown in table 1.
Table 1
Crystal formation Fusing point (℃) ΔH(J/G) Differentiate and transform
IR Raman spectrum PXRD(2θ)
I 162.8 72 3256cm -1 3356cm -1 NA 5.5 °, 5.7 °, 7.2 ° and 16.6 °
II** 161.5 ＜84 Do not have 712cm -1 10.3 °, 13.8 ° and 17.7 °
III 160.8 91 --- --- ---
* other crystal formations are not observed feature and change the pure sample product that * * does not prepare II type YM 177
Dsc (DSC)
Use the feature of DSC with the polymorphic crystal formation of sign YM 177.I type YM 177 is in the polymorphic of 162.8 ℃ of peak melting points, has the heat absorption maximum value in 163.3 ℃.II type YM 177 melts down at 161.5 ℃, and has the heat absorption maximum value in 162.0 ℃.Observe the transformation of the complexity of III type YM 177.The complicacy of this transformation only can be observed under slow sweep velocity, the fusing of its expression III type YM 177, and recrystallization becomes the II YM 177 subsequently, II type YM 177 fusing then.Only with regard to initial endothermic conversion, III type YM 177 has the heat absorption maximum value in 160.8 ℃ of fusings in 161.5 ℃.DSC measures the low-level I type YM 177 in the III type YM 177.
Infrared absorption spectrum
IR differentiates I type YM 177 (referring to Fig. 2) from II type YM 177 and III type YM 177.
Under situation about being described in further detail, think that those skilled in the art can use the content of foregoing description, farthest uses the present invention.Below preferred embodiment only be to explain and be not to limit all the other disclosed contents by any way.
Embodiment
Following examples comprise the detailed description to the preparation method of the crystalline I type YM 177 of the application's record and II type YM 177.These detailed descriptions drop in the scope of the invention, and in order to explanation the present invention.
These detailed descriptions be only be used for the explanation and be not to limit the scope of the invention.Except as otherwise noted, all marks all by weight, and temperature is a centigradetemperature.The starting raw material for preparing the YM 177 of in following each embodiment, using by the method for U.S.5910597.
Preparation embodiment
Preparation example 1: preparation YM 177 DMA solvate (1: 1 YM 177 of ratio-DMA)
Method A. is in a round-bottomed flask, and the 4.84g YM 177 is mixed with about 125mL DMA.60 ℃ of following removal of solvent under reduced pressure to cause crystallization.On strainer, collect drying solid.This process produces 5gl: 1 solvate.Measure with TGA at 10 ℃/min, begin to decompose at about 100 ℃, have maximum value in 148 ℃, all wts loss is 17%.
Method B. stirs adding 38.2g YM 177 in about 1000mL DMA in the 1L beaker.The solution that produces is moved in the 2L beaker.Add about 400ml water and cause crystallization.Use the filtration method isolation of crystalline.Wet output is 5.44g.In filtrate, add the other crystal that water generates obtains.Measure with TGA at 10 ℃/min and to be presented at about 100 ℃ and to decompose, have maximum value in about 150 ℃, all wts loss is 18% solvent.
Preparation example 2: preparation YM 177 DMF solvate (1: 1 YM 177 of ratio-DMF)
In crystallization vessel, about 1g YM 177 is dissolved among the 50mL DMF.Cover this crystallization vessel with the aluminium foil that is installed with aperture, and be placed in the shield cap, it is dried that it is evaporated to.This process produces about 1.02g product.Measuring to be presented at TGA in 10 ℃/min has two weight loss in the decomposition, it starts from 75 ℃, lasts till that 156 ℃ have one second maximum value.The all wts loss is 13.4%.
Operation embodiment:
Embodiment 1: the ordinary method of preparation I type YM 177
A. prepare I type YM 177 by heating YM 177 solvate:
In baking oven, under minimum temperature, heat the open containers of YM 177 solvate, observe desolvation in this temperature.Simply, in baking oven, heated 0.3g YM 177-DMA about 48 hours in about 100 ℃.The sample P XRD that produces shows the reflection of the feature that is caused by I type YM 177, and the reflection of YM 177-DMA; TGA shows that approximately concentrating on about 147 ℃ has 9.6% weight loss, shows that about 50% changes into I type YM 177.
B. by evaporation preparation I type YM 177
Highly purified sample by evaporation crystallization YM 177 from ethyl acetate-heptane solvent.By the liquid chromatography purifying YM 177 (16.03g) of preparation, use the 40-63mcm silicagel column (diameter 50.8mm) of 15/85 (v/v) ethyl acetate/heptane and 150mm.Collect and be incorporated in the cut of wash-out between 270ml and the 900ml.Remove under vacuum in about 35 ℃ and to desolvate causing crystallization, and be evaporated to dried.This process produces 8.6gI type YM 177.Measure the discovery crystallized product with TGA and do not contain solvent, its I type YM 177 PXRD collection of illustrative plates is shown in Fig. 1 a.
C. by fusing preparation I type YM 177:
Usually, YM 177 is placed open containers and heat fused, make its cooling then.In more detail, the beaker that will contain YM 177 is heated to about 170 ℃ on the heat dish, and YM 177 is all melted.Then the YM 177 of fusing is injected on the Watch glass and made its cooling.With 0.5 ℃/mi n scanning, measure by DSC, in about 163 ℃ of fusings of observing I type YM 177.Also observe the melt of III type YM 177 and recrystallization and its melt of II type YM 177.
Embodiment 2: the ordinary method of preparation II type YM 177
A. prepare II type YM 177 by heating YM 177 solvate:
1. use the DMA solvate
Usually, in a baking oven, the open containers of heating YM 177-DMA solvate is observed desolvation under near this peak temperature.Simply, in about 130 ℃ baking oven, 0.3g YM 177-DMA was heated about 48 hours.The sample P XRD that produces shows the feature reflection that is caused by II type YM 177 and III type YM 177; DSC under 0.5 ℃/min shows single fusing heat absorption, and its starting point is at 161.4 ℃, and maximum value is in 161.9 ℃; Below 200 ℃, TGA shows does not have weight loss.The powder x-ray diffraction collection of illustrative plates of mixture is shown in Fig. 1 b.
2. use the solvate of DMF
Usually, in a baking oven, the open containers of heating YM 177-DMA solvate is observed desolvation under near this peak temperature.Simply, in about 130 ℃ baking oven, will about 0.2g YM 177-DMA heated overnight.The sample P XRD that produces shows the feature reflection that is caused by II type YM 177 and III type YM 177; DSC under 0.5 ℃/min shows single fusion heat absorption, and its starting point is at 161.5 ℃, and maximum value is in 161.8 ℃, and has maximum value in about 163.8 ℃ little endothermic transition (I type); Below 200 ℃, TGA shows does not have weight loss.
B. transform by machinery, prepare II type YM 177 from III type YM 177:
Usually, the III type YM 177 of in a ball mill, milling.Simply, use vermiculator, III type YM 177 was milled 30 seconds in maximum strength.The solid that produces is the mixture of III type YM 177 and II type YM 177, and it is measured by powder x-ray diffraction.
C. by fusing preparation II type YM 177:
Use oil bath YM 177 to be melted in the test tube at 170 ℃.The tetrafluoroethylene spatula is stretched in the YM 177 of fusing, spatula is moved, scrapes and get, and the drying solid on the collection spatula.Measure the mixture that this drying solid is II type and III type as powder X-ray-ray.DSC under 10 ℃/min also shows and has I type YM 177.

Claims (23)

1. the I type crystal formation of a YM 177, it has following physical behavior:
(1) has the X-ray powder diffraction that the peak is arranged at 5.5,5.7,7.2 and 16.6 degree, 2 θ places;
(2) having the melting range is 160 ℃ to 164 ℃;
(3) has differential scanning calorimetric heat absorption maximum value in 160.0 ℃ to 164.0 ℃;
(4) have 3250 to 3260cm -1The place infrared spectra at peak is arranged and 3350 to 3360cm -1There is the infrared spectra at peak at the place.
2. the crystal formation of claim 1, it has the melting range is 162 ℃ to 163 ℃.
3. the crystal formation of claim 2, it has fusing point is 162.8 ℃.
4. the crystal formation of claim 1, it has 163.3 ℃ of differential scanning calorimetric heat absorption maximum values.
5. the crystal formation of claim 4, it has 162.8 ℃ fusing point.
6. the crystal formation of claim 1, it has at 3256cm -1There is the infrared spectra at peak at the place.
7. the crystal formation of claim 1, it has at 3356cm -1There is the infrared spectra at peak at the place.
8. the crystal formation of claim 1, it has at 3256cm -1And 3356cm -1There is the infrared spectra at peak at the place, and has 162.8 ℃ fusing point.
9. pharmaceutical composition, it comprises each crystal formation and at least a pharmaceutically acceptable carrier, auxiliary agent or the thinner of claim 1 to 8 for the treatment of significant quantity.
Any described I type YM 177 of claim 1-8 preparation treatment or prevention curee by the application in the medicine of the illness of cyclooxygenase-2-mediation or disease.
11. the application of claim 10, wherein said illness or disease are pain.
12. the application of claim 10, wherein said illness or disease are inflammation.
13. the application of claim 10, wherein said illness or disease are sacroiliitis.
14. the application of claim 10, wherein said illness or disease are tumor growths.
15. the application of claim 10, wherein said illness or disease are metastases.
16. the application of claim 10, wherein said illness or disease are the adenoma polyposises of familial.
17. a method for preparing YM 177 I type crystal formation, wherein this method comprises heating YM 177 solvate, thereby produces I type YM 177, and described solvate comprises YM 177 and amide solvent, and described amide solvent is a N,N-dimethylacetamide.
18. the method for claim 17, wherein said solvate is heated to 100 ℃ temperature.
19. the method for claim 17 is wherein to described solvate heating 48 hours.
20. a method for preparing YM 177 I type crystal formation, wherein this method comprises the heat fused YM 177 and this melt is cooled to 163 ℃ temperature, thereby produces I type YM 177.
21. a method for preparing YM 177 I type crystal formation, this method comprise that from YM 177 and ratio be evaporating solvent the YM 177 solution formed of 15: 85 ethyl acetate and heptane, thereby produce I type YM 177.
22. the method for claim 21, wherein said evaporation are carried out being lower than under the normal atmosphere.
23. the method for claim 21, wherein said evaporation is carried out under 35 ℃ temperature.
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