CN101885718B - Iguratimod crystal habit and composition thereof - Google Patents
Iguratimod crystal habit and composition thereof Download PDFInfo
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- CN101885718B CN101885718B CN2010102366368A CN201010236636A CN101885718B CN 101885718 B CN101885718 B CN 101885718B CN 2010102366368 A CN2010102366368 A CN 2010102366368A CN 201010236636 A CN201010236636 A CN 201010236636A CN 101885718 B CN101885718 B CN 101885718B
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Abstract
The invention relates to a crystal habit (iguratimod) of N-[3- (formamido)-4-oxygen-6-phenoxy-4H-1- benzopyran-7-base]-methylsulfonamid. In addition, the invention also relates to application of iguratimod crystal habit to medicine for treating rheumatoid arthritis, a medicine composition containing the iguratimod crystal habit and a preparation method of the iguratimod crystal habit.
Description
Technical field
The invention belongs to autoimmunization and regulate technical field of pharmaceuticals, in particular, the present invention relates to the Iguratimod crystal form its preparation method and be used for the purposes of pharmaceutical formulations.
Background technology
Rheumatic arthritis (rheumatoid arthritis RA) is the stronger systemic autoimmune disorder of a kind of disabling property, like not active and effective treatment, generally in 1 to 2 year, joint aggressiveness pathology will take place.At present, the RA treatment is two big types of medicines, nonsteroidal anti-inflammatory analgetic (NSAIDs) and change course of disease antirheumatic (DMARDs).NSAIDs mainly acts on to be arthralgia, the swelling that alleviates RA patient and to improve function of joint, but does not change the progress of disease, can not prevent the destruction in joint, and it has limited its use to GI serious adverse reaction.Compare with NSAIDs, the onset of DMARDs is slow, untoward reaction is more, and with prolonging medicine time, curative effect descends, but can stop course of disease progress, prevents destruction of joint.For overcoming above-mentioned defective, Tianjin Inst. of Materia Medica has been researched and developed the inhibition cytokine and (has been comprised il-1,6; 8) generation, the lymphocytic hyperplasia of inhibition suppress cytokine and (comprise il-1; 6,8) generation and suppress lymphocytic outgrowth NSAIDs Ailamode (Iguratimod, T-614); Result of study shows, Ailamode improves the patient of antirheumatic (DMARDs) treatment and all effective concerning the drug-fast patient of this type of medicine to the first Application state of an illness.
The Iguratimod general by name of Ailamode; Chemistry N-[3-(formamido-)-4-oxygen-6-phenoxy-4H-1-chromene-7-yl] by name-NSC-249992; English name is: N-[3-(formylamino)-4-oxo-6-phenoxy-4H-1-benzopyran-7-yl]-methanesulfona mide; Its chemical structure, method of manufacture, purposes are recorded in that the special permission communique of TOHKEMY 2001-240540 is existing; Show flat 6-623714 number more altogether with Japan japanese kokai publication hei 2-49778 number and published Ailamode antipyretic-antalgic, arthritis effect, immunoregulation effect is to prevention, the therapeutic action of autoimmune disease.
Ailamode is a kind of newtype drug of treatment of arthritis, can not only selectivity suppress COX-2, and can regulate the T-cell, has the autoimmunization regulating effect, has better therapeutic and spinoff still less than existing therapy.Chem.Pharm.Bull.48 < 1>131-139.2000. and Japanese Patent No97840 have narrated the Ailamode powdered preparation.About Iguratimod crystal form, do not see the bibliographical information of relevant crystal formation so far.
Summary of the invention
The object of the present invention is to provide one or more Ailamode crystal formations, be used for treatment of arthritis.
Another object of the present invention is to provide the preparation method of the Ailamode crystal formation that is fit to suitability for industrialized production.
A further object of the present invention is to provide the pharmaceutical composition that contains the Ailamode crystal formation.
A further object of the invention is to disclose the application of pharmaceutical composition aspect preparation treatment rheumatic arthritis medicine that contains the Ailamode crystal formation.
The inventor is unexpected in experiment to find that Ailamode has multiple crystal habit; Compare with disclosed Ailamode powder; Crystals with different shows good physico-chemical property; Solvent reclaims economical, thereby water cut is relatively stable and can directly be used for preparation such as the capsule of medicine and the performance that granule has improved preparation.The present invention is based on above-mentioned discovery is accomplished.
The disclosed 1-5 kind of the present invention crystal habit has good fusing point and quality, and its quality purity is at least 99.5%.The Ailamode crystal formation of crystal habit has synthetic on a large scale or is mixed with the required performance of therapeutic preparation, to light, wet, thermally-stabilised, is convenient to produce, store.
For realizing the object of the invention, adopt following technical scheme:
Ailamode novel crystalline form attitude of the present invention; Mainly comprise: alcohol solvent shape (to call " form 1 " in the following text); Acetonitrile solvent shape (to call " form 2 " in the following text); Diformazan formamide solvent shape (to call " form 3 " in the following text), acetone solvent shape (to call " form 4 " in the following text), dichloromethane solvent shape (to call " form 5 " in the following text).
Wherein, Ailamode form 1; It uses the Cu-Ka radiation, about 26.00, about 24.56, about 20.80, about 19.56, about 17.54, about 10.92 and about 6.88 one or more (with any combination) peak is arranged to spend the X-ray powder diffraction spectrum (" XRD ") that 2 θ represent basically at about spectrum;
It has one or more (with any combination) peak about 24.48, about 22.60, about 21.76, about 19.52, about 10.84, about 18.08, about 17.56, about 16.92, about 11.20, about 9.36, about 8.64, about 7.48, about 6.84, about 6.52 and about 5.60 basically with the use Cu-Ka radiating X-ray powder diffraction spectrum (" XRD ") of spending 2 θ and representing the Ailamode of crystal habit 2;
It has one or more (with any combination) peak about 27.28, about 25.68, about 25.24, about 24.40, about 24.04, about 23.08, about 20.16, about 17.52, about 10.56 and about 6.00 basically with the use Cu-Ka radiating X-ray powder diffraction spectrum (" XRD ") of spending 2 θ and representing the Ailamode of crystal habit 3;
It has one or more (with any combination) peak about 20.72, about 19.52, about 18.88, about 17.56, about 10.84, about 9.04 and about 6.80 basically with the use Cu-Ka radiating X-ray powder diffraction spectrum (" XRD ") of spending 2 θ and representing the Ailamode of crystal habit 4
It has the peak about 28.00, about 26.08, about 25.64, about 24.36, about 23.6, about 22.92, about 22.56, about 20.64, about 20.00, about 19.52, about 18.32, about 17.60, about 16.36, about 11.52, about 9.32 and about 6.00 basically with the use Cu-Ka radiating X-ray powder diffraction spectrum (" XRD ") of spending 2 θ and representing the Ailamode of crystal habit 5.
The Ailamode infrared absorption spectrum of 1-5 kind crystal habit according to the invention about 3342,3276,3123,3065,2869,1687,1621,1531,1489,1425,1358,1264 and 1156cm-1 characteristic spectrum belt is arranged, its DSC endothermic transition is at about 236-240 ℃.
The present invention provides crystalline Ailamode 1-5 kind form, and testing method is following:
1.X-ray powder diffraction:
Instrument: Japanese D/MAX-2500X ray polycrystalline powder diffractometer of science
Target: Cu-Ka radiation (λ=1.5405
), 2 θ=2-40 ℃
Step angle: 0.04 ℃
Computing time: 0.5 second
Pipe is pressed: 40KV
Pipe stream: 100mA
Sweep velocity: 8 ℃/min
Filter disc: graphite monochromator
2. dsc (DSC):
Instrument: Japanese standard type TG-DTA analyser of science
TR: room temperature～400 ℃
Heat-up rate: 10 ℃/minute
The crystalline Ailamode 1-5 kind crystal of novel crystalline form attitude, its endothermic transition is at about 236-240 ℃.
3. ir spectra (IR):
Instrument: PE-983G IR
Specimen preparation: KBr compressing tablet
The ir spectra wave number of the novel crystalline form attitude is crystalline Ailamode 1-5 kind crystal (pressing potassium bromide troche) for (cm-1) is: about 3342,3276,3123,3065,2869,1687,1621,1531,1489,1425,1358,1264 and 1156cm-1 characteristic spectrum belt is arranged
4. fusing point:
Instrument: YTR-3 type fusing point appearance (Precision Instrument Factory, Tianjin Univ.)
The novel crystalline form attitude is crystalline, and Ailamode 1-5 kind crystalline melting point is 237-238 ℃.
The present invention prepares the method for 1-5 kind crystal habit Ailamode, comprises the Ailamode raw material is added in the crystallization solvent heating, backflow, filtration; The filtrating room temperature was placed refrigerator 18-24 hour, filtered filter cake washing; 50-60 ℃ of drying under reduced pressure makes crystalline Ailamode.Wherein said crystallization solvent is selected from (1) ethanol (2) acetonitrile (3) diformazan methane amide (4) acetone (5) methylene dichloride.
Crystal habit Ailamode physico-chemical property and pharmacodynamic study thereof
One, the stability under the solid state
The Ailamode of getting 1-5 kind crystal habit is in weighing bottle, and respectively at 60 ℃, 4500 ± 500LX illumination and 75% relative humidity held, in sampling in 5 days, 10 days, the HPLC method was measured related substance, result such as table 1
The Ailamode influence factor of table 11-5 kind crystal habit is measured the result
Conclusion: the Ailamode of 1-5 kind crystal habit was 60 ℃, 4500 ± 500LX illumination and 92.5% relative humidity held 10 days, and related substance is not all seen obvious increase.
Two, the pharmacokinetics behind five kinds of crystal formation raw materials of the oral Ailamode of rat
Crystal habit Ailamode of the present invention is showing higher biological activity aspect the preparation treatment rheumatic arthritis medicine.
Test materials and method
1. tried raw material:
Tianjin Inst. of Materia Medica synthetic Ailamode ethanol crystal formation, acetonitrile crystal formation, acetone crystal formation, DMF crystal formation, methylene dichloride crystal formation
2 grouping administrations
Select 30 of Wistar rats for use, be divided into 5 groups at random, 6 every group by body weight; The male and female dual-purpose; After the fasting 16 hours, each group is five kinds of crystal formations of oral administration gavage Ailamode (ethanol crystal formation, acetonitrile crystal formation, acetone crystal formation, DMF crystal formation, methylene dichloride crystal formation) respectively, and dosage respectively is 10mg/kg.Get blood respectively at 0.17,0.5,1,2,3,4,6,8,12,18 and 24 hour eye socket after the administration, separation of serum ,-20 ℃ of preservations are to be measured.
3 chromatographic conditions
Stationary phase: Diamonsil
TMC
18Post, 10 μ m, 250 * 4.6mm (I.D.), 30 ℃ of column temperatures.
Moving phase: acetonitrile: 0.1% phosphoric acid=40: 60, flow velocity: 1ml/min.
Detect wavelength: 257nm, sensitivity: 0.005AUFS.
Sample size: 20 μ l.
4 blood samples are handled
Get rat blood serum 200 μ l, mark (Ailamode midbody 200 μ g/ml) 10 μ l add DMF (N, dinethylformamide) 200 μ l in adding behind the mixing; Vibration 10min; Placed 30 minutes, and, got supernatant 20 μ l sample introductions with the centrifugal 10min of the speed of 10000 commentaries on classics/min.
5 determination of plasma concentration
Behind the bioassay standard curve, draw linear regression equation (y=ax+b).The ratio of blood sample gained peak area calculates Plasma Concentration according to linear regression equation after the administration of mensuration rat, and calculates medicine for parameter through the 3P97 medicine for computation program.
6 instruments
HPLC test macro: Tianjin, island SPD-10A Uv detector, Hi-Tech P4000 HPP, LabAlliance AS1000 automatic sampler, ANASTAR chromatographic working station.
The HT-230A column oven: Tianjin Hengao Technology Development Co., Ltd. produces.
The TGL-16G table model high speed centrifuge: Anting Scientific Instrument Factory, Shanghai makes.
The miniature vortex mixed instrument of WX-80A: Shanghai Hu Xi analytical instrument factory produces.
7. result of study
Annotate: data are mean number ± standard deviation (n=6) in the table.
Conclusion: the pharmacokinetic behind five kinds of crystal formation raw materials of the oral Ailamode of rat shows; Five kinds of crystal formations of the Ailamode of rat oral administration gavage 10mg/kg, visible for parameter from medicine, there is some difference between the different parameters of five kinds of crystal formations; But basically all in same order of magnitude scope; Five kinds of crystal formations all can be developed to new medicine, the Stability Analysis of Structures of five kinds of crystal formations, absorption in animal body, elimination basically identical.
Pharmaceutical composition provided by the invention contains the Ailamode and the pharmaceutically acceptable carrier of crystal habit.
The Ailamode of crystal habit of the present invention is suitable for oral Preparation, comprises fast-release tablet, chewable tablet, dispersible tablet, effervescent tablet, slow releasing tablet, controlled release tablet, enteric coated tablet etc. like tablet; Capsule comprises hard capsule, soft capsule, slow releasing capsule, controlled release capsule, enteric coated capsule etc.; Granule comprises mix suspension grain, effervescent granule, enteric coated particles, slow-releasing granules, controlled release granule etc.; Oral solution; Oral suspensions; Syrup or the like.Ailamode micro mist of the present invention also is suitable for the preparation of external preparation such as gelifying agent, ointment, ointment, paste, patch or the like.Preparation is during oral solid formulation, can Ailamode and suitable pharmaceutical excipient processed the particle pack or pack gelatine capsule or compacting in flakes.
Acceptable carrier comprises one or more pharmaceutical excipients on the pharmacology, for example tackiness agent, thinner, disintegrating agent, sanitas, dispersion agent, glidant and lubricant.Compsn can contain the Ailamode of the crystal habit of 12.5-125mg (being generally 25-75mg).The peroral administration optimised form of this compsn is a tablet, the general every Ailamode that contains the crystal habit of 12.5-125mg (being generally 25-75mg) of tablet.Best is every Ailamode that contains the 25mg crystal habit.
Description of drawings
Below, specify embodiment of the present invention in conjunction with accompanying drawing, wherein:
Fig. 1 is the crystalline XRD figure of form 1; Fig. 2 carries out the differential scanning calorimetry and the thermogram that obtains to the crystallization of form 1; Fig. 3 is the crystalline infrared spectrogram of form 1, and Fig. 4 is the crystalline XRD figure of form 2, and Fig. 5 is the crystalline XRD figure of form 3; Fig. 6 is the crystalline XRD figure of form 4, and Fig. 7 is the crystalline XRD figure of form 5.
Embodiment
Following embodiment further illustrates of the present invention, rather than limits.
Except as otherwise noted, in this article, temperature be meant centigradetemperature (℃), room temperature is meant about 18-23 ℃.The present inventor has identified several kinds of different crystallization Ailamode forms, has used several method (normally using XRD, DSC and IR) that their characteristic is characterized.
According to the narration of Chem.Pharm.Bull.48 < 1>131-139.2000. and Japanese Patent No97840, be starting raw material with 4-chloro-3-Nitroanisole, with phenol reactant; Generate 4-phenoxy-3-Nitroanisole; Iron powder reducing react 4-phenoxy-3-anisidine, generate 3-Toluidrin-4-phenoxy methyl-phenoxide through the methylsulfonyl chloride acylation reaction, react with the aminoacetonitriles hydrochloride again; Through acidylate, ring and, totally 7 step prepared in reaction Ailamodes.Reaction formula:
Ailamode
The XRD figure of form 1 has the peak about 26.00, about 24.56, about 20.80, about 19.56, about 17.54, about 10.92 and about 6.88, and its DSC endothermic transition is at about 236-240 ℃; This infrared absorption spectrum (IR) (KBr, cm
-1) about 3342,3276,3123,3065,2869,1687,1621,1531,1489,1425,1358,1264 and 1156cm
-1Characteristic spectrum belt is arranged, see Fig. 1-3.
The XRD figure of form 2 has the peak about 24.48, about 22.60, about 21.76, about 19.52, about 10.84, about 18.08, about 17.56, about 16.92, about 11.20, about 9.36, about 8.64, about 7.48, about 6.84, about 6.52 and about 5.60, and its DSC endothermic transition is at about 236-240 ℃; This IR (KBr, cm
-1) about 3342,3276,3123,3065,2869,1687,1621,1531,1489,1425,1358,1264 and 1156cm
-1Characteristic spectrum belt is arranged, thermogram, infrared spectrogram is identical with form 1, sees Fig. 2-3.
The preparation of embodiment 3. forms 3: get Ailamode 10 grams and insert at the bottom of 100 milliliters of gardens in the flask, adds 20 milliliters of analytical pure Ns and gac, heating, reflux, filtration; The filtrating room temperature was placed refrigerator 18 hours, filtered filter cake washing; 50-60 ℃ of drying under reduced pressure gets 9.5 gram forms 3.Fusing point 237-238 ℃.
The XRD figure of form 3 has the peak about 27.28, about 25.68, about 25.24, about 24.40, about 24.04, about 23.08, about 20.16, about 17.52, about 10.56 and about 6.00, and its DSC endothermic transition is at about 236-240 ℃; This IR (KBr, cm
-1) about 3342,3276,3123,3065,2869,1687,1621,1531,1489,1425,1358,1264 and 1156cm
-1Characteristic spectrum belt is arranged, thermogram, infrared spectrogram is identical with form 1, sees Fig. 2-3.
The preparation of embodiment 4. forms 4: get Ailamode 10 grams and insert at the bottom of 2000 milliliters of gardens in the flask, adds 1000 milliliters of analytical pure acetone and gac, heating, reflux, filtration; The filtrating room temperature was placed 18 hours, filtered filter cake washing; 50-60 ℃ of drying under reduced pressure gets 9.7 gram forms 4.Fusing point 237-238 ℃.
The XRD figure of form 4 has the peak about 20.72, about 19.52, about 18.88, about 17.56, about 10.84, about 9.04 and about 6.80, and its DSC endothermic transition is at about 236-240 ℃; This IR (KBr, cm
-1) about 3342,3276,3123,3065,2869,1687,1621,1531,1489,1425,1358,1264 and 1156cm
-1Characteristic spectrum belt is arranged, thermogram, infrared spectrogram is identical with form 1, sees Fig. 2-3.
The preparation of embodiment 5. forms 5: get Ailamode 10 grams and insert at the bottom of 2000 milliliters of gardens in the flask, adds 1000 milliliters of analytical pure methylene dichloride and gac, heating, reflux, filtration; The filtrating room temperature was placed 18 hours, filtered filter cake washing; 50-60 ℃ of drying under reduced pressure gets 9.7 gram forms 5.Fusing point 237-238 ℃.
The XRD figure of form 5 has the peak about 28.00, about 26.08, about 25.64, about 24.36, about 23.6, about 22.92, about 22.56, about 20.64, about 20.00, about 19.52, about 18.32, about 17.60, about 16.36, about 11.52, about 9.32 and about 6.00, and its DSC endothermic transition is at about 236-240 ℃; This IR (KBr, cm
-1) about 3342,3276,3123,3065,2869,1687,1621,1531,1489,1425,1358,1264 and 1156cm
-1Characteristic spectrum belt is arranged, thermogram, infrared spectrogram is identical with form 1, sees Fig. 2-3.
The Ailamode tablet prepn of crystal habit
One. prescription
Ailamode 25g
Microcrystalline Cellulose (PH-101) 70.7g
Sodium starch glycolate 37g
Microcrystalline Cellulose (PH-302) 46.6g
Sodium lauryl sulphate 3.7g
Magnesium Stearate 2g
Process 1000
Two. the preparation process
The Ailamode bulk drug is ground, cross 200 mesh sieves, filter, drain, 60 ℃ of dryings, the inspection related substance promptly gets.Get Microcrystalline Cellulose (PH-101), sodium starch glycolate, sodium lauryl sulphate, the Magnesium Stearate of recipe quantity and cross 100 mesh sieves; Microcrystalline Cellulose (PH-302) is crossed 80 mesh sieves.With the sodium starch glycolate mixing of Microcrystalline Cellulose (PH-101), sodium lauryl sulphate and 1/2 recipe quantity of recipe quantity, cross 80 mesh sieves 3 times.With Ailamode and the mixing of auxiliary material grinding uniformly, cross 60 mesh sieves three times with the stepwise dilution method.The ethanolic soln that adds 20%HPMC60% is an amount of, granulates with 20 mesh sieves.Put 60 ℃ of dryings,, weigh and confirm all the other auxiliary material add-ons, add all the other auxiliary material 1/2 recipe quantity sodium starch glycolatees, Microcrystalline Cellulose (PH-302), Magnesium Stearate, mix, cross 20 mesh sieves 3 times with the whole grain of 30 mesh sieves.Sampling and measuring content and related substance, stator is heavy, and compressing tablet is processed tablet.
Dissolution determination:
According to " Chinese pharmacopoeia 2000 editions two ones (appendix X C second methods) requires operation in accordance with the law; 1000ml is a solvent with phosphate buffered saline buffer (0.05mol/L pH8); The adjustment rotating speed is that PM 100 changes; In sampling in 5,10,20,30,45,60 minutes, determined by ultraviolet spectrophotometry, the dissulution result of sample is following
Ailamode preparation dissolution determination result (%)
| |
5 |
10 |
20 |
30 minutes | 45 |
60 |
| 1 | 80.17 | 91.80 | 99.07 | 101.1 | 102.0 | 102.4 |
| 2 | 79.75 | 92.42 | 98.23 | 100.3 | 101.1 | 101.1 |
| 3 | 78.92 | 83.07 | 98.03 | 98.65 | 99.27 | 99.90 |
| 4 | 74.56 | 90.76 | 98.23 | 98.23 | 99.69 | 99.27 |
| 5 | 76.22 | 95.12 | 99.69 | 100.1 | 100.1 | 101.8 |
The preparation of Ailamode fast-release tablet
One. prescription
Prescription is formed sample 2 samples 3
Ailamode form 1-3 25g 25g
Lactose 25g 50g
Microcrystalline Cellulose 50g 25g
N.F,USP MANNITOL 37.5g/
Sodium Croscarmellose 20g 24g
Sodium lauryl sulphate 5g/
30 POVIDONE K 30 BP/USP 30 is an amount of
Magnesium Stearate 3g 2.3g
Process 1000
Two. the preparation process
(1) former, auxiliary material were pulverized respectively 200 mesh sieves, subsequent use.
(2) except that 30 POVIDONE K 30 BP/USP 30, Magnesium Stearate, take by weighing recipe quantity by prescription, 60 sieves mix, and add 10%PVP-K30 solution system softwood, 30 mesh sieves granulations, 60 ℃ of dryings 2 hours.
(3) get above-mentioned particle, add the Magnesium Stearate of recipe quantity, the whole grain of 20 mesh sieves.Compressing tablet, 3～4 kilograms of control pressures.
Dissolution determination:
According to Chinese Pharmacopoeia version requirement in 2000, be dissolution medium with phosphate buffered saline buffer (pH is 7.8), the slurry method, rotating speed is 100 rev/mins, determined by ultraviolet spectrophotometry, sample 1, sample 2 and conventional sheet dissolution determination result are following:
Claims (10)
1. an Iguratimod crystal form is characterized in that, described Ailamode form is used the Cu-Ka radiation, to spend X-ray powder diffraction spectrum that 2 θ represent shown in Fig. 7 a and 7b.
2. a method for preparing the said Ailamode of claim 1 is characterized in that: the Ailamode raw material is added in the methylene dichloride heating, backflow, filtration; The filtrating room temperature is placed or freezing 18-24 hour, filters filter cake washing; 50-60 ℃ of drying under reduced pressure makes the crystal habit Ailamode.
3. a pharmaceutical composition is characterized in that, said compsn comprises the described Iguratimod crystal form of claim 1 and one or more pharmaceutical excipients.
4. pharmaceutical composition as claimed in claim 3 is characterized in that, described one or more pharmaceutical excipients are selected from tackiness agent, thinner, disintegrating agent, sanitas, dispersion agent, glidant and lubricant.
5. pharmaceutical composition as claimed in claim 3 is characterized in that, described pharmaceutical composition is oral prepns or external preparation, and said oral prepns is selected from tablet, capsule, granule, oral solution, oral suspensions, syrup; Said external preparation is selected from gelifying agent, ointment, ointment, paste and patch.
6. pharmaceutical composition as claimed in claim 5, said tablet is selected from fast-release tablet, slow releasing tablet, controlled release tablet, dispersible tablet, chewable tablet, effervescent tablet, enteric coated tablet.
7. pharmaceutical composition as claimed in claim 5, said capsule is selected from hard capsule, soft capsule, slow releasing capsule, controlled release capsule, enteric coated capsule.
8. pharmaceutical composition as claimed in claim 5, said granule is selected from mix suspension grain, effervescent granule, enteric coated particles, slow-releasing granules, controlled release granule.
9. each described pharmaceutical composition is used for the application of the medicine of treatment of arthritis among described Iguratimod crystal form of claim 1 or the claim 3-8 in preparation.
10. application as claimed in claim 9 is characterized in that, described sacroiliitis is rheumatic arthritis.
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|---|---|---|---|
| CN2010102366368A CN101885718B (en) | 2005-10-09 | 2005-10-09 | Iguratimod crystal habit and composition thereof |
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|---|---|---|---|
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|---|---|---|---|
| CN2005100153402A Division CN1944420B (en) | 2005-10-09 | 2005-10-09 | Iguratimod crystal form and its composition |
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| CN101885718B true CN101885718B (en) | 2012-05-23 |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4954518A (en) * | 1987-10-08 | 1990-09-04 | Toyama Chemical Company, Ltd. | 4H-1-benzopyran-4-one derivative or its salt, process for producing the same and pharmaceutical composition comprising the same as active ingredient |
-
2005
- 2005-10-09 CN CN2010102366368A patent/CN101885718B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4954518A (en) * | 1987-10-08 | 1990-09-04 | Toyama Chemical Company, Ltd. | 4H-1-benzopyran-4-one derivative or its salt, process for producing the same and pharmaceutical composition comprising the same as active ingredient |
Non-Patent Citations (1)
| Title |
|---|
| JP特开平5-125072A 1993.05.21 |
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