CN104761543A

CN104761543A - Ilaprazole compound for treating peptic ulcer and preparation method thereof

Info

Publication number: CN104761543A
Application number: CN201510212253.XA
Authority: CN
Inventors: 魏宝琛
Original assignee: Individual
Current assignee: Individual
Priority date: 2015-04-30
Filing date: 2015-04-30
Publication date: 2015-07-08

Abstract

The invention discloses an ilaprazole compound for treating peptic ulcer and a preparation method thereof, and relates to the technical field of medicines. According to the ilaprazole compound, the diffraction pattern of X-ray powder measured through Cu-Ka rays is shown as in the picture 1. Compared with the prior art, the ilaprazole crystalline compound is high in purity, good in stability and high in medicine effect and bioavailability.

Description

A kind of lY 81149 sodium compound for the treatment of peptide ulceration and preparation method thereof

Technical field

The invention belongs to medical art, relate to a kind of lY 81149 sodium compound for the treatment of peptide ulceration and preparation method thereof.

Background technology

LY 81149, have another name called IY-81149, it is the novel proton pump inhibitor of a kind of irreversible developed by foreign drugmaker of Korea S one, it suppresses helicobacter pylori (HP) effect stronger than omeprazole, effective dose is only 1/4 of omeprazole, not easily develop immunity to drugs, and toxic side effect is not obvious; LY 81149 is compared with original like product, causing delayed gastric emptying, parietal cell swelling and the defect significantly after drug withdrawal in gastric acid secretion bounce-back etc. overcoming original like product in varying degrees, the curative effect to dyskinesis sample functional dyspepsia (GERD) and other acid-related diseases can be strengthened simultaneously, and onset is faster, acid suppression better effects if, t1/2 is longer, can continue acid suppression and control night time acid breakthrough; The dependency of its metabolism to CYP2C19 is little, affects little by enzyme gene pleiomorphism.Long half time, whole day maintains higher acid suppression level, and the time of stomach pH>4 obviously extends, and effectively reduces the phenomenon of Control of Nocturnal Gastric Acid Breakthrough; Curative effect is not by the medicine that liver cell inner cell pigment isozyme CYP2C19 metabolic polymorphism affects, and individual difference is little; It is that treatment comprises taste-blindness rate, and reflux esophagitis and Zollinger-Ellison syndrome syndromes are at interior potent drug for the treatment of with gastric acid-related diseases.

The novel potent proton pump of lY 81149 Shi Li pearl group first listing of the whole world in 2007 suppresses enteric coated tablet, is applicable to duodenal ulcer and reflux esophagitis.Its acid suppression activity is more than 4 times of omeprazole, and the day dosing of omeprazole enteric-coated preparation is 40mg, and lY 81149 then only needs 5 ~ 10mg; Long half time, long action time in body, without CYP2C19 metabolism, also seldom by CYP3A4 enzymes metabolism, to different genotype patient without individual difference; Less adverse effect.For adapting to the patient of digestive tract hemorrhage, playing the feature that lY 81149 Acidinhibitor is strong, making pH in stomach reach more than 6 rapidly, hemostatic factor quick acting.

LY 81149 is weakly alkaline, and very poor at light, heat, water, oxygen, stable under acidic conditions, the approach of existing solution lY 81149 stability problem mainly comprises the crystal formation changing formulation or change medicine.

Chinese patent CN102038648B discloses a kind of injection and the preparation method that treat peptide ulceration, and selected activeconstituents is Ilaprazole Sodium.Said preparation is made up of Ilaprazole Sodium, vehicle, oxidation inhibitor and/or metal ion chelation agent, and wherein above-mentioned each constituent mass mark is than being lY 81149 1 part, vehicle 1 ~ 30,0 ~ 10 part, oxidation inhibitor and/or metal ion chelation agent 0 ~ 0.3 part.Effectively improve the problem of Ilaprazole Sodium stable under acidic conditions difference.But, add Sulfothiorine in this patent of invention prescription, add the risk of medicine to blood vessel irritation.Simultaneously according to actual production, on the basis ensureing curative effect of medication, solubility and product appearance, the kind of auxiliary material and consumption are more few better, are not only conducive to reducing corresponding toxic side effect, increase Drug safety, can also save production cost.

Patent CN101687848B discloses A, B, E, F, the I crystal of lY 81149 compound.Wherein racemic ilaprazole crystal form A is that in all crystal formations, in aqueous solvent, solubleness is minimum, but a kind of crystal formation that thermokinetics is the most stable; Other four kinds of crystal formations are derived by diverse ways by crystal form A and obtain.Crystal formation F, compared with crystal form A, is more soluble in aqueous solvent, and the biology of crystal form B and crystal formation F is acceptable poor, and it can be used to prepare depot drug product composition.Which describe the preparation method of crystal form A: 3%NH4OH/ acetonitrile (MeCN) (6.00kg, 15.0 parts) load in flask, adjust the temperature to 5 DEG C (2-8 DEG C), add lY 81149 (0.400kg), stir 1 hour, elimination filtrate, filter cake 3%NH4OH/ acetonitrile (MeCN) (2 × 0.400kg, 2 × 1.00 parts) rinsing.Filter cake load flask, add 0.5%NH4OH/EtOH (0.200kg, 0.500 part) and at 20-25 DEG C concentrating under reduced pressure, until there is no overhead product.0.5%NH4OH/EtOH (1.00kg, 2.50 parts) is added again in flask, and methylene dichloride (2.40kg, 6.00 parts).The solution obtained is evaporated to ca.1.2L (3.00 amount) at 20-25 DEG C.Add 0.5%NH4OH/EtOH (0.200kg, 0.500 part) again, be adjusted to 5 DEG C (2-8 DEG C), stir 45 minutes.With 0.5%NH4OH/EtOH (0.200kg, 0.500 part) after elimination filtrate, EtOH (0.200kg, 0.500 part) and MTBE (2 × 0.200kg, 2 × 0.500 parts) rinsing.Filtration cakes torrefaction 2 hours, then vacuum-drying 92 hours under top temperature is 53 DEG C of conditions, obtain racemic ilaprazole crystal form A.

Patent CN103172618A discloses Ilaprazole crystal form X, which describe the preparation method of crystal form X: be dissolved in by lY 81149 in the mixed solvent of halogenated alkane and anhydrous methanol, again above-mentioned solvent is slowly added in ether solvent, stir until crystallize out, crystal Precipitation Temperature is 25 DEG C, wherein said halogenated alkane is the one in methylene dichloride, trichloromethane, and the volume ratio of halogenated alkane and ether is 1:25 ~ 10, and the volume ratio of halogenated alkane and anhydrous methanol is 1:1.

Patent CN104370886A discloses Ilaprazole crystal form M, which describes the preparation method of M crystal formation: 1) be dissolved in 5 ~ 20mL chloroform by 1 ~ 2g lY 81149; 2) by above-mentioned solution evaporated under reduced pressure below 30 DEG C, after evaporate to dryness, add 5 ~ 40mL ethyl acetate, dissolve, stir, crystallization at least 20 minutes; 3) filtered by crystal, filter cake ethyl acetate is washed, 20 ~ 35 DEG C of dryings, obtains lY 81149 M crystal formation.

But above-mentioned crystal formation still exists, and drug effect is lower, the problem of less stable etc., the present inventor starts with from the research of Ilaprazole Sodium solid chemical material existence, a kind of Ilaprazole Sodium compound crystal has been prepared through a large amount of tests, surprisingly find through overtesting, this compound crystal significantly improves its stability, foreign matter content obviously reduces, and drug effect and bioavailability also improve greatly.

Summary of the invention

Primary goal of the invention of the present invention is to propose a kind of lY 81149 sodium compound for the treatment of peptide ulceration.

Second goal of the invention of the present invention is the preparation method proposing above-mentioned lY 81149 sodium compound.

In order to realize object of the present invention, the technical scheme of employing is:

Treat a lY 81149 sodium compound for peptide ulceration, it is characterized in that, the X-ray powder diffraction pattern that described lY 81149 sodium compound uses the measurement of Cu-K alpha-ray to obtain as shown in Figure 1.

The preparation method of described lY 81149 sodium compound is: be dissolved in by Ilaprazole Sodium in the mixed solvent A of anhydrous isopropyl alcohol, anhydrous propanone; First add with the speed of 15-24ml/min the 8-10 mixed solvent B doubly that volume is Ilaprazole Sodium weight, limit edged stirs, control temperature 10-25 DEG C, growing the grain 0.5-1 hour; And then add with the speed of 10-15ml/min the 12-25 mixed solvent B doubly that volume total amount is Ilaprazole Sodium weight, after growing the grain 2-5 hour, be cooled to-5 DEG C, then keep stirring velocity 200-400 rev/min of stirring and crystallizing, growing the grain 1-3 hour; Filter, after drying, obtain Ilaprazole Sodium crystalline compounds.

The volume of described mixed solvent A is 4-8 times of Ilaprazole Sodium weight, and temperature is 10-25 DEG C.

In described mixed solvent A, the volume ratio of anhydrous isopropyl alcohol and anhydrous propanone is 1:1.5.

Described mixed solvent B is the mixed solvent of N-Methyl pyrrolidone and methylene dichloride, and the volume ratio of N-Methyl pyrrolidone and methylene dichloride is 1:4.

Described cooling rate is 15-20 DEG C/h.

Described drying is 35-45 DEG C, drying under reduced pressure 5-7 hour.

Below summary of the invention of the present invention is further described:

LY 81149 sodium compound of the present invention, uses the X-ray powder diffraction of Cu-K alpha-ray measurement as shown in Figure 1.

This Ilaprazole Sodium crystalline compounds is prepared from by the following method:

Ilaprazole Sodium is dissolved in the mixed solvent A of anhydrous isopropyl alcohol, anhydrous propanone; First add with the speed of 15-24ml/min the 8-10 mixed solvent B doubly that volume is Ilaprazole Sodium weight, limit edged stirs, control temperature 10-25 DEG C, growing the grain 0.5-1 hour; And then add with the speed of 10-15ml/min the 12-25 mixed solvent B doubly that volume total amount is Ilaprazole Sodium weight, after growing the grain 2-5 hour, be cooled to-5 DEG C, then keep stirring velocity 200-400 rev/min of stirring and crystallizing, growing the grain 1-3 hour; Filter, after drying, obtain Ilaprazole Sodium crystalline compounds.

By mixed solvent A anhydrous isopropyl alcohol, anhydrous propanone, preferred anhydrous isopropyl alcohol, anhydrous propanone mixed solvent volume are 4-8 times of Ilaprazole Sodium weight, and temperature is 10-25 DEG C, and the volume ratio of anhydrous isopropyl alcohol and anhydrous propanone is 1:1.5.After the mixing solutions of this ratio is by Ilaprazole Sodium dissolution of solid, add mixed solvent B at twice, first add with the speed of 15-24ml/min the 8-10 mixed solvent B doubly that volume is Ilaprazole Sodium weight, control temperature 10-25 DEG C, growing the grain 0.5-1 hour; The 12-25 mixed solvent B doubly that volume total amount is Ilaprazole Sodium weight is added again with the speed of 10-15ml/min, after growing the grain 2-5 hour, be cooled to-5 DEG C, the mixed solvent B of preferred N-Methyl pyrrolidone and methylene dichloride, the volume ratio of N-Methyl pyrrolidone and methylene dichloride is 1:4.The speed cooling of preferred 15-20 DEG C/h, stirrings, crystallization, growing the grain 1-3 hour, filter, dry must crystalline compounds.

The present invention by mixed solvent A dissolve after, add mixed solvent B at twice, by control solvent volume, temperature, stir and add speed etc., obtain a kind of new Ilaprazole sodium crystal form compound.This Ilaprazole Sodium crystalline compounds significantly improves its stability, and foreign matter content obviously reduces, and drug effect and bioavailability also improve greatly, brings convenience to the preparation of various preparation.

accompanying drawing illustrates:

Fig. 1 is the X-ray powder diffraction pattern of lY 81149 sodium compound prepared by embodiment 1.

Embodiment

The specific embodiment of the present invention is only limitted to explain further and the present invention is described, does not limit Composition of contents of the present invention.

embodiment 1:the preparation of lY 81149 sodium compound

Be dissolved in by Ilaprazole Sodium in the mixed solvent A of anhydrous isopropyl alcohol that 10 DEG C of volumes are 4 times of Ilaprazole Sodium weight, anhydrous propanone, the volume ratio of anhydrous isopropyl alcohol and anhydrous propanone is 1:1.5; First add the N-Methyl pyrrolidone of 8 times that volume total amount is Ilaprazole Sodium weight and the mixed solvent B of methylene dichloride with the speed of 15ml/min, the volume ratio of N-Methyl pyrrolidone and methylene dichloride is 1:4, limit edged stirs, control temperature 10 DEG C, growing the grain 0.5 hour; And then add the N-Methyl pyrrolidone of 12 times that volume total amount is Ilaprazole Sodium weight and the mixed solvent B of methylene dichloride with the speed of 10ml/min, the volume ratio of N-Methyl pyrrolidone and methylene dichloride is 1:4, growing the grain is after 2 hours, be cooled to-5 DEG C with the speed of 15 DEG C/h, then keep stirring velocity 200 revs/min of stirring and crystallizing, growing the grain 1 hour; Filter, 35 DEG C, drying under reduced pressure obtains Ilaprazole Sodium crystalline compounds in 5 hours.

This compound crystal detects through high performance liquid chromatography, and purity is 99.99%, yield 97.9%; The X-ray powder diffraction pattern that the measurement of use Cu-K alpha-ray obtains as shown in Figure 1.

embodiment 2:the preparation of lY 81149 sodium compound

Be dissolved in by Ilaprazole Sodium in the mixed solvent A of anhydrous isopropyl alcohol that 25 DEG C of volumes are 8 times of Ilaprazole Sodium weight, anhydrous propanone, the volume ratio of anhydrous isopropyl alcohol and anhydrous propanone is 1:1.5; First add the N-Methyl pyrrolidone of 10 times that volume total amount is Ilaprazole Sodium weight and the mixed solvent B of methylene dichloride with the speed of 24ml/min, the volume ratio of N-Methyl pyrrolidone and methylene dichloride is 1:4, limit edged stirs, control temperature 25 DEG C, growing the grain 1 hour; And then add the N-Methyl pyrrolidone of 25 times that volume total amount is Ilaprazole Sodium weight and the mixed solvent B of methylene dichloride with the speed of 15ml/min, the volume ratio of N-Methyl pyrrolidone and methylene dichloride is 1:4, growing the grain is after 5 hours, be cooled to-5 DEG C with the speed of 20 DEG C/h, then keep stirring velocity 400 revs/min of stirring and crystallizing, growing the grain 3 hours; Filter, 45 DEG C, drying under reduced pressure obtains Ilaprazole Sodium crystalline compounds in 7 hours.

embodiment 3:the preparation of lY 81149 sodium compound

Be dissolved in by Ilaprazole Sodium in the mixed solvent A of anhydrous isopropyl alcohol that 17.5 DEG C of volumes are 6 times of Ilaprazole Sodium weight, anhydrous propanone, the volume ratio of anhydrous isopropyl alcohol and anhydrous propanone is 1:1.5; First add the N-Methyl pyrrolidone of 9 times that volume total amount is Ilaprazole Sodium weight and the mixed solvent B of methylene dichloride with the speed of 19.5ml/min, the volume ratio of N-Methyl pyrrolidone and methylene dichloride is 1:4, limit edged stirs, control temperature 17.5 DEG C, growing the grain 0.75 hour; And then add the N-Methyl pyrrolidone of 18.5 times that volume total amount is Ilaprazole Sodium weight and the mixed solvent B of methylene dichloride with the speed of 12.5ml/min, the volume ratio of N-Methyl pyrrolidone and methylene dichloride is 1:4, growing the grain is after 3.5 hours, be cooled to-5 DEG C with the speed of 17.5 DEG C/h, then keep stirring velocity 300 revs/min of stirring and crystallizing, growing the grain 2 hours; Filter, 40 DEG C, drying under reduced pressure obtains Ilaprazole Sodium crystalline compounds in 6 hours.

comparative example 1:the preparation (with reference to patent WO2011071314A2) of Ilaprazole crystal form A

10g Ilaprazole Sodium is dissolved in 200mL dehydrated alcohol, neutralizes, stirring at normal temperature 2h with the ethanolic soln containing acetic acid 10%, and filter, with the washing with alcohol filter cake of 40mL50%, 40 DEG C of dry 12h, obtain off-white color solid 8.5g, yield 85%.

comparative example 2:the preparation (with reference to patent WO2011071314A2) of Ilaprazole crystal form B

10g lY 81149 is dissolved in the methyl alcohol of 50mL and the mixed solvent of methylene dichloride, slowly drips 250mL ether, stirring at normal temperature 45min, filters, filter cake washed with diethylether, and 30 DEG C are dried 12h, off-white color solid 8.5g, yield 85%.

comparative example 3:the preparation (referenced patent US20110082174) of Ilaprazole crystal form E

10g lY 81149 crystal form A is dissolved in 700mL methyl alcohol drip in the solution of a triethylamine.Solid supersound process is dissolved.Membrane filtration is in vial, and bottle covers mouth with the aluminium foil having 5 apertures and then at room temperature evaporates.Obtain dark green solid after 6 days, obtain Ilaprazole crystal form E.

comparative example 4:the preparation (referenced patent US20110082174) of Ilaprazole crystal form F

Getting lY 81149 crystal form A 10g is dissolved in 200mL methylene dichloride, drips a triethylamine.Solution evaporates with under room temperature after membrane filtration with 0.2.Obtaining slight colored solid after about 1 day, is Ilaprazole crystal form F.

comparative example 5:the preparation of Ilaprazole crystal form I

Getting lY 81149 crystal form A 10g is dissolved in 200mL methyl alcohol, drips a triethylamine, freezing after membrane filtration.About 2 days final vacuum collecting by filtration white solids, this solid is Methanol Solvate.White solid is put into vial, and opening is placed in room temperature under vacuo, and obtaining white solid after about 1 day is crystalline form I.

comparative example 6:the preparation (referenced patent CN103172618A) of Ilaprazole crystal form X

At 25 DEG C, in the single port bottle of 250m1, add l0g lY 81149, add 100m1 methylene dichloride, 100m1 anhydrous methanol successively, stirred solution dissolves completely to lY 81149, then is transferred in constant pressure funnel by solution.Slowly be added drop-wise in 250m1 ether by above-mentioned lY 81149 mixing solutions, control temperature of reaction system in dropping process in the scope of 25 scholar 2 DEG C, time for adding controls between 25-30min.After dropwising, keep temperature 25 DEG C of stirred solutions 40 minutes crystallizatioies.Decompress filter, with 150mL ether washing leaching cake, dry 24 hours of ambient temperature in vacuum, obtaining off-white powder, is Ilaprazole crystal form X, and productive rate is 84%.

comparative example 7:the preparation (referenced patent CN104370886A) of Ilaprazole crystal form M

1) 1g lY 81149 is dissolved in 20mL chloroform, lucifuge rapid solution;

2) by above-mentioned solution evaporated under reduced pressure below 30 DEG C, 20mL ethyl acetate is added after evaporate to dryness, lucifuge rapid solution, lucifuge stirring and crystallizing 1h after dissolving;

3) filtered by crystal, filter cake ethyl acetate washes three times, 28 DEG C of dryings.Obtain off-white color crystalline powder 0.789g, productive rate 78.9%.

experimental example 1:the stability test of product of the present invention

The stability difference of the present invention and Ilaprazole crystal form of the prior art is described below by way of contrast experiment.

1, temperatures involved Factor Experiment

Get comparative example 1-7 (Ilaprazole crystal form A respectively, B, E, F, I.X, M) and the Ilaprazole sodium crystal form of the embodiment of the present invention 1 at temperature 60 C, place 10 days under the condition of relative humidity 75%, respectively the 0th, 5, its outward appearance, color and luster measure foreign matter content, the results detailed in Table 1 are observed in sampling in 10 days.

Table 1 temperatures involved Factor Experiment result

Result shows, from table 1, and lY 81149 A, B, E, F, the placement under the high temperature conditions of I, X, M crystal formation is after 10 days, from proterties, see lY 81149 A in appearance, B, E, F, I darken, and lY 81149 X and M does not have change substantially, Ilaprazole sodium crystal form of the present invention is compared with other Ilaprazole crystal form, and the content placing its impurity after 10 days is under the high temperature conditions starkly lower than other lY 81149 crystalline forms, and stability is better.

2, high humidity influence factor experiment

Get 1g comparative example 1-7 (Ilaprazole crystal form A, B, E respectively, F, I, X, and the Ilaprazole sodium crystal form of embodiment 1 M), in the moisture eliminator containing saturated potassium nitrate solution, (25 DEG C, relative humidity 92.5%) are placed 10 days, respectively the 0th, 5, sampling in 10 days, observes its outward appearance, color and luster measure foreign matter content, the results detailed in Table 2.

Table 2 high humidity influence factor experimental result

Result shows, from table 1, and lY 81149 A, B, E, F, the placement under the high temperature conditions of I, X, M crystal formation is after 10 days, from proterties, see lY 81149 A in appearance, B, E, F, I darken, and lY 81149 X and M does not have change substantially, Ilaprazole sodium crystal form of the present invention is compared with other Ilaprazole crystal form, and the content placing its impurity after 10 days is under conditions of high humidity starkly lower than other Ilaprazole crystal form, and stability is better.

3, high light influence factor experiment

Get 1g comparative example 1-7 Ilaprazole crystal form A respectively, B, E, F, I, X, M) and embodiment 1 Ilaprazole sodium crystal form, place 10 days in the lighting box that illumination is the fluorescent lamp of (4500 scholar 500) lx, sampling in 0th, 5,10 days respectively, observe its outward appearance, color and luster measure foreign matter content, the results detailed in Table 3.

Table 3 high light influence factor experimental result

Result shows, from table 1, and lY 81149 A, B, E, F, the placement under the high temperature conditions of I, X, M crystal formation is after 10 days, from proterties, see lY 81149 A in appearance, B, E, F, I darken, and lY 81149 X and M does not have change substantially, Ilaprazole sodium crystal form of the present invention is compared with other Ilaprazole crystal form, and the content placing its impurity after 10 days under intense light conditions is starkly lower than other Ilaprazole crystal form, and stability is better.

As above test other embodiments, the result obtained is similar to embodiment 1.

experimental example 2:ilaprazole crystal form pharmacodynamic experiment

To the pharmacodynamic experiment of the mouse gastric ulcer caused by acetylsalicylic acid

Get male and female half and half mouse 70, body weight 18-22g, be divided into 7 groups at random, group is divided into: group 1: blank group; Group 2: Ilaprazole crystal form A3mg/kg dosage group; Group 3: Ilaprazole crystal form B3mg/kg dosage group; Group 4: Ilaprazole crystal form E3mg/kg dosage group; Group 5: Ilaprazole crystal form F3mg/kg dosage group; Group 6: Ilaprazole crystal form I3mg/kg dosage group; Group 7: Ilaprazole crystal form X3mg/kg dosage group, group 8: Ilaprazole crystal form M3mg/kg dosage group, group 9: Ilaprazole sodium crystal form M3mg/kg dosage group of the present invention, after water 24h is can't help in mouse fasting, group 2-6 presses the corresponding medicine of 0.2ml/10g body weight gavage respectively, and the blank group of group 1 presses the body weight gavage distilled water of 0.2ml/10g.The equal gavage acetylsalicylic acid 150mg/kg of each group after mouse administration 30min, mouse is put to death after 4h, open mouse peritoneal, ligation orifice of the stomach and pylorus and inject in gastral cavity through coat of the stomach 1% formalin 2ml, stomach is taken out in immersion 1% formalin, cut open along greater gastric curvature after 30min, a situation arises to observe stomach ulcer under dissecting microscope, calculates ulcer area and ulcer inhibition rate.Concrete outcome is as shown in table 4:

Ulcer inhibition rate account form:

Table 4 Ilaprazole crystal form is on the impact of the stomach ulcer caused by aspirin in mouse

Result shows: seen by table 4, and the group 9 i.e. ulcer average area of Ilaprazole sodium crystal form 3mg/kg dosage group of the present invention is 0.66 mm ², ulcer inhibition rate is 90.22% compared with other Ilaprazole crystal form, and the ulcer area of Ilaprazole sodium crystal form of the present invention reduces obviously, and ulcer inhibition rate obviously raises.

experimental example 3:bioavailability study

This experimental example has investigated the bioavailability of lY 81149 sodium compound by pharmacokinetic.

Trial drug: commercially available lY 81149, lY 81149 sodium compound of the present invention are made enteric coated capsule respectively.

Experimental animal: Beagle dog.

Dosage and mode: dosage is respectively 10mg, after animal fasting morning oral administration, each cleaning intersects administration after one week.

Sample collecting: respectively at before animals administer and administration after different time (0.5,0.75,1,1.33,1.67,2,2.5,3,4,6,8,12h) get blood by dog forelimb, get blood at every turn and be about 2ml, add and use in the centrifuge tube of anticoagulant heparin in advance, the insulating foam box being built-in with ice bag is put at once interior standing 20 minutes after blood specimen collection, 3000rpm low-temperature centrifugation is separated plasma after 10 minutes,-40 DEG C of preservations, to be checked.

The pre-treatment of sample: plasma sample thawed at room temperature, the blood plasma getting 0.2ml joins in 1.5ml centrifuge tube, add 100 μ L 50mM ammonium formate solution again, mark liquid in the omeprazole of 50mL 280ng/ml, vortex mixed 30s, add the t-butyl methyl ether of 0.6ml again, vortex shakes 2 minutes, centrifugal (13,000 rev/min) after 10min, get supernatant liquor 30 DEG C of heating in water bath N2 and volatilize, residue 200 μ l moving phases are dissolved, get 10 μ l and carry out LC/MS/MS analysis, record color atlas.

The oral pharmacokinetic studies data of the commercially available lY 81149 of table 5

The oral medicine of table 6 lY 81149 sodium compound of the present invention is for dynamic experiment data

Pharmacokinetic results is in table 5 and table 6.From table 5 and table 6, the eastern thing Plasma Concentration taking lY 81149 sodium compound of the present invention is significantly higher than the Plasma Concentration of commercially available lY 81149 lY 81149, shows that Ilaprazole Sodium crystalline compound of the present invention makes effective constituent bioavailability in vivo be significantly improved.

Claims

1. treat a lY 81149 sodium compound for peptide ulceration, it is characterized in that: the X-ray powder diffraction pattern that described lY 81149 sodium compound uses the measurement of Cu-K alpha-ray to obtain as shown in Figure 1.

2. lY 81149 sodium compound according to claim 1, is characterized in that: the preparation method of described lY 81149 sodium compound is: be dissolved in by Ilaprazole Sodium in the mixed solvent A of anhydrous isopropyl alcohol, anhydrous propanone; First add with the speed of 15-24ml/min the 8-10 mixed solvent B doubly that volume is Ilaprazole Sodium weight, limit edged stirs, control temperature 10-25 DEG C, growing the grain 0.5-1 hour; And then add with the speed of 10-15ml/min the 12-25 mixed solvent B doubly that volume total amount is Ilaprazole Sodium weight, after growing the grain 2-5 hour, be cooled to-5 DEG C, then keep stirring velocity 200-400 rev/min of stirring and crystallizing, growing the grain 1-3 hour; Filter, after drying, obtain Ilaprazole Sodium crystalline compounds.

3. lY 81149 sodium compound according to claim 2, is characterized in that: the volume of described mixed solvent A is 4-8 times of Ilaprazole Sodium weight, and temperature is 10-25 DEG C.

4. lY 81149 sodium compound according to claim 2, is characterized in that: in described mixed solvent A, the volume ratio of anhydrous isopropyl alcohol and anhydrous propanone is 1:1.5.

5. lY 81149 sodium compound according to claim 2, is characterized in that: described mixed solvent B is the mixed solvent of N-Methyl pyrrolidone and methylene dichloride, and the volume ratio of N-Methyl pyrrolidone and methylene dichloride is 1:4.

6. lY 81149 sodium compound according to claim 2, is characterized in that: described cooling rate is 15-20 DEG C/h.

7. lY 81149 sodium compound according to claim 2, is characterized in that: described drying temperature is 35-45 DEG C, drying under reduced pressure 5-7 hour.