CN104784146A - Pharmaceutical Ilaprazole sodium composition for treating peptic ulcer - Google Patents
Pharmaceutical Ilaprazole sodium composition for treating peptic ulcer Download PDFInfo
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Abstract
The invention discloses a pharmaceutical Ilaprazole sodium composition for treating peptic ulcer, and belongs to the technical field of medicines. The pharmaceutical Ilaprazole sodium composition is composed of a pill core, an isolation layer and an enteric layer, wherein the component of the pill core comprises Ilaprazole sodium, Ilaprazole sodium is a crystal, and an X-ray powder diffraction pattern measured by a Cu-K alpha ray is as shown in figure 1. The Ilaprazole sodium is different from the Ilaprazole sodium reported in the prior art, tests find that the Ilaprazole sodium crystal compound disclosed by the invention is high in purity and good in stability, and prepared capsules have high efficacy and bioavailability.
Description
Technical field
The invention belongs to medical art, relate to a kind of medicine ilaprazole composition of sodium for the treatment of peptic ulcer, be specifically related to a kind of Ilaprazole Sodium enteric coated capsule compositions.
Background technology
Ilaprazole, 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 and side effects is not obvious; Ilaprazole 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 hepatocyte inner cell pigment isozyme CYP2C19 metabolic polymorphism affects, and individual variation is little; It is that treatment comprises taste-blindness rate, and reflux esophagitis and Zollinger-Ellison syndrome syndrome are at interior potent drug for the treatment of with gastric acid-related diseases.
The novel potent proton pump of ilaprazole Shi Li pearl group first listing of the whole world in 2007 suppresses enteric coatel tablets, 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 ilaprazole 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 variation; Less adverse effect.For adapting to the patient of digestive tract hemorrhage, playing the feature that ilaprazole Acidinhibitor is strong, making gastric pH reach more than 6 rapidly, hemostatic factor quick acting.
Ilaprazole is alkalescence, and very poor at light, heat, water, oxygen, stable under acidic conditions, the approach of existing solution ilaprazole stability problem mainly comprises the crystal formation changing dosage form or change medicine.
Chinese patent CN102038648A discloses a kind of injectable powder and preparation method for the treatment of peptic ulcer, and selected active component is Ilaprazole Sodium.Said preparation is made up of Ilaprazole Sodium, excipient, antioxidant and/or metal ion chelation agent, and wherein above-mentioned each constituent mass mark is than being ilaprazole 1 part, excipient 1-30, antioxidant 0-10 part and/or metal ion chelation agent 0-0.3 part.Effectively improve the problem of Ilaprazole Sodium stable under acidic conditions difference.But, add sodium thiosulfate 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 adjuvant and consumption are more few better, are not only conducive to reducing corresponding toxic and side effects, increase Drug safety, can also save production cost.
Patent CN101687848A discloses A, B, E, F, the I crystal of ilaprazole compound.Wherein racemic ilaprazole crystal form A is that in all crystal formations, in aqueous solvent, dissolubility 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 ilaprazole (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 distillation.0.5%NH4OH/EtOH (1.00kg, 2.50 parts) is added again in flask, and dichloromethane (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 under maximum temperature is 53 DEG C of conditions vacuum drying 92 hours, 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 ilaprazole in the mixed solvent of halogenated alkane and absolute 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 dichloromethane, chloroform, and the volume ratio of halogenated alkane and ether is 1:25-10, and the volume ratio of halogenated alkane and absolute 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 ilaprazole; 2) by above-mentioned solution evaporated under reduced pressure below 30 DEG C, after evaporate to dryness, add 5-40mL ethyl acetate, dissolve, stir, crystallize at least 20 minutes; 3) filtered by crystal, filter cake ethyl acetate is washed, 20-35 DEG C of drying, obtains ilaprazole 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, impurity content obviously reduces, and drug effect and the bioavailability of the capsule made improve greatly.
Summary of the invention
Goal of the invention of the present invention is to provide a kind of Ilaprazole Sodium enteric coated capsule compositions.
In order to complete object of the present invention, the technical scheme of employing is:
The present invention relates to a kind of medicine ilaprazole composition of sodium for the treatment of peptic ulcer, described compositions is made up of ball core, sealing coat and enteric layer; The component of described ball core comprises Ilaprazole Sodium, and wherein said Ilaprazole Sodium is crystal, and the X-ray powder diffraction pattern that the measurement of use Cu-K alpha ray obtains as shown in Figure 1.
First optimal technical scheme of the present invention is: with parts by weight, and described ball core is made up of the Ilaprazole Sodium of 70 weight portions, the starch of 120 weight portions, the mannitol of 70 weight portions, the calcium sulfate of 60 weight portions, the sodium carboxymethyl cellulose of 45 weight portions, the sodium carbonate of 25 weight portions, the sucrose of 120 weight portions, the poloxamer of 3.5 weight portions, the purified water of 145 weight portions.
Second optimal technical scheme of the present invention is: with parts by weight, and described sealing coat is dissolved in the purified water of 440 weight portions by the film coating pre-mix dose of 110 weight portions to be mixed with.
3rd optimal technical scheme of the present invention is: with parts by weight, and described enteric layer is dissolved in the purified water of 360 weight portions by the Opadry of 120 weight portions to be mixed with.
4th optimal technical scheme of the present invention is: the preparation method of described compositions comprises the following steps:
1) supplementary material process: raw material Ilaprazole Sodium is sieved with pulverizer;
2) supplementary material is weighed according to prescription consumption;
3) prepared by powder of preparing burden: Ilaprazole Sodium, starch, mannitol, calcium sulfate, sodium carboxymethyl cellulose, sodium carbonate are placed in three-dimensional motion mixer, arrange motor rotation frequency 200r/min, opens mixer and mixes 50 minutes; 4) syrup preparation: take after the purified water of recipe quantity and sucrose puts in reaction pot and be heated to while stirring to seethe with excitement, sucrose is all dissolved, to be cooled to room temperature, add poloxamer and stir for subsequent use;
5) pill: above-mentioned batching powder and syrup are joined pill in centrifugal pellet processing machine, main control system rotating speed, when granule reaches 18-30 order, releases plain ball, dry with boiling drier;
6) sealing coat coating: get dried 18-30 order element ball and join in fluidized-bed coating machine, film coating pre-mix dose is dissolved in purified water and is mixed with insulating liquid, coating pan inlet temperature is set, coating;
7) enteric coating: be dissolved in by Opadry in purified water and be mixed with enteric liquid, arranges coating pan inlet temperature, coating;
8) use Autocapsulefillingmachine fill, guarantee that content uniformity conforms with the regulations;
9) pack.
Preferably, in described step 1), raw material Ilaprazole Sodium is crossed 120 mesh sieves.
Preferably, in described step 5), main control system rotating speed is 30-40Hz.
Preferably, drying condition described in described step 5) is be dried to moisture≤2.0% at 55 DEG C.
Preferably, arranging coating pan inlet temperature in described step 6) is 60 DEG C, coating weight gain 18-21%; Arranging coating pan inlet temperature in step 7) is 60 DEG C, coating weight gain 16-19%.
The preparation method of the ilaprazole sodium crystal in the present composition comprises the following steps:
(1) Ilaprazole Sodium crude product is joined in the mixed solution of dehydrated alcohol that volume is 10 times of Ilaprazole Sodium weight, carbon tetrachloride, cyclohexane extraction, the volume ratio of dehydrated alcohol, carbon tetrachloride, cyclohexane extraction is: 3.5:1.5:1, be warming up to 35-45 DEG C, be stirred to and dissolve completely;
(2) frequency be 18-20KHz, under output is the sound field of 30-40W, adding volume is while stirring the dichloromethane of Ilaprazole Sodium weight 8 times, the mixed solution of chloroform, the volume ratio of dichloromethane and chloroform is 3.5:1, mixing speed is 130-180 rev/min, and adding speed is 50-75 ml/min;
(3) after the mixed solution of dichloromethane and chloroform adds, frequency be 15-20KHz, under output is the sound field of 10-20W, be cooled to-2-0 DEG C with 8-10 DEG C/h, growing the grain 3-6 hour, washing, vacuum drying, obtains ilaprazole sodium compound.
The present inventor, after having carried out large quantifier elimination to it, obtains above-mentioned preparation method, by selective solvent, controls volume, the temperature of solvent, stirs and add speed etc., obtain a kind of new Ilaprazole sodium crystal form compound.This Ilaprazole Sodium crystalline compounds significantly improves its stability, and impurity content obviously reduces, and the capsule drug effect made and bioavailability also improve greatly.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction of ilaprazole sodium crystal prepared by the embodiment of the present invention 1.
Detailed description of the invention
Below by specific embodiment, summary of the invention of the present invention is described in further detail, but does not therefore limit content of the present invention.
embodiment 1:the preparation of ilaprazole sodium crystal
(1) Ilaprazole Sodium crude product is joined in the mixed solution of dehydrated alcohol that volume is 10 times of Ilaprazole Sodium weight, carbon tetrachloride, cyclohexane extraction, the volume ratio of dehydrated alcohol, carbon tetrachloride, cyclohexane extraction is: 3.5:1.5:1, be warming up to 35-45 DEG C, be stirred to and dissolve completely;
(2) frequency be 18-20KHz, under output is the sound field of 30-40W, adding volume is while stirring the dichloromethane of Ilaprazole Sodium weight 8 times, the mixed solution of chloroform, the volume ratio of dichloromethane and chloroform is 3.5:1, mixing speed is 130-180 rev/min, and adding speed is 50-75 ml/min;
(3) after the mixed solution of dichloromethane and chloroform adds, frequency be 15-20KHz, under output is the sound field of 10-20W, be cooled to-2-0 DEG C with 8-10 DEG C/h, growing the grain 3-6 hour, washing, vacuum drying, obtains ilaprazole sodium compound.
As shown in Figure 1, its purity of high-performance liquid chromatogram determination is 99.99% to the X-ray powder diffraction pattern that the ilaprazole sodium crystal prepared uses the measurement of Cu-K alpha ray to obtain.
embodiment 2:the preparation of Ilaprazole Sodium enteric coated capsule, step is as follows:
Prescription: with parts by weight
Preparation method:
1) supplementary material process: raw material Ilaprazole Sodium is crossed 120 mesh sieves with pulverizer;
2) supplementary material is weighed according to prescription consumption;
3) prepared by powder of preparing burden: Ilaprazole Sodium, starch, mannitol, calcium sulfate, sodium carboxymethyl cellulose, sodium carbonate are placed in three-dimensional motion mixer, arrange motor rotation frequency 200r/min, opens mixer and mixes 50 minutes;
4) syrup preparation: take after the purified water of recipe quantity and sucrose puts in reaction pot and be heated to while stirring to seethe with excitement, sucrose is all dissolved, to be cooled to room temperature, add poloxamer and stir for subsequent use;
5) pill: above-mentioned batching powder and syrup are joined pill in centrifugal pellet processing machine, main control system rotating speed 30-40Hz, when granule reaches 18-30 order, releases plain ball, is dried to moisture≤2.0% with at boiling drier 55 DEG C;
6) sealing coat coating: get dried 18-30 order element ball and join in fluidized-bed coating machine, be dissolved in purified water by film coating pre-mix dose and be mixed with insulating liquid, arranging coating pan inlet temperature is 60 DEG C, coating weight gain 18-21%;
7) enteric coating: Opadry is dissolved in purified water and is mixed with enteric liquid, arranging coating pan inlet temperature is 60 DEG C, coating weight gain 16-19%;
8) use Autocapsulefillingmachine fill, guarantee that content uniformity conforms with the regulations;
9) pack.
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 alcoholic solution 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 ilaprazole is dissolved in the methanol of 50mL and the mixed solvent of dichloromethane, 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 ilaprazole crystal form A is dissolved in 700mL methanol 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 ilaprazole crystal form A 10g is dissolved in 200mL dichloromethane, 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 ilaprazole crystal form A 10g is dissolved in 200mL methanol, 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 ilaprazole, add 100m1 dichloromethane, 100m1 absolute methanol successively, agitating solution dissolves completely to ilaprazole, then is transferred in constant pressure funnel by solution.Slowly be added drop-wise in 250m1 ether by above-mentioned ilaprazole mixed solution, 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 agitating solutions 40 minutes crystallizes.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 ilaprazole 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:
This experimental example is 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%, its outward appearance, color and luster measure impurity content, the results detailed in Table 1 is observed respectively sampling in the 0th, 5,10 day.
Table 1 temperatures involved Factor Experiment result
Result shows, from table 1, and ilaprazole A, B, E, F, the placement under the high temperature conditions of I, X, M crystal formation is after 10 days, from character, see ilaprazole A in appearance, B, E, F, I darken, and ilaprazole 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 Ilaprazole crystal form, 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 exsiccator 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 impurity content, the results detailed in Table 2.
Table 2 high humidity influence factor experimental result
Result shows, from table 2, and ilaprazole A, B, E, F, the placement under the high temperature conditions of I, X, M crystal formation is after 10 days, from character, see ilaprazole A in appearance, B, E, F, I darken, and ilaprazole 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 daylight lamp of (4500 scholar 500) lx, sampling in 0th, 5,10 days respectively, observe its outward appearance, color and luster measure impurity content, the results detailed in Table 3.
Table 3 high light influence factor experimental result
Result shows, from table 3, and ilaprazole A, B, E, F, the placement under the high temperature conditions of I, X, M crystal formation is after 10 days, from character, see ilaprazole A in appearance, B, E, F, I darken, and ilaprazole 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.
experimental example 2:ilaprazole crystal form pharmacodynamic experiment
To the pharmacodynamic experiment of the mouse gastric ulcer caused by aspirin
Get male and female half and half mice 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 mice 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 aspirin 150mg/kg of each group after mice administration 30min, mice is put to death after 4h, open mouse peritoneal, ligation cardia and pylorus and inject in gastral cavity through coat of the stomach 1% formalin 2ml, stomach is taken out in immersion 1% formalin, 30min tailing edge greater gastric curvature is cut open, and a situation arises to observe stomach ulcer under anatomic 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 gastric ulcer caused by aspirin in mouse
Result shows: from 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 0.53 mm
2, ulcer inhibition rate is 93.45%, and compared with other Ilaprazole crystal form, 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 ilaprazole sodium compound by pharmacokinetic.
Trial drug: commercially available Ilaprazole Sodium, ilaprazole 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 pretreatment 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 30 DEG C of heating in water bath N2 and volatilize, residue 200 μ l mobile phases dissolve, get 10 μ l and carry out LC/MS/MS analysis, record chromatogram.
The oral pharmacokinetic studies data of the commercially available ilaprazole of table 5
The oral medicine of table 6 ilaprazole 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 blood drug level of ilaprazole sodium compound of the present invention is significantly higher than the blood drug level of commercially available ilaprazole, shows that Ilaprazole Sodium crystalline compound of the present invention makes effective ingredient bioavailability in vivo be significantly improved.
Claims (9)
1. treat a medicine ilaprazole composition of sodium for peptic ulcer, it is characterized in that: described compositions is made up of ball core, sealing coat and enteric layer; The component of described ball core comprises Ilaprazole Sodium, and wherein said Ilaprazole Sodium is crystal, and the X-ray powder diffraction pattern that the measurement of use Cu-K alpha ray obtains as shown in Figure 1.
2. the medicine ilaprazole composition of sodium for the treatment of peptic ulcer according to claim 1, it is characterized in that: with parts by weight, described ball core is made up of the Ilaprazole Sodium of 70 weight portions, the starch of 120 weight portions, the mannitol of 70 weight portions, the calcium sulfate of 60 weight portions, the sodium carboxymethyl cellulose of 45 weight portions, the sodium carbonate of 25 weight portions, the sucrose of 120 weight portions, the poloxamer of 3.5 weight portions, the purified water of 145 weight portions.
3. the medicine ilaprazole composition of sodium for the treatment of peptic ulcer according to claim 1, is characterized in that: with parts by weight, and described sealing coat is dissolved in the purified water of 440 weight portions by the film coating pre-mix dose of 110 weight portions to be mixed with.
4. the medicine ilaprazole composition of sodium for the treatment of peptic ulcer according to claim 1, is characterized in that: with parts by weight, and described enteric layer is dissolved in the purified water of 360 weight portions by the Opadry of 120 weight portions to be mixed with.
5. prepare a method for the medicine ilaprazole composition of sodium for the treatment of peptic ulcer according to claim 1, it is characterized in that comprising the following steps:
1) supplementary material process: raw material Ilaprazole Sodium is sieved with pulverizer;
2) supplementary material is weighed according to prescription consumption;
3) prepared by powder of preparing burden: Ilaprazole Sodium, starch, mannitol, calcium sulfate, sodium carboxymethyl cellulose, sodium carbonate are placed in three-dimensional motion mixer, arrange motor rotation frequency 200r/min, opens mixer and mixes 50 minutes; 4) syrup preparation: take after the purified water of recipe quantity and sucrose puts in reaction pot and be heated to while stirring to seethe with excitement, sucrose is all dissolved, to be cooled to room temperature, add poloxamer and stir for subsequent use;
5) pill: above-mentioned batching powder and syrup are joined pill in centrifugal pellet processing machine, main control system rotating speed, when granule reaches 18-30 order, releases plain ball, dry with boiling drier;
6) sealing coat coating: get dried 18-30 order element ball and join in fluidized-bed coating machine, film coating pre-mix dose is dissolved in purified water and is mixed with insulating liquid, coating pan inlet temperature is set, coating;
7) enteric coating: be dissolved in by Opadry in purified water and be mixed with enteric liquid, arranges coating pan inlet temperature, coating;
8) use Autocapsulefillingmachine fill, guarantee that content uniformity conforms with the regulations;
9) pack.
6. the preparation method of the medicine ilaprazole composition of sodium for the treatment of peptic ulcer according to claim 5, is characterized in that: in described step 1), raw material Ilaprazole Sodium is crossed 120 mesh sieves.
7. the preparation method of the medicine ilaprazole composition of sodium for the treatment of peptic ulcer according to claim 5, is characterized in that: in described step 5), main control system rotating speed is 30-40Hz.
8. the preparation method of the medicine ilaprazole composition of sodium for the treatment of peptic ulcer according to claim 5, is characterized in that: drying condition described in described step 5) is be dried to moisture≤2.0% at 55 DEG C.
9. the preparation method of the medicine ilaprazole composition of sodium for the treatment of peptic ulcer according to claim 5, is characterized in that: arranging coating pan inlet temperature in described step 6) is 60 DEG C, coating weight gain 18-21%; Arranging coating pan inlet temperature in step 7) is 60 DEG C, coating weight gain 16-19%.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105012244A (en) * | 2015-08-03 | 2015-11-04 | 青岛蓝盛洋医药生物科技有限责任公司 | Medicine ezetimibe composition granules for treating hyperlipidemia |
| CN105030772A (en) * | 2015-09-22 | 2015-11-11 | 青岛华之草医药科技有限公司 | Ilaprazole sodium composition serving as medicine for treating digestive diseases |
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2015
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105012244A (en) * | 2015-08-03 | 2015-11-04 | 青岛蓝盛洋医药生物科技有限责任公司 | Medicine ezetimibe composition granules for treating hyperlipidemia |
| CN105030772A (en) * | 2015-09-22 | 2015-11-11 | 青岛华之草医药科技有限公司 | Ilaprazole sodium composition serving as medicine for treating digestive diseases |
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Inventor after: Xu Liyan Inventor after: Ding Xiuming Inventor before: Lu Yan |
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Application publication date: 20150722 |