CN104650035A - Dexlansoprazole hemihydrate compound - Google Patents
Dexlansoprazole hemihydrate compound Download PDFInfo
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- CN104650035A CN104650035A CN201310595498.6A CN201310595498A CN104650035A CN 104650035 A CN104650035 A CN 104650035A CN 201310595498 A CN201310595498 A CN 201310595498A CN 104650035 A CN104650035 A CN 104650035A
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- Prior art keywords
- lansoprazole
- semihydrate
- dexlansoprazole
- hemihydrate
- composition
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of medicines, and concretely relates to a dexlansoprazole hemihydrate and a preparation method thereof. The dexlansoprazole hemihydrate obtained in the invention contains one and a half crystal waters. The dexlansoprazole hemihydrate has the advantages of high purity, good stability and unobvious moisture absorption weight increment under highly humid conditions; and the dexlansoprazole hemihydrates improves the gastric acid inhibition effect by near 20%. The invention also relates to an application of compositions containing the dexlansoprazole hemihydrate in digestion disease treatment.
Description
Technical field
The invention belongs to medical art, be specifically related to R-lansoprazole times semihydrate and preparation method thereof, the invention still further relates to the application of the composition treatment digestive system using this hydrate.
Background technology
Hydrochloric acid in gastric juice can help digest, but if hyperchlorhydria can injure Stomach duodenum on the contrary.Work as gastroxia, there will be the symptom of acid regurgitation, acid regurgitation, sour regurgitation, except causing taste-blindness rate, also can cause reflux esophagitis.The disease that taste-blindness rate right and wrong are usually shown in, as treated not in time, also can cause many serious complication, as hemorrhage, pyloric obstruction, perforation, even canceration, and threat to life.And reflux esophagitis also increases year by year at China's sickness rate.So the too much secretion of gastric acid inhibitory seems particularly important.Clinically, conventional acid inhibitor has three kinds: antacid, proton pump inhibitor (PPIs) and H
2receptor antagonist.
The appearance of proton pump inhibitor facilitates the development of gastroenterology, and no matter a series of comprehensive analysis display is in the onset speed or the effect of acid suppression of acid suppression, the antacid that proton pump inhibitor is all better than and H
2receptor antagonist, especially increases the curative effect of disease to peptide ulceration, reflux esophagitis and idiopathic gastric acid secretion more obvious.So proton pump inhibitor is the choice drug of gastric acid secretion inhibiting clinically.
R-lansoprazole is the S-isomer of lansoprazole, is PPI up-to-date at present.It by secrete sour microtubule at parietal cell high acid environment in concentrate and be converted into activity form, thus suppress the H at this position
+, K
+-ATP enzyme (proton pump), all produces suppression to the gastric acid secretion of basal gastric acid secretion and stimulation.Because R-lansoprazole is the S-isomer that lansoprazole is single, its bioavailability is than lansoprazole and R type isomery height, and liver head crosses that clean-up effect low, inherent clearance rate is slow, AUC value is high, active agent concentration is high and lastingly in blood plasma.
Research shows, the Acidinhibitor of R-lansoprazole is better than lansoprazole, omeprazole and rabeprazole, can gastric acid secretion inhibiting fast and effectively, relief of symptoms.And R-lansoprazole untoward reaction is low, there is good tolerance.Gerontal patient and gently moderate hepatic insufficiency patient, renal insufficiency patient are all without the need to adjusting dosage.The research of a summary 31 clinical trials shows, 16583 patients taking R-lansoprazole take R-lansoprazole contrast with other acid suppression medicines with 12044, and result shows, R-lansoprazole group is similar to placebo adverse reaction rate, safe and effective.
As everyone knows, the Disease Clinical sickness rate caused due to gastroxia is very high, in taste-blindness rate crowd, sickness rate is just more than more than 10%, heartburn symptom (for reflux esophagitis cardinal symptom) is had the people of the U.S. more than 44%, and reflux esophagitis is at China's sickness rate also cumulative year after year, so very large for the demand of acid inhibitor.
In the face of the patient of more than one hundred million stomach ulcer, duodenal ulcer and the Reflux exophagitis of China, the R-lansoprazole medicine that existing market is sold can not meet the market requirement of expanding day.My company researchist is through experiment repeatedly, filter out optimum pharmaceutical adjunct, the basis that cost reduces also assures that quality, not only there is the curative effect suitable with import drugs, reasonable price simultaneously, especially be applicable to the patient needing long-term prescription, while meeting the need of market, also benefit extensive patients.
R-lansoprazole has great advantage in validity and security; but in actual production process; applicant finds, there is purification difficult, foreign matter content is higher, crystal formation is by patent protection and have the problems such as certain moisture absorption weightening finish in R-lansoprazole preparation technology.
The R-lansoprazole times hemi-hydrate crystalline that the present inventor obtains on the basis of great many of experiments, the advantage had: purity is high, maximum contaminant is less than 1 ‰; Good stability, even if moisture absorption weightening finish is also not obvious under high humidity conditions.
Allow people surprisingly, identical prescription and technique, wait R-lansoprazole times semihydrate tablet and the R-lansoprazole tablet of dosage (R-lansoprazole times semihydrate is converted into R-lansoprazole), to the restraining effect of hydrochloric acid in gastric juice, the former exceeds the latter about 20%.
Summary of the invention
One object of the present invention, discloses a kind of R-lansoprazole times semihydrate.
Another object of the present invention, discloses the preparation method of R-lansoprazole times semihydrate.
Another object of the present invention, discloses the pharmaceutical composition comprising R-lansoprazole times semihydrate.
The invention also discloses R-lansoprazole times semihydrate and prepare treatment use.
Now in conjunction with object of the present invention, content of the present invention is specifically described.
The invention provides a kind of R-lansoprazole times semihydrate (shown in formula I),
(formula I)
Thermogravimetry a kind ofly measures in the chemical process of moisture in material, and, method the most accurately the most single-minded to water, has been listed in the standard method of moisture determination in many materials, especially organic compound, reliable results.Through multiple batches of mensuration, the moisture that described invention compound contains is between 7.20%-7.40% (weight percent).In R-lansoprazole times semihydrate, the theoretical content of water is 7.30%, can assert that invention compound contains a hypocrystalline water.
Wherein the measurement result of 6 batches is as follows:
This R-lansoprazole times hemi-hydrate crystalline, adopts D/Max-2500.9161 type x-ray diffractometer to measure, condition determination: Cu Ka target, tube voltage 40KV, tube current 100mA.X-ray powder diffraction charateristic avsorption band (2 θ), D value and relative intensity are as follows,
In the present invention, the mensuration of 2 θ values uses light source, and precision is ± 0.2 °, and therefore represent above-mentioned got value and allowed certain reasonably limit of error, its limit of error is ± 0.2 °.
Fusing point test: measure fusing point according to Pharmacopoeia of People's Republic of China (2010 editions, two) annex VI C first method, the fusing point recorded is 196 DEG C-200 DEG C.
Another object of the present invention, discloses the preparation method of R-lansoprazole times hemi-hydrate crystalline, by being dissolved at n-hexyl alcohol-furans-heated in water solution by R-lansoprazole, naturally cools to room temperature, then is incubated for some time and obtains.
Specifically comprise the following steps: that R-lansoprazole semihydrate adds in the mixed solution of 6-8 times of (weight or measurement (WM) ratio) n-hexyl alcohol-furans-water=3.7-5.1:0.4-0.7:7-10, be heated to dissolve, filtrate naturally cools to 25 DEG C-30 DEG C, leave standstill insulation 3-5 hour again, crystallization, filter, drying obtains.
A large amount of experiments proves: the adding of furans, the proportioning of mixed solution, standing temperature and time are most important to obtaining R-lansoprazole of the present invention times hemi-hydrate crystalline.
Another object of the present invention, provides the composition comprising the R-lansoprazole times semihydrate that R-lansoprazole times hemi-hydrate crystalline and one or more pharmaceutically acceptable carriers form.
Pharmaceutical composition of the present invention is prepared as follows: use standard and conventional technology; the compounds of this invention acceptable solid or liquid vehicle on technology of pharmaceutics are combined, and make it at random on technology of pharmaceutics acceptable auxiliary and vehicle be combined and be prepared into particulate or microballoon.Said composition is for the preparation of oral preparations.
Allow people surprisingly, identical prescription and technique, wait R-lansoprazole times semihydrate tablet and the R-lansoprazole tablet of dosage (R-lansoprazole times semihydrate is converted into R-lansoprazole), to the restraining effect of hydrochloric acid in gastric juice, the former exceeds the latter about 20%.
The amount of the active ingredient (the compounds of this invention) contained in pharmaceutical composition and unit dosage form specifically can be applied according to the situation of the state of an illness of patient, diagnosis, the amount of compound used or concentration regulate in a wider scope, and the weight range of active compound is 1% ~ 30%(weight of composition).
Present invention also offers the application of R-lansoprazole times semihydrate in the medicine manufacturing treatment digestive system.
r-lansoprazole times semihydrate, R-lansoprazole and lansoprazole are to the transplanting Experiment on Function of rat hydrochloric acid in gastric juice.
Implant chronic gastric fistula (near the gland district inner chamber of parietal cell) to rat (the SD rat of fasting), give pentagastrin by subcutaneous injection and carbachol carrys out gastric acid secretion in 2 hours.The gastric juice volume (ml/30 min) that acid output (representing with μm ol+H/30 min) is secreted with these rats calculates (mmol/L is titrated to pH7 in every 30 minutes) with g and acidity.Three groups of rats (n=10/ group) stimulate first 75 minutes oral (7 μm of ol/kg) to give lansoprazole, R-lansoprazole times semihydrate and R-lansoprazole in gastric acid secretion.The selection of dosage exports ED based on lansoprazole acid
50the dosage range drawn.Lansoprazole, R-lansoprazole times semihydrate and R-lansoprazole group all can obvious gastric acid secretion inhibitings (133,160,134 μm of ol H+/30min).Wherein, R-lansoprazole times semihydrate exceeds more than 20% than the acid suppression effect of lansoprazole and R-lansoprazole.
stability test
At 40 DEG C, under different relative humidity (RH) condition (75%, 92.5%), the mensuration of moisture in hydrate crystal of the present invention:
Result: at 40 DEG C, under different relative humidity (RH) condition (75%, 92.5%), water tariff collection is constant, and explanation has good stability, and is applicable to manufacture and the standing storage of pharmaceutical preparation.
embodiment:
Below in conjunction with embodiment, the present invention is described further, makes professional and technical personnel in the field better understand the present invention.Embodiment is only indicative, never means that it limits the scope of the invention by any way.
embodiment 1
In the 10L reactor that stirring, thermometer, condenser are housed, add 320 grams of R-lansoprazoles and 970.0ml n-hexyl alcohol, 16.5ml furans, 980.0ml water, starts stirring, is heated to dissolve, filtrate naturally cools to 25 DEG C-30 DEG C, then leaves standstill insulation 4 hours, crystallization, filter, through indoor seasoning, obtain R-lansoprazole times semihydrate white crystals 254.6 grams, fusing point is the fusing point recorded is 196-198 DEG C, content 99.76%, single contaminant is less than 0.06%.Measure through thermogravimetry, the moisture containing 3.65% (weight percent).
Use standard and conventional technology, make the compounds of this invention acceptable solid or liquid vehicle on technology of pharmaceutics be combined, and make it at random on technology of pharmaceutics acceptable auxiliary and vehicle be combined and be prepared into particulate or microballoon.Said composition is for the preparation of oral preparations, injection.Only citing is illustrated, and never means that it limits the scope of the invention by any way.
embodiment 2
Tablet containing R-lansoprazole times semihydrate
Prescription: R-lansoprazole times semihydrate 10.7 grams, Microcrystalline Cellulose 12 g, pregelatinized Starch 16g, carboxymethylstach sodium 5 g, lactose 210 grams, 25 grams of PEG-4000, Magnesium Stearate 6 grams, 30 grams of PVP K30s, croscarmellose sodium 33 grams, distilled water is appropriate, makes 10000.
Technique:
The preparation of label: mixed with auxiliary material by main ingredient by determined prescription, granulate, particle air seasoning below 40 DEG C, with the whole grain of l6 mesh sieve, adds Magnesium Stearate and remaining starch, compressing tablet, to obtain final product.
Sealing coat dressing: added by talcum powder in 5% polyvinylpyrrolidone (PVP) anhydrous alcohol solution, stir, is mixed with the suspension of 20% as sealing coat coating liquid.In fluidized-bed, carry out dressing, its processing condition are as follows: spray pressure 0.3 MPa, feed liquor speed 5mL/min, inlet temperature 37 DEG C, temperature out 31 DEG C, dry air flow 200 m
3/ h, sealing coat weightening finish for essence blade heavy 9%.
Enteric layers dressing: No. II resin is dissolved in dehydrated alcohol, clothing liquid concentration is 10% (w/v), its processing condition except spray speed be except 4mL/min, all the other are with sealing coat coating conditions, enteric layers weightening finish for wrap isolate synusia heavy 6%.
Claims (6)
1. times semihydrate of R-lansoprazole shown in formula I,
（Ⅰ）
Measure with thermogravimetry, described hydrate contains the moisture of weight percent 7.20%-7.40%;
The crystal of described R-lansoprazole times semihydrate, in measuring as characteristic X-ray powder with CuKa ray, its collection of illustrative plates has following 2 θ diffraction angle, spacing (d value) and relative intensity (I/I
0),
The error of 2 θ diffraction angle is ± 0.2.
2. the preparation method of times hemi-hydrate crystalline of R-lansoprazole described in claim 1, by being dissolved at n-hexyl alcohol-furans-heated in water solution by R-lansoprazole, naturally cools to room temperature, then is incubated for some time and obtains.
3. according to the method for claim 2, it is characterized in that comprising the following steps: that R-lansoprazole semihydrate adds in the mixed solution of 6-8 times of (weight or measurement (WM) ratio) n-hexyl alcohol-furans-water=3.7-5.1:0.4-0.7:7-10, be heated to dissolve, filtrate naturally cools to 25 DEG C-30 DEG C, leave standstill insulation 3-5 hour again, crystallization, filter, drying obtains.
4. one kind forms the composition of R-lansoprazole times semihydrate containing R-lansoprazole according to claim 1 times hemi-hydrate crystalline and one or more pharmaceutically acceptable carriers.
5. the composition of R-lansoprazole according to claim 4 times semihydrate, is characterized in that said composition is for the preparation of oral preparations.
6. times semihydrate of R-lansoprazole described in claim 1 is manufacturing the application in the medicine being used for digestive system.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310595498.6A CN104650035A (en) | 2013-11-25 | 2013-11-25 | Dexlansoprazole hemihydrate compound |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310595498.6A CN104650035A (en) | 2013-11-25 | 2013-11-25 | Dexlansoprazole hemihydrate compound |
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| CN104650035A true CN104650035A (en) | 2015-05-27 |
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| CN201310595498.6A Pending CN104650035A (en) | 2013-11-25 | 2013-11-25 | Dexlansoprazole hemihydrate compound |
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1355798A (en) * | 1999-06-17 | 2002-06-26 | 武田药品工业株式会社 | Benzimidazole compound crystal |
| US20060057195A1 (en) * | 2002-10-16 | 2006-03-16 | Takeda Pharmaceutical Company Limited | Stable solid preparations |
| EP2216333A2 (en) * | 2009-02-06 | 2010-08-11 | Dipharma Francis S.r.l. | Crystalline forms of Dexlansoprazole |
| US20100286400A1 (en) * | 2007-12-31 | 2010-11-11 | Takeda Pharmaceutical Company Limited | Crystalline solvated forms of (r)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1h-benzimidazole |
| US20110028728A1 (en) * | 2009-07-29 | 2011-02-03 | Dipharma Francis S.R.L. | Process for the preparation of crystalline dexlansoprazole |
| US20130197232A1 (en) * | 2010-01-29 | 2013-08-01 | Ranbaxy Laboratories Limited | Process for the preparation of crystalline forms of dexlansoprazole |
| WO2013140120A1 (en) * | 2012-03-22 | 2013-09-26 | Cipla Limited | Glycerol solvate forms of (r) - 2 - [ [ [3 -methyl -4 (2,2, 2 - trifluoroethoxy) pyridin- 2 - yl] methyl] sulphinyl] - 1h - ben zimidazole |
-
2013
- 2013-11-25 CN CN201310595498.6A patent/CN104650035A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1355798A (en) * | 1999-06-17 | 2002-06-26 | 武田药品工业株式会社 | Benzimidazole compound crystal |
| US20060057195A1 (en) * | 2002-10-16 | 2006-03-16 | Takeda Pharmaceutical Company Limited | Stable solid preparations |
| US20100286400A1 (en) * | 2007-12-31 | 2010-11-11 | Takeda Pharmaceutical Company Limited | Crystalline solvated forms of (r)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1h-benzimidazole |
| EP2216333A2 (en) * | 2009-02-06 | 2010-08-11 | Dipharma Francis S.r.l. | Crystalline forms of Dexlansoprazole |
| US20110028728A1 (en) * | 2009-07-29 | 2011-02-03 | Dipharma Francis S.R.L. | Process for the preparation of crystalline dexlansoprazole |
| US20130197232A1 (en) * | 2010-01-29 | 2013-08-01 | Ranbaxy Laboratories Limited | Process for the preparation of crystalline forms of dexlansoprazole |
| WO2013140120A1 (en) * | 2012-03-22 | 2013-09-26 | Cipla Limited | Glycerol solvate forms of (r) - 2 - [ [ [3 -methyl -4 (2,2, 2 - trifluoroethoxy) pyridin- 2 - yl] methyl] sulphinyl] - 1h - ben zimidazole |
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Application publication date: 20150527 |
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