CN107311984B - Dextro-ilaprazole sodium compound, and pharmaceutical composition and preparation method thereof - Google Patents
Dextro-ilaprazole sodium compound, and pharmaceutical composition and preparation method thereof Download PDFInfo
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Abstract
The invention provides a dexilaprazole sodium compound, a pharmaceutical composition thereof and a preparation method thereof, wherein the dexilaprazole sodium compound has characteristic peaks at 6.2 degrees, 15.4 degrees, 17.1 degrees and 27.5 degrees in X-ray diffraction represented by a2 theta angle; the dexilaprazole sodium compound provided by the invention has a new crystal form, and the stability of the dexilaprazole sodium compound is obviously improved compared with the existing crystal form of ilaprazole sodium; in addition, the invention also provides freeze-dried powder and an enteric-coated tablet containing the dexilaprazole sodium compound, and the enteric-coated tablet has the effects of high stability, slow release and the like and has better curative effect than the existing enteric-coated tablet.
Description
Technical Field
The invention belongs to the field of medicaments for treating stomach diseases, and particularly relates to a dexilaprazole sodium compound, a pharmaceutical composition and a preparation method thereof.
Background
Ilaprazole (Ilaprazole) with molecular formula C19H18N4O2S, chemical name: 5- (1-hydro-pyrrol-1-yl) -2[ (4-methoxy-3-methyl) -2-pyridinyl]-methyl-sulfinyl-1-hydro-benzimidazole, the structure of which belongs to the benzimidazole class, is a powerful drug for treating gastric ulcer, duodenal ulcer, reflux or erosive esophagitis and the like.
Compared with other proton pump inhibitors such as omeprazole and the like, the compound has the advantages of long half life, strong acid inhibition effect, no individual difference in treatment and the like, and the compound and the sodium salt thereof have poor stability, in order to improve the stability of the compound, the prior art researches a plurality of crystal forms of the compound and the sodium salt thereof, for example, CN101687878A discloses a A, B, E, F, I crystal form of ilaprazole and a preparation method thereof, CN103172618A discloses an M crystal form of ilaprazole, further, CN102746275A discloses a crystal form of ilaprazole sodium, further, CN105461692A discloses a C crystal form of ilaprazole sodium, and the like. Although the prior art discloses a plurality of crystal forms of ilaprazole and sodium salt thereof, the stability of the crystal forms disclosed above is still poor, and currently marketed ilaprazole powder injection or enteric-coated tablets are prone to moisture absorption and poor in stability.
Disclosure of Invention
In order to solve the technical problems, the invention provides a dexilaprazole sodium compound, a pharmaceutical composition and a preparation method thereof.
The specific scheme of the invention is as follows:
the invention provides a dextro-ilaprazole sodium compound, which has characteristic peaks at 6.2 degrees, 15.4 degrees, 17.1 degrees and 27.5 degrees in X-ray diffraction represented by a2 theta angle.
In a further improvement, the compound has characteristic peaks at 12.9 degrees, 16.2 degrees, 19.1 degrees, 23.7 degrees, 32.6 degrees and 36.3 degrees in an X-ray diffraction manner expressed by an angle of 2 theta.
The invention also provides a preparation which is freeze-dried powder or an enteric-coated tablet, wherein the weight part ratio of the compound to the auxiliary material is 1: 10-50.
In a further improvement, the preparation is an enteric-coated tablet, wherein the auxiliary materials comprise the following components in parts by weight:
in the invention, croscarmellose sodium and polyvinylpyrrolidone are added into auxiliary materials as a filler and an adhesive, so that the enteric-coated tablet is easy to form and divide dosage.
In a further improvement, the auxiliary material also comprises 1.5 to 2.5 parts by weight of slow release materials.
Further improved, the slow release material comprises the following components in parts by weight:
polyglycerol fatty acid ester 0.8-1
Quaternary amino methacrylate copolymer 0.7-1.5.
Further improved, the enteric-coated tablet comprises the following components in parts by weight:
in another aspect, the invention provides a method for preparing a dexilaprazole sodium compound, comprising the following steps:
1) dissolving 1g of dexilaprazole sodium in a mixture of acetone and ethanol with the volume ratio of 10:1.5-2.5, stirring and mixing at the rotating speed of 200r/min, separating liquid, and concentrating under reduced pressure to be dry;
2) adding 5-10mL of n-butanol into the concentrated mixture obtained in the step 1), then slowly dropwise adding 2-4mL of 0.01mol/L sodium bicarbonate, standing and crystallizing.
The invention also provides a preparation method of the enteric-coated tablet, which comprises the following steps:
s1: crushing and sieving the dextro-ilaprazole sodium compound and the croscarmellose sodium, and adding the crushed dextro-ilaprazole sodium compound and the croscarmellose sodium into a wet granulator to be stirred to obtain a mixture of the dextro-ilaprazole sodium compound and the croscarmellose sodium;
s2: adding polyvinylpyrrolidone into the mixture of the dexilaprazole sodium compound and the croscarmellose sodium obtained in step S1, wetting with water, and uniformly mixing in a wet granulator to obtain a dexilaprazole sodium compound soft material;
s3: preparing the soft material of the dexilaprazole sodium compound obtained in the step S2 into a strip-shaped material by using an extruder, adding the strip-shaped material into a particle swing machine for granulation and size stabilization, and tabletting by using a tabletting machine to obtain a dexilaprazole sodium compound tablet;
s4: uniformly mixing hydroxypropyl methylcellulose phthalate, glyceryl monostearate and triethyl citrate in a slurry preparation tank to obtain an enteric coating solution, spraying the enteric coating solution into the dextro-ilaprazole sodium compound tablets obtained in the step S3, and drying to obtain dextro-ilaprazole sodium compound coated tablets;
s5: and (3) putting the polyglycerol fatty acid ester and the quaternary amino methacrylate copolymer into a slurry preparation tank, uniformly mixing to obtain a slow-release coating solution, spraying the slow-release coating solution into the dextrorotatory ilaprazole sodium compound coated tablet obtained in the step S4, and drying to obtain the dextrorotatory ilaprazole sodium compound slow-release enteric-coated tablet.
The invention has the beneficial effects that the invention provides a dexilaprazole sodium compound which has a new crystal form, and the stability of the compound is obviously improved compared with the existing crystal form of ilaprazole sodium; in addition, the invention also provides an enteric-coated tablet containing the dexilaprazole sodium compound, which has the effects of high stability, slow release and the like, and the curative effect is superior to other existing formulations of the dexilaprazole sodium.
Drawings
FIG. 1 is an X-ray diffraction pattern of a dexilaprazole sodium compound;
fig. 2 is an in vitro release profile of enteric coated tablets.
Detailed description of the preferred embodiments
Example 1A dexilaprazole sodium compound
The compound has characteristic peaks at 6.2 degrees, 15.4 degrees, 17.1 degrees and 27.5 degrees by X-ray diffraction represented by 2 theta, and the relative intensities of the characteristic peaks are shown as follows as shown in figure 1:
example 2A dexilaprazole sodium compound
The compound has characteristic peaks at 6.2 °, 12.9 °, 15.4 °, 16.2 °, 17.1 °, 19.1 °, 23.7 °, 27.5 °, 32.6 °, and 36.3 ° by X-ray diffraction represented by 2 θ, and the relative intensities of the above characteristic peaks are as follows as shown in fig. 1:
| 2θ | relative Strength (%) |
| 6.2° | 59.9 |
| 12.9° | 27.9 |
| 15.4° | 100 |
| 16.2° | 20.3 |
| 17.1° | 52.8 |
| 19.1° | 23.3 |
| 23.7° | 21.5 |
| 27.5° | 89.4 |
| 32.6° | 23.9 |
| 36.3° | 27.5 |
EXAMPLE 3 enteric coated tablet
The dosage of each component of the enteric-coated tablet is as follows:
EXAMPLE 4 enteric coated tablet
The dosage of each component of the enteric-coated tablet is as follows:
the preparation method comprises the following steps:
s1: crushing and sieving 1g of the dexilaprazole sodium compound and 40g of croscarmellose sodium, and adding the crushed materials into a wet granulator to stir to obtain a mixture of the dexilaprazole sodium compound and the croscarmellose sodium;
s2: adding 0.5 polyvinylpyrrolidone into the mixture of the dexilaprazole sodium compound and the croscarmellose sodium obtained in step S1, wetting with water, and uniformly mixing in a wet granulator to obtain a soft material of the dexilaprazole sodium compound;
s3: using an extruder to obtain a strip-shaped material from the soft material of the dexilaprazole sodium compound obtained in the step S2, adding the strip-shaped material into a particle swing machine for granulation and size stabilization, and tabletting by using a tabletting machine to obtain a dexilaprazole sodium compound tablet;
s4: and (3) uniformly mixing 2g of hydroxypropyl methylcellulose phthalate, 0.9g of glycerin monostearate and 0.2g of triethyl citrate in a slurry preparation tank to obtain an enteric coating solution, spraying the enteric coating solution into the dexilaprazole sodium compound tablets obtained in the step S3, and drying to obtain the dexilaprazole sodium compound enteric tablets.
EXAMPLE 5 enteric coated tablet
The dosage of each component of the enteric-coated tablet is as follows:
EXAMPLE 6 enteric coated tablet
The dosage of each component of the enteric-coated tablet is as follows:
EXAMPLE 7 enteric coated tablet
The dosage of each component of the enteric-coated tablet is as follows:
the preparation method comprises the following steps:
s1: crushing and sieving 1.45g of the dexilaprazole sodium compound and 38g of croscarmellose sodium, and adding the crushed materials into a wet granulator to stir to obtain a mixture of the dexilaprazole sodium compound and the croscarmellose sodium;
s2: adding 0.4g of polyvinylpyrrolidone into the mixture of the dexilaprazole sodium compound and the croscarmellose sodium obtained in step S1, wetting with water, and uniformly mixing in a wet granulator to obtain a soft dexilaprazole sodium compound material;
s3: using an extruder to obtain a strip-shaped material from the soft material of the dexilaprazole sodium compound obtained in the step S2, adding the strip-shaped material into a particle swing machine for granulation and size stabilization, and tabletting by using a tabletting machine to obtain a dexilaprazole sodium compound tablet;
s4: uniformly mixing 1.8g of hydroxypropyl methylcellulose phthalate, 0.8g of glycerin monostearate and 0.15g of triethyl citrate in a slurry preparation tank to obtain an enteric coating solution, spraying the enteric coating solution into the dextro-ilaprazole sodium compound tablets obtained in the step S3, and drying to obtain the dextro-ilaprazole sodium compound coated tablets;
s5: and (3) putting 0.95g of polyglycerol fatty acid ester and 1.4g of quaternary amino methacrylate copolymer in a slurry preparation tank, uniformly mixing to obtain a slow-release coating solution, spraying the slow-release coating solution into the dexilaprazole sodium compound coated tablet obtained in the step S4, and drying to obtain the dexilaprazole sodium compound slow-release enteric-coated tablet.
Comparative example 1 enteric coated tablet
The dosage of each component of the enteric-coated tablet is as follows:
prepared according to the method of example 4.
Comparative example 2 enteric coated tablet
The dosage of each component of the enteric-coated tablet is as follows:
prepared according to the method of example 4.
Comparative example 3 enteric coated tablet
The dosage of each component of the enteric-coated tablet is as follows:
prepared according to the method of example 4.
Comparative example 4 enteric coated tablet
The dosage of each component of the enteric-coated tablet is as follows:
prepared according to the method of example 7.
Comparative example 5 enteric coated tablet
The dosage of each component of the enteric-coated tablet is as follows:
prepared according to the method of example 7.
Experimental example 1 stability test of Compound
The differences between the present invention and the related art ilaprazole sodium crystal form in stability and in vitro drug release are illustrated by comparative experiments.
1. Experiment of high temperature influence factor
The ilaprazole sodium or ilaprazole crystals of example 2 and comparative example 1 (crystal form C disclosed in CN10546169a 2), comparative example 2 (crystal form ilaprazole sodium disclosed in CN 102746277A), comparative example 3 (crystal form of ilaprazole sodium disclosed in CN 104922080A), comparative example 4 (crystal form ii of ilaprazole disclosed in CN 106749191), and comparative example 5 (crystal form ii of ilaprazole sodium in a gastric acid secretion-resistant pharmaceutical ilaprazole sodium composition disclosed in CN 105147680A) were each taken, and left at 60 ℃ and a relative humidity of 75% for 10 days, and samples were taken on days 0, 5, and 10 to observe the appearance, color, and determine the impurity content, and the results are shown in table 1.
TABLE 1 high temperature influencing factor test results
The results show that the example 2 provided by the invention is placed under the high temperature condition for 10 days, the change of related substances and contents is smaller than that of the comparative examples 4 and 5, and is obviously better than that of the comparative examples 1-3.
2. Experiment of high humidity influence factor
The ilaprazole sodium or ilaprazole crystals of example 2 and comparative example 1 (crystal form C disclosed in CN10546169a 2), comparative example 2 (crystal form ilaprazole sodium disclosed in CN 102746277A), comparative example 3 (crystal form of ilaprazole sodium disclosed in CN 104922080A), comparative example 4 (crystal form ii of ilaprazole disclosed in CN 106749191), and comparative example 5 (crystal form ii of ilaprazole sodium in a gastric acid secretion-resistant pharmaceutical ilaprazole sodium composition disclosed in CN 105147680A) were each taken, and left at 25 ℃ and a relative humidity of 92.5% for 10 days, and samples were taken on days 0, 5, and 10 to observe the appearance and color thereof and measure the impurity content, and the results are shown in table 2.
Table 2 high humidity influence factor experiment results
The results show that example 2 provided by the present invention was stored under high humidity conditions for 10 days, and the changes of the related substances and contents were smaller than those of comparative examples 4 and 5, and were significantly better than those of comparative examples 1 to 3.
3. Experiment of strong light influence factor
The ilaprazole sodium or ilaprazole crystals of example 2 and comparative example 1 (crystal form C disclosed in CN10546169a 2), comparative example 2 (crystal form ilaprazole sodium disclosed in CN 102746277A), comparative example 3 (crystal form of ilaprazole sodium disclosed in CN 104922080A), comparative example 4 (crystal form ii of ilaprazole disclosed in CN 106749191), and comparative example 5 (crystal form of ilaprazole sodium in a gastric acid secretion-resistant pharmaceutical ilaprazole sodium composition disclosed in CN 105147680A) were respectively taken, placed in an illumination box of a fluorescent lamp with illumination of 4000-5000lx for 10 days, and sampled and observed in appearance, color and luster and measured for impurity content on days 0, 5 and 10, respectively, and the results are shown in table 3.
TABLE 3 Experimental results of the strong light influencing factors
The results show that the example 2 provided by the invention is placed under the strong light condition for 10 days, the change of related substances and contents is smaller than that of the comparative examples 4 and 5, and is obviously better than that of the comparative examples 1-3.
Experimental example 2 stability experiment of enteric coated tablet
1 accelerated test
The enteric-coated tablets of example 3, example 7 and comparative examples 1, 2 and 3 of the present invention were all placed at 40 ℃ ± 2 ℃ under a relative humidity of 75% ± 5% for 6 months, and were sampled once at the end of 1 month, 2 months, 3 months and 6 months during the test period, and the properties of the enteric-coated tablets, the content (labeled amount%) of dexilaprazole sodium, and related substances (%, total impurities) were measured as specified in the "chinese pharmacopoeia" of 2015 edition, and the results are shown in table 4.
TABLE 4 accelerated test results for enteric coated tablets
As can be seen from the table, the accelerated test results show that the properties, the amount of the dexilaprazole sodium and related substances of the enteric-coated tablets provided in the embodiments 3 and 7 of the present invention have not changed significantly after being placed for 6 months; after the enteric-coated tablets of the comparative examples 1 to 3 are placed for 6 months, the enteric-coated tablets become yellow, the content of the dexilaprazole sodium is obviously reduced, and related substances are obviously increased; it is shown that the enteric coated tablets of the present invention have significantly improved stability compared to the comparative examples 1-3, and the stability of example 7 is higher than that of example 3.
1.2 Long term test
The enteric-coated tablets of example 3, example 7 and comparative examples 1 to 3 were all placed at 25 ℃ ± 2 ℃ under a relative humidity of 60% ± 10% for 12 months, sampled every 3 months, and sampled at 0 month, 3 months, 6 months, 9 months, 12 months, and 24 months, respectively, to test the properties of the enteric-coated tablets, the content of dexilaprazole sodium (labeled amount%) and related substances (%, total impurities), and the results are shown in table 5.
TABLE 5 Long-term test results for enteric-coated tablets
As can be seen from the table, the long-term test results show that the properties, the amount of the dexilaprazole sodium and related substances of the enteric-coated tablets provided in the embodiments 3 and 7 of the present invention have not changed significantly after being placed for 24 months; after the enteric-coated tablets of the comparative examples 1 to 3 are placed for 24 months, the enteric-coated tablets become yellow, the content of the dexilaprazole sodium is obviously reduced, and the content of related substances is increased, which shows that the stability of the enteric-coated tablets is obviously improved compared with the enteric-coated tablets of the comparative examples 1 to 3.
Experimental example 3 in vitro Release assay
The detection of drug release refers to the examination of drug release in vitro in appendix XIXD of the 'Chinese pharmacopoeia' 2015 edition.
The enteric-coated tablets of examples 5 to 7 and comparative examples 4 to 5 were taken, respectively, placed in a drug dissolution apparatus, sampled for 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 16 hours, and 24 hours, respectively, and the dissolution percentage was measured by high performance liquid chromatography, and the cumulative release percentage of the drug was calculated, and the results are shown in fig. 2.
As can be seen from the figure, the enteric-coated tablets of comparative examples 4-5 have higher burst release within 1 hour and lower cumulative drug release rate, while the enteric-coated tablets of examples 5-7 have lower burst release and higher cumulative drug release rate than those of comparative examples 4-5, the drug is slowly released within 24 hours, and the sustained-release effect of example 7 is better than that of examples 5-6.
Claims (6)
1. A preparation comprises a dexilaprazole sodium compound and an auxiliary material, and is characterized in that the compound has characteristic peaks at 6.2 degrees, 15.4 degrees, 17.1 degrees, 27.5 degrees, 12.9 degrees, 16.2 degrees, 19.1 degrees, 23.7 degrees, 32.6 degrees and 36.3 degrees in X-ray diffraction represented by a2 theta angle, the preparation is an enteric-coated tablet, the weight part ratio of the compound to the auxiliary material is 1:10-50, and the auxiliary material comprises the following components in parts by weight:
2. the preparation of claim 1, wherein the adjuvant further comprises 1.5-2.5 parts by weight of a sustained-release material.
3. The preparation of claim 1, wherein the sustained-release material comprises the following components in parts by weight:
polyglycerol fatty acid ester 0.8-1
Quaternary amino methacrylate copolymer 0.7-1.5.
4. The preparation of claim 1, wherein the enteric-coated tablet comprises the following components in parts by weight:
5. a formulation according to claim 1, wherein said compound is prepared by a process comprising the steps of:
1) dissolving 1g of dexilaprazole sodium in a mixture of acetone and ethanol with the volume ratio of 10:1.5-2.5, stirring and mixing at the rotating speed of 200r/min, separating liquid, and concentrating under reduced pressure to be dry;
2) adding 5-10mL of n-butanol into the concentrated mixture obtained in the step 1), then slowly dropwise adding 2-4mL of 0.01mol/L sodium bicarbonate aqueous solution, standing and crystallizing.
6. A method of preparing the formulation of claim 3, comprising the steps of:
s1: crushing and sieving the dextro-ilaprazole sodium compound and the croscarmellose sodium, and adding the crushed dextro-ilaprazole sodium compound and the croscarmellose sodium into a wet granulator to be stirred to obtain a mixture of the dextro-ilaprazole sodium compound and the croscarmellose sodium;
s2: adding polyvinylpyrrolidone into the mixture of the dexilaprazole sodium compound and the croscarmellose sodium obtained in step S1, wetting with water, and uniformly mixing in a wet granulator to obtain a dexilaprazole sodium compound soft material;
s3: using an extruder to obtain a strip-shaped material from the soft material of the dexilaprazole sodium compound obtained in the step S2, adding the strip-shaped material into a particle swing machine for granulation and size stabilization, and tabletting by using a tabletting machine to obtain a dexilaprazole sodium compound tablet;
s4: uniformly mixing hydroxypropyl methylcellulose phthalate, glyceryl monostearate and triethyl citrate in a slurry preparation tank to obtain an enteric coating solution, spraying the enteric coating solution into the dextro-ilaprazole sodium compound tablets obtained in the step S3, and drying to obtain dextro-ilaprazole sodium compound coated tablets;
s5: and (3) putting the polyglycerol fatty acid ester and the quaternary amino methacrylate copolymer into a slurry preparation tank, uniformly mixing to obtain a slow-release coating solution, spraying the slow-release coating solution into the dextrorotatory ilaprazole sodium compound coated tablet obtained in the step S4, and drying to obtain the dextrorotatory ilaprazole sodium compound slow-release enteric-coated tablet.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101098867A (en) * | 2005-03-25 | 2008-01-02 | 丽珠医药集团股份有限公司 | Substituted sulfoxide compound and its preparing method and application |
| CN105055342A (en) * | 2015-08-13 | 2015-11-18 | 青岛蓝盛洋医药生物科技有限责任公司 | Sodium ilaprazole medicine composition freeze-dried powder injection for treating peptic ulcer |
| CN105566294A (en) * | 2014-10-08 | 2016-05-11 | 江苏奥赛康药业股份有限公司 | D-ilaprazole sodium compound and pharmaceutical composition thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101098867A (en) * | 2005-03-25 | 2008-01-02 | 丽珠医药集团股份有限公司 | Substituted sulfoxide compound and its preparing method and application |
| CN105566294A (en) * | 2014-10-08 | 2016-05-11 | 江苏奥赛康药业股份有限公司 | D-ilaprazole sodium compound and pharmaceutical composition thereof |
| CN105055342A (en) * | 2015-08-13 | 2015-11-18 | 青岛蓝盛洋医药生物科技有限责任公司 | Sodium ilaprazole medicine composition freeze-dried powder injection for treating peptic ulcer |
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