CN105168153A - Medicinal lansoprazole composition lyophilized powder injection for treating gastric ulcer - Google Patents

Abstract

The invention relates to a medicinal lansoprazole composition lyophilized powder injection for treating gastric ulcer, and belongs to the technical field of medicines. The composition lyophilized powder injection comprises lansoprazole and excipient, wherein the excipient is low-molecular dextran, and the lansoprazole is a novel crystal compound. The X-ray powder diffraction pattern measured by using a Cu-K alpha ray is as shown in a pattern 1. The composition lyophilized powder injection is different from lansoprazole reported in the prior art. Tests discover that the lansoprazole crystal compound has the advantages that no impurity E exists, the content of impurities A and B is remarkably reduced and has relatively small variation along with storage time extension, the fluidity is excellent, and the solubility is remarkably improved. The lyophilized powder injection prepared by utilizing the novel crystal compound has good stability after being compatible with a solvent, has extremely low content of insoluble particles, and is very suitable for clinical application.

Description

A kind of medicine Lansoprazole composition freeze-dried powder injection for the treatment of gastric ulcer

Technical field

The invention belongs to medical art, relate to a kind of medicine Lansoprazole composition freeze-dried powder injection for the treatment of gastric ulcer.

Background technology

The benzimidazoles derivative with antiacid effect that lansoprazole is developed in December, 1991 by Japanese Wu Tian company, it acts on the H+-K+-ATP enzyme of parietal cell, the H+ of parietal cell can not be transported in stomach go, so that gastric acid amount greatly reduces in gastric juice, be used for the treatment of gastric ulcer, duodenal ulcer and reflux esophagitis, and be used for eliminating pylorus.

Lansoprazole is novel proton pump inhibitor, it is the upgraded product of omeprazole, lansoprazole is because importing fluorine at pyridine ring 4 side chains and have trifluoro ethoxy substituent group, make the comparatively omeprazole raising more than 30% of its bioavailability, lipotropy is also better than omeprazole, therefore this product promptly can play drug effect through parietal cell film changes sulfenic acids and time sulfonyl derivative in acid condition, the bacteriostatic activity of HP is risen to four times of omeprazole.

A lot of crystal formations of lansoprazole are disclosed, as the 1.5 crystal types (II type) of the anhydrous crystal forms (I type) and lansoprazole that disclose lansoprazole in CN1355798A in prior art.Describe lansoprazole A crystal formation and B crystal form in US2009/0018339A1, in fact, B crystal form is unstable, is metastable-state crystal, can experience solid-to-solid transition under certain condition, forms A crystal formation.

CN102558154A discloses a kind of lansoprazole crystalline compounds, and the X-ray powder diffraction pattern represented with the 2 θ ± 0.2 ° angle of diffraction demonstrates characteristic diffraction peak at 5.8 °, 7.5 °, 9.1 °, 11.8 °, 12.1 °, 12.8 °, 13.3 °, 15.6 °, 16.7 °, 18.3 °, 20.4 °, 25.7 °, 26.8 ° and 31.5 ° of places.

CN102180866A discloses M crystal formation and the N crystal form of lansoprazole, and wherein the X-ray powder diffraction of M crystal formation at angle of diffraction 2 θ is: 6.519,9.373,9.989,10.548,13.123,14.298,14.914,15.642,18.104,18.720,19.672,20.231,24.205,25.492,27.899 time there is characteristic peak; The X-ray powder diffraction of N crystal form at angle of diffraction 2 θ is: 5.438,7.062,8.230,9.216,11.022,11.789,12.610,13.541,20.603,21.862,26.242 time there is characteristic peak.

CN1681802A discloses three kinds of crystalline solid form of lansoprazole, and called after D, E and F type, also discloses the preparation method of these crystalline solid form of lansoprazole simultaneously respectively.

CN103664889A also discloses a kind of Lansoprazole crystal compound.

Lansoprazole has a chiral centre sulphur atom, therefore has two optical isomers.Research shows that the lansoprazole drug effect of (R)-configuration is obviously better than lansoprazole raceme, and optically active lansoprazole toxic and side effects is lower than raceme.

But according to the chemical constitution feature of lansoprazole, lansoprazole is being produced, is being deposited easy generation following impurity A, impurity B and impurity E in process, and these trace impurities can affect drug quality.Although some crystal formation of above-mentioned lansoprazole improves its hygroscopicity, dissolubility or stability to a certain extent, the present inventor's its result after the impurity of some crystal formation above-mentioned being carried out to investigation is unsatisfactory.

The present inventor starts with from the research of lansoprazole solid chemical substance existence, has prepared a kind of new compound of Lansoprazole crystal through a large amount of tests.

Summary of the invention

Goal of the invention of the present invention is to provide a kind of medicine Lansoprazole composition freeze-dried powder injection for the treatment of gastric ulcer.

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

The present invention relates to a kind of medicine Lansoprazole composition freeze-dried powder injection for the treatment of gastric ulcer, comprise lansoprazole and excipient, described lansoprazole is crystal, and the X-ray powder diffraction pattern that the measurement of use Cu-K alpha ray obtains as shown in Figure 1.

As preferably, with parts by weight, described composite freeze-dried powder agent is made up of the lansoprazole of 1-2 weight portion, the excipient of 3-5 weight portion.

As preferably, with parts by weight, described composite freeze-dried powder agent by by the lansoprazole of 1.5 weight portions, 4 weight portions excipient form.

As preferably, the preparation method of described composite freeze-dried powder agent comprises the following steps:

Get compound of Lansoprazole of the present invention, use water for injection stirring and dissolving, add the excipient of recipe quantity, adjust ph, be then stirred to pH constant after, mend inject water to 100 times that liquor capacity is lansoprazole weight, then active carbon coarse filtration is used, successively through 1.0 μm, 0.45 μm, the microporous filter membrane aseptic filtration of 0.22 μm, filters into sterilizing room, measure pH and content qualified after, fill, pressure half plug, puts into the freeze drying box being cooled to-40 DEG C, frozen drying, tamponade outlet, rolls lid.

As preferably, described excipient is low molecular dextran.

As preferably, described lyophilization is: first-40 DEG C of pre-freezes 5 hours, then dry 13 hours of reduced vacuum under-25 DEG C of conditions, finally 30 DEG C of high temperature dryings 5 hours.

As preferably, described adjustment pH is 8.0-9.0.

The preparation method of the lansoprazole crystal in the present composition comprises the following steps:

Prepare the saturated dichloromethane solution of lansoprazole crude product of 40 DEG C, then adding volume is the water of 8 times of saturated dichloromethane solution volume and the mixed solvent of 2-picoline, the volume ratio of described water and 2-picoline is 4:1.5, and after stirring, cooling limit, limit is stirred, cooling rate is 15 DEG C/h, mixing speed is 100 revs/min, stops stirring, leave standstill growing the grain 2 hours after being cooled to-5 DEG C, filter, after drying under reduced pressure, obtain lansoprazole crystalline compounds.

Below technical scheme of the present invention is made further explanation:

The present invention is by the precise controlling to crystallization condition, and prepared a kind of lansoprazole novel crystal forms unlike the prior art, the X-ray powder diffraction pattern of this lansoprazole crystal unlike the prior art.Simultaneously due to the ins and outs of this crystal formation, find through test, Lansoprazole crystal compound provided by the invention E free from foreign meter, and the content of impurity A and impurity B significantly reduces, and along with its changes of contents of prolongation of period of storage less, the dissolution that there is excellent mobility and significantly improve, utilize the lyophilized injectable powder that this crystal compound is obtained, good stability, good with solvent compatibility rear stability, particulate matter content is extremely low, is very suitable for clinical practice.

Accompanying drawing explanation

Fig. 1 is the X-ray powder diffraction that the lansoprazole crystal of the embodiment of the present invention 1 preparation uses the measurement of Cu-K alpha ray to obtain.

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 lansoprazole crystal

Prepare the saturated dichloromethane solution of lansoprazole crude product of 40 DEG C, then adding volume is the water of 8 times of saturated dichloromethane solution volume and the mixed solvent of 2-picoline, the volume ratio of described water and 2-picoline is 4:1.5, and after stirring, cooling limit, limit is stirred, cooling rate is 15 DEG C/h, mixing speed is 100 revs/min, stops stirring, leave standstill growing the grain 2 hours after being cooled to-5 DEG C, filter, after drying under reduced pressure, obtain lansoprazole crystalline compounds.

The X-ray powder diffraction pattern that the lansoprazole crystal prepared uses the measurement of Cu-K alpha ray to obtain as shown in Figure 1.

embodiment 2:the preparation of Lansoprazole freeze-dried injection

Prescription: with parts by weight, the Lansoprazole crystal compound 1.5 parts that embodiment 1 is obtained, low molecular dextran 3 parts.

Get compound of Lansoprazole prepared by the embodiment of the present invention 1, use water for injection stirring and dissolving, add the low molecular dextran of recipe quantity, adjust ph is 8.0-9.0, be then stirred to pH constant after, mend inject water to 100 times that liquor capacity is lansoprazole weight, then active carbon coarse filtration is used, successively through 1.0 μm, 0.45 μm, the microporous filter membrane aseptic filtration of 0.22 μm, filter into sterilizing room, measure pH and content qualified after, fill, pressure half plug, put into the freeze drying box being cooled to-40 DEG C, frozen drying, tamponade outlet, rolls lid.

Described lyophilization is:

First-40 DEG C of pre-freezes 5 hours, then dry 13 hours of reduced vacuum under-25 DEG C of conditions, finally 30 DEG C of high temperature dryings 5 hours.

embodiment 3:the preparation of Lansoprazole freeze-dried injection

Prescription: with parts by weight, the Lansoprazole crystal compound 1.5 parts that embodiment 1 is obtained, low molecular dextran 4 parts.

Get compound of Lansoprazole prepared by the embodiment of the present invention 1, use water for injection stirring and dissolving, add the low molecular dextran of recipe quantity, adjust ph is 8.0-9.0, be then stirred to pH constant after, mend inject water to 100 times that liquor capacity is lansoprazole weight, then active carbon coarse filtration is used, successively through 1.0 μm, 0.45 μm, the microporous filter membrane aseptic filtration of 0.22 μm, filter into sterilizing room, measure pH and content qualified after, fill, pressure half plug, put into the freeze drying box being cooled to-40 DEG C, frozen drying, tamponade outlet, rolls lid.

Described lyophilization is:

First-40 DEG C of pre-freezes 5 hours, then dry 13 hours of reduced vacuum under-25 DEG C of conditions, finally 30 DEG C of high temperature dryings 5 hours.

embodiment 4:the preparation of Lansoprazole freeze-dried injection

Prescription: with parts by weight, the Lansoprazole crystal compound 1.5 parts that embodiment 1 is obtained, low molecular dextran 5 parts.

Get compound of Lansoprazole prepared by the embodiment of the present invention 1, use water for injection stirring and dissolving, add the low molecular dextran of recipe quantity, adjust ph is 8.0-9.0, be then stirred to pH constant after, mend inject water to 100 times that liquor capacity is lansoprazole weight, then active carbon coarse filtration is used, successively through 1.0 μm, 0.45 μm, the microporous filter membrane aseptic filtration of 0.22 μm, filter into sterilizing room, measure pH and content qualified after, fill, pressure half plug, put into the freeze drying box being cooled to-40 DEG C, frozen drying, tamponade outlet, rolls lid.

Described lyophilization is:

First-40 DEG C of pre-freezes 5 hours, then dry 13 hours of reduced vacuum under-25 DEG C of conditions, finally 30 DEG C of high temperature dryings 5 hours.

test example 1:determination of foreign matter in stability test

Prepare 3 batch samples according to embodiment 1, be numbered 001,002,003;

Reference substance 1: according to " improvement in synthesis of lansoprazole " [Liu Yanfei, Li Yongxin etc. the improvement in synthesis [J] of lansoprazole, fine-chemical intermediate, 2011, the lansoprazole fine work of method synthesis 41(3): 26-28 and 42], m.p.169-171 DEG C (decomposition);

Reference substance 2: according to the lansoprazole form D that the method for CN1681802A embodiment 2 is obtained;

Reference substance 3: commercially available lansoprazole bulk drug.

Determination of foreign matter method: with reference to " in lansoprazole intestine dissolving capsule the structural identification of impurity, inspection and control " [Xia Guimin, Deng. the structural identification of impurity, inspection and control in lansoprazole intestine dissolving capsule. pharmaceutical analysis impurity, 2012,32(6): 1022-1027] in method measure each impurity content in each sample.The results are shown in Table shown in 1:

Determination of foreign matter in table 1 lansoprazole stability test

Can be found out by result of the test, compared with reference substance, lansoprazole prepared by the present invention E free from foreign meter, and the content of impurity A and impurity B significantly reduces.

test example 2: fluidity test

Method: prepare 3 batch samples according to embodiment 1, be numbered 001,002,003, sample respectively, adopt fixed funnel method, funnel is placed in the suitable height on graph paper, lansoprazole is freely flowed down from bell mouth, until the cone top formed contacts with bell mouth, measures hypotenuse and the horizontal angle (θ angle of repose) of lansoprazole accumulation horizon.The results are shown in Table shown in 2:

The fluidity test result of table 2 lansoprazole

Can be found out by result of the test, lansoprazole mobility prepared by the present invention is better.

test example 3: Dissolution Rate Testing

Prepare 3 batch samples according to embodiment 1, be numbered 001,002,003;

Reference substance 1: according to " improvement in synthesis of lansoprazole " [Liu Yanfei, Li Yongxin etc. the improvement in synthesis [J] of lansoprazole, fine-chemical intermediate, 2011, the lansoprazole fine work of method synthesis 41(3): 26-28 and 42], m.p.169-171 DEG C (decomposition);

Reference substance 2: according to the lansoprazole form D that the method for CN1681802A embodiment 2 is obtained;

Reference substance 3: commercially available lansoprazole bulk drug.

Method: different lansoprazoles is investigated dissolution according to Pharmacopoeia of the People's Republic of China version in 2010 two annex XC method second methods.With pH6.8 phosphate buffer 900mL for dissolution medium, temperature is 37 DEG C, and rotating speed is 75rmin ^-1, the medication amount in each testing sample is 30mg.Adopt ultraviolet spectrophotometry to carry out dissolution determination respectively at 5,10,15,20 and 30min sampling, determined wavelength is 284nm, at 5-25mgL ^-1internal linear relation is good, and the response rate, Precision Experiment all meet methodology requirement.The results are shown in Table 3:

The dissolution of table 3 lansoprazole investigates result

Can be found out by result of the test, compared with reference substance, the dissolution of lansoprazole prepared by the present invention significantly improves.

Claims (8)

1. treat a medicine Lansoprazole composition freeze-dried powder injection for gastric ulcer, comprise lansoprazole and excipient, it is characterized in that: described lansoprazole is crystal, the X-ray powder diffraction pattern that the measurement of use Cu-K alpha ray obtains as shown in Figure 1.

2. the medicine Lansoprazole composition freeze-dried powder injection for the treatment of gastric ulcer according to claim 1, is characterized in that: with parts by weight, is made up of the lansoprazole of 1-2 weight portion, the excipient of 3-5 weight portion.

3. the medicine Lansoprazole composition freeze-dried powder injection for the treatment of gastric ulcer according to claim 2, is characterized in that: with parts by weight, by the lansoprazole of 1.5 weight portions, 4 weight portions excipient form.

4. prepare the medicine Lansoprazole composition freeze-dried powder injection according to the arbitrary described treatment gastric ulcer of claim 1-3, it is characterized in that comprising the following steps:

Get recipe quantity compound of Lansoprazole, use water for injection stirring and dissolving, add the excipient of recipe quantity, adjust ph, be then stirred to pH constant after, mend inject water to 100 times that liquor capacity is lansoprazole weight, then active carbon coarse filtration is used, successively through 1.0 μm, 0.45 μm, the microporous filter membrane aseptic filtration of 0.22 μm, filters into sterilizing room, measure pH and content qualified after, fill, pressure half plug, puts into the freeze drying box being cooled to-40 DEG C, frozen drying, tamponade outlet, rolls lid.

5. the medicine Lansoprazole composition freeze-dried powder injection for the treatment of gastric ulcer according to claim 1, is characterized in that: described excipient is low molecular dextran.

6. the preparation method of the medicine Lansoprazole composition freeze-dried powder injection for the treatment of gastric ulcer according to claim 4, it is characterized in that: described lyophilization is for first-40 DEG C of pre-freezes 5 hours, then dry 13 hours of reduced vacuum under-25 DEG C of conditions, finally 30 DEG C of high temperature dryings 5 hours.

7. the preparation method of the medicine Lansoprazole composition freeze-dried powder injection for the treatment of gastric ulcer according to claim 4, is characterized in that: described adjustment pH is 8.0-9.0.

8. the medicine Lansoprazole composition freeze-dried powder injection for the treatment of gastric ulcer according to claim 1, it is characterized in that, the preparation method of the crystal of described lansoprazole comprises the following steps:

Prepare the saturated dichloromethane solution of lansoprazole crude product of 40 DEG C, then adding volume is the water of 8 times of saturated dichloromethane solution volume and the mixed solvent of 2-picoline, the volume ratio of described water and 2-picoline is 4:1.5, and after stirring, cooling limit, limit is stirred, cooling rate is 15 DEG C/h, mixing speed is 100 revs/min, stops stirring, leave standstill growing the grain 2 hours after being cooled to-5 DEG C, filter, after drying under reduced pressure, obtain lansoprazole crystalline compounds.