CN105106206A - Medicine of lansoprazole composition for treating digestive system diseases - Google Patents

Abstract

The invention discloses medicine of a lansoprazole composition for treating digestive system diseases, and belongs to the technical field of medicine. The composition consists of lansoprazole and monosodium orthophosphate. The lansoprazole is a novel crystal form compound; an X-ray powder diffraction figure obtained through Cu-Ka ray measurement is shown as the Figure 1; the lansoprazole composition belongs to the lansoprazole different from that reported in the prior art. Experiments show that the lansoprazole crystal form compound provided by the invention does not contain impurities E; in addition, the content of impurities A and the content of impurities B are obviously reduced; the content change is small along with the storage time increase; good flowability is realized; the dissolution rate is obviously improved; powder injection prepared from the novel crystal form compounds has high stability; the stability is high after the composition is matched with solvents; the content of insoluble micro particles is very low; the lansoprazole composition is very suitable for clinic application.

Description

A kind of medicine Lansoprazole composition for the treatment of digestive system disease

Technical field

The invention belongs to medical art, relate to a kind of medicine Lansoprazole composition for the treatment of digestive system disease.

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 of parietal cell ⁺-K ⁺-ATP enzyme, makes the H of parietal cell ⁺can not be transported in stomach and go, so that in gastric juice, gastric acid amount greatly reduces, 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 for the treatment of digestive system disease.

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

A kind of medicine Lansoprazole composition for the treatment of digestive system disease of the present invention, described compositions is made up of lansoprazole, sodium dihydrogen phosphate; 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.

First optimal technical scheme of the present invention is: with parts by weight, and described compositions is made up of the lansoprazole of 1 weight portion, the sodium dihydrogen phosphate of 0.002-0.004 weight portion.

Second optimal technical scheme of the present invention is: with parts by weight, and described compositions is made up of the lansoprazole of 1 weight portion, the sodium dihydrogen phosphate of 0.003 weight portion.

3rd optimal technical scheme of the present invention is that the preparation method of described compositions comprises the following steps:

(1) take lansoprazole crystal and sodium dihydrogen phosphate in proportion, fully mix;

(2) to divide in the cillin bottle after being filled to sterilizing and to jump a queue.

4th optimal technical scheme of the present invention is that the preparation method of the crystal of described lansoprazole comprises the following steps:

(1) be that in the methanol of 10 times of lansoprazole weight and the mixed solution of carbon tetrachloride, the volume ratio of described methanol and carbon tetrachloride is 4:2.5 to 35 DEG C of volumes by lansoprazole dissolving crude product;

(2) add the activated carbon decolorizing that weight is 0.2 times of lansoprazole weight, filter, obtain lansoprazole solution;

(3) by lansoprazole solution warms to 45 DEG C, in lansoprazole solution, drip distilled water under the condition of stirring, the volume of distilled water is 8 times of lansoprazole weight, at the uniform velocity dropwises in 0.5h, and described stir speed (S.S.) is 30rmp;

(4) be cooled to-15 DEG C with the speed of 15 DEG C/h after being added dropwise to complete, continue to stir 2h under the stir speed (S.S.) of 15rmp, leave standstill 3h crystallize out, filter, washing, vacuum drying obtains lansoprazole crystal.

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 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

(1) be that in the methanol of 10 times of lansoprazole weight and the mixed solution of carbon tetrachloride, the volume ratio of described methanol and carbon tetrachloride is 4:2.5 to 35 DEG C of volumes by lansoprazole dissolving crude product;

(2) add the activated carbon decolorizing that weight is 0.2 times of lansoprazole weight, filter, obtain lansoprazole solution;

(3) by lansoprazole solution warms to 45 DEG C, in lansoprazole solution, drip distilled water under the condition of stirring, the volume of distilled water is 8 times of lansoprazole weight, at the uniform velocity dropwises in 0.5h, and described stir speed (S.S.) is 30rmp;

(4) be cooled to-15 DEG C with the speed of 15 DEG C/h after being added dropwise to complete, continue to stir 2h under the stir speed (S.S.) of 15rmp, leave standstill 3h crystallize out, filter, washing, vacuum drying obtains lansoprazole crystal.

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 composition

Consist of: lansoprazole crystal 1 weight portion prepared by the present invention, sodium dihydrogen phosphate 0.002 weight portion.

Preparation method is:

(1) take lansoprazole crystal and sodium dihydrogen phosphate in proportion, fully mix;

(2) to divide in the cillin bottle after being filled to sterilizing and to jump a queue.

embodiment 3:the preparation of Lansoprazole composition

Consist of: lansoprazole crystal 1 weight portion prepared by the present invention, sodium dihydrogen phosphate 0.003 weight portion.

Preparation method is:

(1) take lansoprazole crystal and sodium dihydrogen phosphate in proportion, fully mix;

(2) to divide in the cillin bottle after being filled to sterilizing and to jump a queue.

embodiment 4:the preparation of Lansoprazole composition

Consist of: lansoprazole crystal 1 weight portion prepared by the present invention, sodium dihydrogen phosphate 0.004 weight portion.

Preparation method is:

(1) take lansoprazole crystal and sodium dihydrogen phosphate in proportion, fully mix;

(2) to divide in the cillin bottle after being filled to sterilizing and to jump a queue.

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] method in measures 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

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, measure 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

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

Claims (5)

1. treat a medicine Lansoprazole composition for digestive system disease, it is characterized in that: described compositions is made up of lansoprazole, sodium dihydrogen phosphate; 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.

2. the medicine Lansoprazole composition for the treatment of digestive system disease according to claim 1, is characterized in that: with parts by weight, and described compositions is made up of the lansoprazole of 1 weight portion, the sodium dihydrogen phosphate of 0.002-0.004 weight portion.

3. the medicine Lansoprazole composition for the treatment of digestive system disease according to claim 2, is characterized in that: with parts by weight, and described compositions is made up of the lansoprazole of 1 weight portion, the sodium dihydrogen phosphate of 0.003 weight portion.

4. the medicine Lansoprazole composition of the treatment digestive system disease according to any one of claim 1-3, is characterized in that, the preparation method of described compositions comprises the following steps:

(1) take lansoprazole crystal and sodium dihydrogen phosphate in proportion, fully mix;

(2) to divide in the cillin bottle after being filled to sterilizing and to jump a queue.

5. the medicine Lansoprazole composition for the treatment of digestive system disease according to claim 1, is characterized in that, the preparation method of the crystal of described lansoprazole comprises the following steps:

(1) be that in the methanol of 10 times of lansoprazole weight and the mixed solution of carbon tetrachloride, the volume ratio of described methanol and carbon tetrachloride is 4:2.5 to 35 DEG C of volumes by lansoprazole dissolving crude product;

(2) add the activated carbon decolorizing that weight is 0.2 times of lansoprazole weight, filter, obtain lansoprazole solution;

(3) by lansoprazole solution warms to 45 DEG C, in lansoprazole solution, drip distilled water under the condition of stirring, the volume of distilled water is 8 times of lansoprazole weight, at the uniform velocity dropwises in 0.5h, and described stir speed (S.S.) is 30rmp;

(4) be cooled to-15 DEG C with the speed of 15 DEG C/h after being added dropwise to complete, continue to stir 2h under the stir speed (S.S.) of 15rmp, leave standstill 3h crystallize out, filter, washing, vacuum drying obtains lansoprazole crystal.