CN109620961A - The composition being made of morpholone derivative and cellulose derivative - Google Patents
The composition being made of morpholone derivative and cellulose derivative Download PDFInfo
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- CN109620961A CN109620961A CN201910050775.2A CN201910050775A CN109620961A CN 109620961 A CN109620961 A CN 109620961A CN 201910050775 A CN201910050775 A CN 201910050775A CN 109620961 A CN109620961 A CN 109620961A
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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Abstract
The present invention provides a kind of composition being made of morpholone derivative and cellulose derivative, the composition can significantly reduce the effect of cellulose derivative enhancing chlamydia trachomatis growth.
Description
Technical field
The invention belongs to biomedicine technical fields, and in particular to a kind of by morpholone derivative and cellulose or its derivative
The composition that object is constituted.
Background technique
It is common a kind of auxiliary material in oral and external solid preparation by the cellulose derivative of representative of hyetellose,
However, Raffai T et al. is published in the one of Antimicrob Agents Chemother. magazine the 1st phase of volume 63 in 2018
Item result of study but confirms that hydroxy ethyl cellulose can but significantly increase the growth and infectivity of chlamydia trachomatis D type and E type.
Although the research be carried out in vagina simulated solution, however, it has been reported that, chlamydia trachomatis also result in alimentary canal infection
(such as Genitourin Med.1990Feb；66 (1): 26-7.), and the present invention is carried out using gastric acid simulated solution as medium
Test discovery, cellulose acetate, low-substituted hydroxypropyl methylcellulose, low-substituted hydroxypropyl cellulose, methylcellulose, crosslinking carboxylic first
Base sodium cellulosate, microcrystalline cellulose, cellacefate, ethyl cellulose, ethyl hydroxy cellulose, hydroxypropyl methylcellulose, hydroxypropyl fiber
The cellulose derivatives class auxiliary material such as element, hymetellose, hyetellose, sodium carboxymethylcellulose all has similar work
With.Therefore, contain cellulose derivative may also can promote after oral administration as the oral preparation of auxiliary material it is in the digestive tract
Chlamydia trachomatis growth, brings some potential safety problems to high-risk patient.
Summary of the invention
The purpose of the present invention is to provide a kind of composition being made of morpholone derivative and cellulose derivative, the groups
Closing object can significantly reduce the effect of cellulose derivative enhancing chlamydia trachomatis growth.
To achieve the goals above, the present invention provides a kind of groups being made of morpholone derivative and cellulose derivative
Close object, which is characterized in that the cellulose derivative be selected from cellulose acetate (C1), low-substituted hydroxypropyl methylcellulose (C2),
Low-substituted hydroxypropyl cellulose (C3), methylcellulose (C4), croscarmellose sodium (C5), microcrystalline cellulose (C6), fibre
Tie up vinegar method ester (C7), ethyl cellulose (C8), ethyl hydroxy cellulose (C9), hydroxypropyl methylcellulose (C10), hydroxypropylcellulose (C11),
One of hymetellose (C12), hyetellose (C13), sodium carboxymethylcellulose (C14)；The morpholone is derivative
Object is selected from one of compound 1~10 as follows.
Morpholone derivative class compound of the present invention is the compound for being seen in prior art record, specifically
, 1~compound of compound 4 as described above is seen in the record of CN106432218A, and 5~compound of compound 10 is seen in
In " Chinese Journal of Pharmaceuticals ", the record of 2014,45 (4).
Cellulose derivative of the present invention is the Handbook of for being seen in Raymond C Rowe et al. and writing
Auxiliary material in Pharmaceutical Excipients (Six Edition), and meet quality standard therein.
Preferably, the mass ratio of cellulose derivative and morpholone derivative is not higher than in composition of the present invention
100000:1。
On the one hand preferred, according to the AUC data of D type in table 2, combination of the present invention is in following composition
One kind:
The composition being made of hydroxypropyl methylcellulose and compound 9,
The composition being made of hydroxypropylcellulose and compound 9,
The composition being made of methylcellulose and compound 9,
The composition being made of ethyl cellulose and compound 9,
The composition being made of hyetellose and compound 9,
The composition being made of cellulose acetate and compound 9,
The composition being made of low-substituted hydroxypropyl cellulose and compound 4,
The composition being made of sodium carboxymethylcellulose and compound 9,
The composition being made of hymetellose and compound 9,
The composition being made of croscarmellose sodium and compound 9,
The composition being made of cellulose acetate and compound 5,
The composition being made of hyetellose and compound 5,
The composition being made of cellacefate and compound 1,
The composition being made of cellacefate and compound 5,
The composition being made of ethyl cellulose and compound 10,
The composition being made of hydroxypropyl methylcellulose and compound 5,
The composition being made of hyetellose and compound 6,
The composition being made of low-substituted hydroxypropyl cellulose and compound 7,
The composition being made of hyetellose and compound 10,
The composition being made of ethyl hydroxy cellulose and compound 5,
The composition being made of low-substituted hydroxypropyl methylcellulose and compound 9,
The composition being made of microcrystalline cellulose and compound 9,
The composition being made of cellulose acetate and compound 6,
The composition being made of cellacefate and compound 9,
The composition being made of hydroxypropyl methylcellulose and compound 7,
The composition being made of low-substituted hydroxypropyl methylcellulose and compound 10,
The composition being made of cellulose acetate and compound 4,
The composition being made of ethyl cellulose and compound 5,
The composition being made of ethyl cellulose and compound 7,
The composition being made of ethyl hydroxy cellulose and compound 9,
The composition being made of croscarmellose sodium and compound 10,
The composition being made of cellacefate and compound 3,
The composition being made of low-substituted hydroxypropyl cellulose and compound 9,
The composition being made of low-substituted hydroxypropyl cellulose and compound 10,
The composition being made of methylcellulose and compound 5,
The composition being made of hydroxypropylcellulose and compound 10,
The composition being made of hymetellose and compound 4,
The composition being made of croscarmellose sodium and compound 5,
The composition being made of microcrystalline cellulose and compound 5,
The composition being made of ethyl hydroxy cellulose and compound 10,
The composition being made of hymetellose and compound 6,
The composition being made of ethyl hydroxy cellulose and compound 6,
The composition being made of sodium carboxymethylcellulose and compound 4,
The composition being made of hyetellose and compound 4,
The composition being made of low-substituted hydroxypropyl methylcellulose and compound 6,
The composition being made of hydroxypropylcellulose and compound 5,
The composition being made of ethyl cellulose and compound 2,
The composition being made of cellulose acetate and compound 10,
The composition being made of low-substituted hydroxypropyl cellulose and compound 2,
The composition being made of methylcellulose and compound 7,
The composition being made of microcrystalline cellulose and compound 6,
The composition being made of cellacefate and compound 10,
The composition being made of ethyl cellulose and compound 6,
The composition being made of cellulose acetate and compound 7,
The composition being made of cellacefate and compound 6,
The composition being made of sodium carboxymethylcellulose and compound 6,
The composition being made of croscarmellose sodium and compound 4,
The composition being made of methylcellulose and compound 6,
The composition being made of hydroxypropylcellulose and compound 6,
The composition being made of methylcellulose and compound 10,
The composition being made of cellulose acetate and compound 2,
The composition being made of hydroxypropylcellulose and compound 4,
The composition being made of croscarmellose sodium and compound 7,
The composition being made of methylcellulose and compound 4,
The composition being made of hydroxypropyl methylcellulose and compound 3,
The composition being made of ethyl hydroxy cellulose and compound 7,
The composition being made of sodium carboxymethylcellulose and compound 7,
The composition being made of cellulose acetate and compound 8,
The composition being made of ethyl hydroxy cellulose and compound 2,
The composition being made of low-substituted hydroxypropyl methylcellulose and compound 7.
It is furthermore preferred that composition of the present invention is selected from one of following composition:
The composition being made of hydroxypropyl methylcellulose and compound 9,
The composition being made of hydroxypropylcellulose and compound 9,
The composition being made of methylcellulose and compound 9,
The composition being made of ethyl cellulose and compound 9,
The composition being made of hyetellose and compound 9,
The composition being made of cellulose acetate and compound 9,
The composition being made of low-substituted hydroxypropyl cellulose and compound 4,
The composition being made of sodium carboxymethylcellulose and compound 9,
The composition being made of hymetellose and compound 9,
The composition being made of croscarmellose sodium and compound 9,
The composition being made of cellulose acetate and compound 5,
The composition being made of hyetellose and compound 5,
The composition being made of cellacefate and compound 1,
The composition being made of cellacefate and compound 5,
The composition being made of ethyl cellulose and compound 10,
The composition being made of hydroxypropyl methylcellulose and compound 5,
The composition being made of hyetellose and compound 6,
The composition being made of low-substituted hydroxypropyl cellulose and compound 7,
The composition being made of hyetellose and compound 10,
The composition being made of ethyl hydroxy cellulose and compound 5,
The composition being made of low-substituted hydroxypropyl methylcellulose and compound 9,
The composition being made of microcrystalline cellulose and compound 9,
The composition being made of cellulose acetate and compound 6,
The composition being made of cellacefate and compound 9,
The composition being made of hydroxypropyl methylcellulose and compound 7,
The composition being made of low-substituted hydroxypropyl methylcellulose and compound 10,
The composition being made of cellulose acetate and compound 4,
The composition being made of ethyl cellulose and compound 5,
The composition being made of ethyl cellulose and compound 7,
The composition being made of ethyl hydroxy cellulose and compound 9,
The composition being made of croscarmellose sodium and compound 10,
The composition being made of cellacefate and compound 3,
The composition being made of low-substituted hydroxypropyl cellulose and compound 9,
The composition being made of low-substituted hydroxypropyl cellulose and compound 10,
The composition being made of methylcellulose and compound 5.
It is further preferred that composition of the present invention is selected from one of following composition:
The composition being made of hydroxypropyl methylcellulose and compound 9,
The composition being made of hydroxypropylcellulose and compound 9,
The composition being made of methylcellulose and compound 9,
The composition being made of ethyl cellulose and compound 9,
The composition being made of hyetellose and compound 9,
The composition being made of cellulose acetate and compound 9,
The composition being made of low-substituted hydroxypropyl cellulose and compound 4,
The composition being made of sodium carboxymethylcellulose and compound 9,
The composition being made of hymetellose and compound 9,
The composition being made of croscarmellose sodium and compound 9,
The composition being made of cellulose acetate and compound 5,
The composition being made of hyetellose and compound 5,
The composition being made of cellacefate and compound 1,
The composition being made of cellacefate and compound 5,
The composition being made of ethyl cellulose and compound 10,
The composition being made of hydroxypropyl methylcellulose and compound 5,
The composition being made of hyetellose and compound 6,
The composition being made of low-substituted hydroxypropyl cellulose and compound 7.
Most preferably, composition of the present invention is selected from one of following composition:
The composition being made of hydroxypropyl methylcellulose and compound 9,
The composition being made of hydroxypropylcellulose and compound 9,
The composition being made of methylcellulose and compound 9,
The composition being made of ethyl cellulose and compound 9,
The composition being made of hyetellose and compound 9,
The composition being made of cellulose acetate and compound 9,
The composition being made of low-substituted hydroxypropyl cellulose and compound 4,
The composition being made of sodium carboxymethylcellulose and compound 9,
The composition being made of hymetellose and compound 9.
On the other hand preferred, according to the AUC data of E type in table 2, composition of the present invention is selected from following combination
One of object:
The composition being made of low-substituted hydroxypropyl cellulose and compound 8,
The composition being made of methylcellulose and compound 4,
The composition being made of hymetellose and compound 10,
The composition being made of croscarmellose sodium and compound 8,
The composition being made of sodium carboxymethylcellulose and compound 10,
The composition being made of sodium carboxymethylcellulose and compound 4,
The composition being made of hydroxypropyl methylcellulose and compound 8,
The composition being made of low-substituted hydroxypropyl cellulose and compound 1,
The composition being made of hydroxypropyl methylcellulose and compound 2,
The composition being made of cellulose acetate and compound 8,
The composition being made of hymetellose and compound 2,
The composition being made of microcrystalline cellulose and compound 10,
The composition being made of low-substituted hydroxypropyl methylcellulose and compound 8,
The composition being made of microcrystalline cellulose and compound 8,
The composition being made of low-substituted hydroxypropyl cellulose and compound 2,
The composition being made of hydroxypropyl methylcellulose and compound 4,
The composition being made of low-substituted hydroxypropyl methylcellulose and compound 10,
The composition being made of croscarmellose sodium and compound 6,
The composition being made of ethyl cellulose and compound 10,
The composition being made of cellulose acetate and compound 4,
The composition being made of sodium carboxymethylcellulose and compound 2,
The composition being made of cellacefate and compound 10,
The composition being made of hydroxypropylcellulose and compound 10,
The composition being made of hyetellose and compound 10,
The composition being made of ethyl cellulose and compound 9,
The composition being made of ethyl cellulose and compound 6,
The composition being made of ethyl hydroxy cellulose and compound 6,
The composition being made of ethyl cellulose and compound 8,
The composition being made of hydroxypropyl methylcellulose and compound 6,
The composition being made of ethyl hydroxy cellulose and compound 8,
The composition being made of microcrystalline cellulose and compound 2,
The composition being made of sodium carboxymethylcellulose and compound 6,
The composition being made of croscarmellose sodium and compound 4,
The composition being made of hydroxypropyl methylcellulose and compound 10,
The composition being made of hydroxypropylcellulose and compound 2,
The composition being made of methylcellulose and compound 8,
The composition being made of hydroxypropylcellulose and compound 8,
The composition being made of hyetellose and compound 8,
The composition being made of cellacefate and compound 4,
The composition being made of ethyl cellulose and compound 2,
The composition being made of sodium carboxymethylcellulose and compound 8,
The composition being made of methylcellulose and compound 10,
The composition being made of cellulose acetate and compound 10,
The composition being made of low-substituted hydroxypropyl methylcellulose and compound 1 is made of ethyl hydroxy cellulose and compound 9
Composition,
The composition being made of low-substituted hydroxypropyl cellulose and compound 4,
The composition being made of hyetellose and compound 6,
The composition being made of hydroxypropylcellulose and compound 6,
The composition being made of cellacefate and compound 8,
The composition being made of hymetellose and compound 6,
The composition being made of cellacefate and compound 6,
The composition being made of cellacefate and compound 2,
The composition being made of cellacefate and compound 1,
The composition being made of methylcellulose and compound 2,
The composition being made of hydroxypropylcellulose and compound 4,
The composition being made of ethyl cellulose and compound 4,
The composition being made of croscarmellose sodium and compound 2,
The composition being made of hyetellose and compound 2,
The composition being made of methylcellulose and compound 6,
The composition being made of ethyl hydroxy cellulose and compound 2,
The composition being made of low-substituted hydroxypropyl methylcellulose and compound 7,
The composition being made of microcrystalline cellulose and compound 1,
The composition being made of microcrystalline cellulose and compound 4,
The composition being made of microcrystalline cellulose and compound 6,
The composition being made of ethyl hydroxy cellulose and compound 10,
The composition being made of cellacefate and compound 9,
The composition being made of low-substituted hydroxypropyl cellulose and compound 7,
The composition being made of ethyl hydroxy cellulose and compound 3,
The composition being made of cellulose acetate and compound 2,
The composition being made of croscarmellose sodium and compound 10.
It is furthermore preferred that composition of the present invention is selected from one of following composition:
The composition being made of low-substituted hydroxypropyl cellulose and compound 8,
The composition being made of methylcellulose and compound 4,
The composition being made of hymetellose and compound 10,
The composition being made of croscarmellose sodium and compound 8,
The composition being made of sodium carboxymethylcellulose and compound 10,
The composition being made of sodium carboxymethylcellulose and compound 4,
The composition being made of hydroxypropyl methylcellulose and compound 8,
The composition being made of low-substituted hydroxypropyl cellulose and compound 1,
The composition being made of hydroxypropyl methylcellulose and compound 2,
The composition being made of cellulose acetate and compound 8,
The composition being made of hymetellose and compound 2,
The composition being made of microcrystalline cellulose and compound 10,
The composition being made of low-substituted hydroxypropyl methylcellulose and compound 8,
The composition being made of microcrystalline cellulose and compound 8,
The composition being made of low-substituted hydroxypropyl cellulose and compound 2,
The composition being made of hydroxypropyl methylcellulose and compound 4,
The composition being made of low-substituted hydroxypropyl methylcellulose and compound 10,
The composition being made of croscarmellose sodium and compound 6,
The composition being made of ethyl cellulose and compound 10,
The composition being made of cellulose acetate and compound 4,
The composition being made of sodium carboxymethylcellulose and compound 2,
The composition being made of cellacefate and compound 10,
The composition being made of hydroxypropylcellulose and compound 10,
The composition being made of hyetellose and compound 10,
The composition being made of ethyl cellulose and compound 9,
The composition being made of ethyl cellulose and compound 6,
The composition being made of ethyl hydroxy cellulose and compound 6,
The composition being made of ethyl cellulose and compound 8,
The composition being made of hydroxypropyl methylcellulose and compound 6,
The composition being made of ethyl hydroxy cellulose and compound 8,
The composition being made of microcrystalline cellulose and compound 2,
The composition being made of sodium carboxymethylcellulose and compound 6,
The composition being made of croscarmellose sodium and compound 4,
The composition being made of hydroxypropyl methylcellulose and compound 10,
The composition being made of hydroxypropylcellulose and compound 2,
The composition being made of methylcellulose and compound 8,
The composition being made of hydroxypropylcellulose and compound 8,
The composition being made of hyetellose and compound 8.
It is further preferred that composition of the present invention is selected from one of following composition:
The composition being made of low-substituted hydroxypropyl cellulose and compound 8,
The composition being made of methylcellulose and compound 4,
The composition being made of hymetellose and compound 10,
The composition being made of croscarmellose sodium and compound 8,
The composition being made of sodium carboxymethylcellulose and compound 10,
The composition being made of sodium carboxymethylcellulose and compound 4,
The composition being made of hydroxypropyl methylcellulose and compound 8,
The composition being made of low-substituted hydroxypropyl cellulose and compound 1,
The composition being made of hydroxypropyl methylcellulose and compound 2,
The composition being made of cellulose acetate and compound 8,
The composition being made of hymetellose and compound 2,
The composition being made of microcrystalline cellulose and compound 10,
The composition being made of low-substituted hydroxypropyl methylcellulose and compound 8,
The composition being made of microcrystalline cellulose and compound 8,
The composition being made of low-substituted hydroxypropyl cellulose and compound 2,
The composition being made of hydroxypropyl methylcellulose and compound 4,
The composition being made of low-substituted hydroxypropyl methylcellulose and compound 10,
The composition being made of croscarmellose sodium and compound 6.
Most preferably, composition of the present invention is selected from one of following composition:
The composition being made of low-substituted hydroxypropyl cellulose and compound 8,
The composition being made of methylcellulose and compound 4,
The composition being made of hymetellose and compound 10,
The composition being made of croscarmellose sodium and compound 8,
The composition being made of sodium carboxymethylcellulose and compound 10,
The composition being made of sodium carboxymethylcellulose and compound 4,
The composition being made of hydroxypropyl methylcellulose and compound 8,
The composition being made of low-substituted hydroxypropyl cellulose and compound 1,
The composition being made of hydroxypropyl methylcellulose and compound 2.
On the other hand, the present invention provides foregoing compositions in the purposes for preparing solid pharmaceutical preparation.
Preferably, solid pharmaceutical preparation of the present invention is selected from one of tablet and capsule.
In vitro test is the results show that composition of the present invention can significantly reduce cellulose derivative class auxiliary material enhancing sand
The effect of the growth of chlamydia oculogenitale.
Specific embodiment
Below with reference to the embodiment of the present invention, clear, complete description is carried out to technical solution of the present invention, it is clear that retouched
The embodiment stated is only a part of the embodiments of the present invention, instead of all the embodiments.Based on the embodiments of the present invention,
Every other embodiment obtained by those of ordinary skill in the art without making creative efforts, belongs to this hair
The range of bright protection.
The preparation of example 1 group conjunction object
Various cellulose derivatives shown in table 1 are taken to be sufficiently mixed with morpholone derivative with corresponding mass ratio, both.
The influence of 1 cellulose derivative of test example and composition to chlamydia trachomatis D type and the growth of E type
It is draped over one's shoulders using the superfine people of Liu Zhi in " Chinese Amphixenosis's journal " the 2nd interim delivered article of volume 33 in 2017
The influence of cellulose derivative and composition to chlamydia trachomatis D type and the growth of E type shown in the method measurement table 1 of dew.Specifically
Method is as described below.
Step 1: gastric acid simulated solution being prepared using the method that the Wang Qian of The Fourth Military Medical University is disclosed in its Master's thesis, is had
Body, it takes 18.6mL citric acid solution (1mol/L) to be added in 20m L volumetric flask, adds the sodium citrate solution of 1.4m L
(1mol/L) with pH detection assay pH is about 3.0 after mixing.
Step 2: taking basis weight of fiber element derivative and composition, being prepared with the gastric acid simulated solution of step 1 becomes final concentration of
The tested material of 35% (w/v), and the concentration of composition tested material is represented with the concentration of cellulose derivative.It is spare.For can not
The tested material of dispersed system is formed, its dispersion can be helped using ultrasound before facing.
Step 3: using gastric acid simulated solution culture Hela cell 48h.
Step 4: the good Hela cell of growth conditions being reached into 6 orifice plates, continues culture for 24 hours, forms fine and close single layer.
Step 5: chlamydia trachomatis E type, D type clinical strain that infection rate is 3-5MOI are seeded to different 6 orifice plates respectively.
6:32 DEG C of step, 3000r/min, it is centrifuged 1h, 5%CO2After 37 DEG C of incubators stand 2h, gastric acid simulated solution is used respectively
(control), gastric acid simulated solution add the cellulose derivative tested material of step 2, gastric acid simulated solution that step 2 composition tested material is added to train
Support chlamydia trachomatis bacterial strain.Every kind of cellulose derivative-morpholone derivative composition (all mass ratioes) designs a control
Group.
Step 7: continuing after cultivating 48h, collect supernatant respectively, and dissolve cell with ice distilled water, collect above-mentioned whole
Mixed liquor is inoculated to new Hela cell 6 orifice plates, continues to cultivate 48h according to the above method.
Step 8: after inclusion body method of counting cell culture 48h, discarding liquid in culture plate, methanol is fixed after air-drying
15min is dyed with Lugol's iodine solution, counts the lower inclusion body number of different culture solutions effect, 30 visuals field of every hole counting (×
Under 400 times of mirrors) take mean value.
The equal replication of every kind of tested material 4 times calculates chlamydia trachomatis D type and E type after tested material processing according to the following formula
Relative growth rate (RGR).
In above formula, control group inclusion body is counted as the mean value of 4 measured values, and tested material group inclusion body is counted as single survey
Determine as a result, gained RGR is denoted as RGR respectively1~4。
The t checking function provided using Excel carries out statistics credit to the difference of each composition and cellulose derivative RGR
Analysis, the results are shown in Table 1.
Table 1.
Linear regression is carried out with logarithm (log (c)) of the average RGR of every kind of composition in table 1 to mass ratio, is calculated
Slope (a value), intercept (b value) and the related coefficient (r of regression equation2Value), then by regression equation calculation 1000 → 100000
Area under the curve.The results are shown in Table 2.
Table 2.
Embodiment 2: tablet and capsule containing the composition being made of cellulose derivative and morpholone derivative
Preparation
Take the 500g Imatinib, 480g lactose, 200g microcrystalline cellulose that sieve with 100 mesh sieve (abundant with 200mg compound 10
Mix), 100g crospovidone, 100g starch；It takes 75g to be sufficiently mixed by hydroxypropyl methylcellulose and 75mg compound 9, is configured to
The solution for being 10% by hydroxypropyl methylcellulose element meter concentration is added with newborn acid for adjusting pH to 3.0~4.0 to above-mentioned mixed material
In softwood processed, with 16 meshes granulation, 80 DEG C of dry 3~4h.With 16 mesh sieves, 30g superfine silica gel powder, 15g magnesium stearate is added
Mixing mix, tabletting to get.
Take the 500g Imatinib, 480g lactose, 200g microcrystalline cellulose that sieve with 100 mesh sieve (abundant with 200mg compound 8
Mix), 100g crospovidone, 100g starch；75g is taken to be sufficiently mixed by low-substituted hydroxypropyl methylcellulose and 75mg compound 8,
It is configured to, with newborn acid for adjusting pH to 3.0~4.0, be added extremely according to the solution for being 10% by low-substituted hydroxypropyl methylcellulose meter concentration
Softwood processed in said mixture material, with the granulation of 16 meshes, 80 DEG C of dry 3~4h.With 16 mesh sieves, be added 30g superfine silica gel powder,
15g magnesium stearate mixing mix, filling capsule to get.
Claims (10)
1. a kind of composition being made of morpholone derivative and cellulose derivative, which is characterized in that the cellulose is derivative
Object is selected from cellulose acetate, low-substituted hydroxypropyl methylcellulose, low-substituted hydroxypropyl cellulose, methylcellulose, cross-linked carboxymethyl
Sodium cellulosate, microcrystalline cellulose, cellacefate, ethyl cellulose, ethyl hydroxy cellulose, hydroxypropyl methylcellulose, hydroxypropylcellulose,
One of hymetellose, hyetellose, sodium carboxymethylcellulose；The morpholone derivative is selected from as follows
One of compound 1~10.
2. composition according to claim 1, which is characterized in that cellulose derivative and morpholone derivative in the composition
Mass ratio be not higher than 100000:1.
3. composition according to claim 1 or 2, which is characterized in that the combination is selected from one of following composition:
The composition being made of hydroxypropyl methylcellulose and compound 9,
The composition being made of hydroxypropylcellulose and compound 9,
The composition being made of methylcellulose and compound 9,
The composition being made of ethyl cellulose and compound 9,
The composition being made of hyetellose and compound 9,
The composition being made of cellulose acetate and compound 9,
The composition being made of low-substituted hydroxypropyl cellulose and compound 4,
The composition being made of sodium carboxymethylcellulose and compound 9,
The composition being made of hymetellose and compound 9,
The composition being made of croscarmellose sodium and compound 9,
The composition being made of cellulose acetate and compound 5,
The composition being made of hyetellose and compound 5,
The composition being made of cellacefate and compound 1,
The composition being made of cellacefate and compound 5,
The composition being made of ethyl cellulose and compound 10,
The composition being made of hydroxypropyl methylcellulose and compound 5,
The composition being made of hyetellose and compound 6,
The composition being made of low-substituted hydroxypropyl cellulose and compound 7,
The composition being made of hyetellose and compound 10,
The composition being made of ethyl hydroxy cellulose and compound 5,
The composition being made of low-substituted hydroxypropyl methylcellulose and compound 9,
The composition being made of microcrystalline cellulose and compound 9,
The composition being made of cellulose acetate and compound 6,
The composition being made of cellacefate and compound 9,
The composition being made of hydroxypropyl methylcellulose and compound 7,
The composition being made of low-substituted hydroxypropyl methylcellulose and compound 10,
The composition being made of cellulose acetate and compound 4,
The composition being made of ethyl cellulose and compound 5,
The composition being made of ethyl cellulose and compound 7,
The composition being made of ethyl hydroxy cellulose and compound 9,
The composition being made of croscarmellose sodium and compound 10,
The composition being made of cellacefate and compound 3,
The composition being made of low-substituted hydroxypropyl cellulose and compound 9,
The composition being made of low-substituted hydroxypropyl cellulose and compound 10,
The composition being made of methylcellulose and compound 5,
The composition being made of hydroxypropylcellulose and compound 10,
The composition being made of hymetellose and compound 4,
The composition being made of croscarmellose sodium and compound 5,
The composition being made of microcrystalline cellulose and compound 5,
The composition being made of ethyl hydroxy cellulose and compound 10,
The composition being made of hymetellose and compound 6,
The composition being made of ethyl hydroxy cellulose and compound 6,
The composition being made of sodium carboxymethylcellulose and compound 4,
The composition being made of hyetellose and compound 4,
The composition being made of low-substituted hydroxypropyl methylcellulose and compound 6,
The composition being made of hydroxypropylcellulose and compound 5,
The composition being made of ethyl cellulose and compound 2,
The composition being made of cellulose acetate and compound 10,
The composition being made of low-substituted hydroxypropyl cellulose and compound 2,
The composition being made of methylcellulose and compound 7,
The composition being made of microcrystalline cellulose and compound 6,
The composition being made of cellacefate and compound 10,
The composition being made of ethyl cellulose and compound 6,
The composition being made of cellulose acetate and compound 7,
The composition being made of cellacefate and compound 6,
The composition being made of sodium carboxymethylcellulose and compound 6,
The composition being made of croscarmellose sodium and compound 4,
The composition being made of methylcellulose and compound 6,
The composition being made of hydroxypropylcellulose and compound 6,
The composition being made of methylcellulose and compound 10,
The composition being made of cellulose acetate and compound 2,
The composition being made of hydroxypropylcellulose and compound 4,
The composition being made of croscarmellose sodium and compound 7,
The composition being made of methylcellulose and compound 4,
The composition being made of hydroxypropyl methylcellulose and compound 3,
The composition being made of ethyl hydroxy cellulose and compound 7,
The composition being made of sodium carboxymethylcellulose and compound 7,
The composition being made of cellulose acetate and compound 8,
The composition being made of ethyl hydroxy cellulose and compound 2,
The composition being made of low-substituted hydroxypropyl methylcellulose and compound 7.
4. composition according to claim 3, which is characterized in that the composition is selected from one of following composition:
The composition being made of hydroxypropyl methylcellulose and compound 9,
The composition being made of hydroxypropylcellulose and compound 9,
The composition being made of methylcellulose and compound 9,
The composition being made of ethyl cellulose and compound 9,
The composition being made of hyetellose and compound 9,
The composition being made of cellulose acetate and compound 9,
The composition being made of low-substituted hydroxypropyl cellulose and compound 4,
The composition being made of sodium carboxymethylcellulose and compound 9,
The composition being made of hymetellose and compound 9,
The composition being made of croscarmellose sodium and compound 9,
The composition being made of cellulose acetate and compound 5,
The composition being made of hyetellose and compound 5,
The composition being made of cellacefate and compound 1,
The composition being made of cellacefate and compound 5,
The composition being made of ethyl cellulose and compound 10,
The composition being made of hydroxypropyl methylcellulose and compound 5,
The composition being made of hyetellose and compound 6,
The composition being made of low-substituted hydroxypropyl cellulose and compound 7,
The composition being made of hyetellose and compound 10,
The composition being made of ethyl hydroxy cellulose and compound 5,
The composition being made of low-substituted hydroxypropyl methylcellulose and compound 9,
The composition being made of microcrystalline cellulose and compound 9,
The composition being made of cellulose acetate and compound 6,
The composition being made of cellacefate and compound 9,
The composition being made of hydroxypropyl methylcellulose and compound 7,
The composition being made of low-substituted hydroxypropyl methylcellulose and compound 10,
The composition being made of cellulose acetate and compound 4,
The composition being made of ethyl cellulose and compound 5,
The composition being made of ethyl cellulose and compound 7,
The composition being made of ethyl hydroxy cellulose and compound 9,
The composition being made of croscarmellose sodium and compound 10,
The composition being made of cellacefate and compound 3,
The composition being made of low-substituted hydroxypropyl cellulose and compound 9,
The composition being made of low-substituted hydroxypropyl cellulose and compound 10,
The composition being made of methylcellulose and compound 5.
5. composition according to claim 4, which is characterized in that the composition is selected from one of following composition:
The composition being made of hydroxypropyl methylcellulose and compound 9,
The composition being made of hydroxypropylcellulose and compound 9,
The composition being made of methylcellulose and compound 9,
The composition being made of ethyl cellulose and compound 9,
The composition being made of hyetellose and compound 9,
The composition being made of cellulose acetate and compound 9,
The composition being made of low-substituted hydroxypropyl cellulose and compound 4,
The composition being made of sodium carboxymethylcellulose and compound 9,
The composition being made of hymetellose and compound 9,
The composition being made of croscarmellose sodium and compound 9,
The composition being made of cellulose acetate and compound 5,
The composition being made of hyetellose and compound 5,
The composition being made of cellacefate and compound 1,
The composition being made of cellacefate and compound 5,
The composition being made of ethyl cellulose and compound 10,
The composition being made of hydroxypropyl methylcellulose and compound 5,
The composition being made of hyetellose and compound 6,
The composition being made of low-substituted hydroxypropyl cellulose and compound 7.
6. composition according to claim 5, which is characterized in that the composition is selected from one of following composition:
The composition being made of hydroxypropyl methylcellulose and compound 9,
The composition being made of hydroxypropylcellulose and compound 9,
The composition being made of methylcellulose and compound 9,
The composition being made of ethyl cellulose and compound 9,
The composition being made of hyetellose and compound 9,
The composition being made of cellulose acetate and compound 9,
The composition being made of low-substituted hydroxypropyl cellulose and compound 4,
The composition being made of sodium carboxymethylcellulose and compound 9,
The composition being made of hymetellose and compound 9.
7. composition according to claim 1 or 2, which is characterized in that the composition is one in following composition
Kind:
The composition being made of low-substituted hydroxypropyl cellulose and compound 8,
The composition being made of methylcellulose and compound 4,
The composition being made of hymetellose and compound 10,
The composition being made of croscarmellose sodium and compound 8,
The composition being made of sodium carboxymethylcellulose and compound 10,
The composition being made of sodium carboxymethylcellulose and compound 4,
The composition being made of hydroxypropyl methylcellulose and compound 8,
The composition being made of low-substituted hydroxypropyl cellulose and compound 1,
The composition being made of hydroxypropyl methylcellulose and compound 2,
The composition being made of cellulose acetate and compound 8,
The composition being made of hymetellose and compound 2,
The composition being made of microcrystalline cellulose and compound 10,
The composition being made of low-substituted hydroxypropyl methylcellulose and compound 8,
The composition being made of microcrystalline cellulose and compound 8,
The composition being made of low-substituted hydroxypropyl cellulose and compound 2,
The composition being made of hydroxypropyl methylcellulose and compound 4,
The composition being made of low-substituted hydroxypropyl methylcellulose and compound 10,
The composition being made of croscarmellose sodium and compound 6,
The composition being made of ethyl cellulose and compound 10,
The composition being made of cellulose acetate and compound 4,
The composition being made of sodium carboxymethylcellulose and compound 2,
The composition being made of cellacefate and compound 10,
The composition being made of hydroxypropylcellulose and compound 10,
The composition being made of hyetellose and compound 10,
The composition being made of ethyl cellulose and compound 9,
The composition being made of ethyl cellulose and compound 6,
The composition being made of ethyl hydroxy cellulose and compound 6,
The composition being made of ethyl cellulose and compound 8,
The composition being made of hydroxypropyl methylcellulose and compound 6,
The composition being made of ethyl hydroxy cellulose and compound 8,
The composition being made of microcrystalline cellulose and compound 2,
The composition being made of sodium carboxymethylcellulose and compound 6,
The composition being made of croscarmellose sodium and compound 4,
The composition being made of hydroxypropyl methylcellulose and compound 10,
The composition being made of hydroxypropylcellulose and compound 2,
The composition being made of methylcellulose and compound 8,
The composition being made of hydroxypropylcellulose and compound 8,
The composition being made of hyetellose and compound 8,
The composition being made of cellacefate and compound 4,
The composition being made of ethyl cellulose and compound 2,
The composition being made of sodium carboxymethylcellulose and compound 8,
The composition being made of methylcellulose and compound 10,
The composition being made of cellulose acetate and compound 10,
The composition being made of low-substituted hydroxypropyl methylcellulose and compound 1,
The composition being made of ethyl hydroxy cellulose and compound 9,
The composition being made of low-substituted hydroxypropyl cellulose and compound 4,
The composition being made of hyetellose and compound 6,
The composition being made of hydroxypropylcellulose and compound 6,
The composition being made of cellacefate and compound 8,
The composition being made of hymetellose and compound 6,
The composition being made of cellacefate and compound 6,
The composition being made of cellacefate and compound 2,
The composition being made of cellacefate and compound 1,
The composition being made of methylcellulose and compound 2,
The composition being made of hydroxypropylcellulose and compound 4,
The composition being made of ethyl cellulose and compound 4,
The composition being made of croscarmellose sodium and compound 2,
The composition being made of hyetellose and compound 2,
The composition being made of methylcellulose and compound 6,
The composition being made of ethyl hydroxy cellulose and compound 2,
The composition being made of low-substituted hydroxypropyl methylcellulose and compound 7,
The composition being made of microcrystalline cellulose and compound 1,
The composition being made of microcrystalline cellulose and compound 4,
The composition being made of microcrystalline cellulose and compound 6,
The composition being made of ethyl hydroxy cellulose and compound 10,
The composition being made of cellacefate and compound 9,
The composition being made of low-substituted hydroxypropyl cellulose and compound 7,
The composition being made of ethyl hydroxy cellulose and compound 3,
The composition being made of cellulose acetate and compound 2,
The composition being made of croscarmellose sodium and compound 10.
8. composition according to claim 7, which is characterized in that the composition is selected from one of following composition:
The composition being made of low-substituted hydroxypropyl cellulose and compound 8,
The composition being made of methylcellulose and compound 4,
The composition being made of hymetellose and compound 10,
The composition being made of croscarmellose sodium and compound 8,
The composition being made of sodium carboxymethylcellulose and compound 10,
The composition being made of sodium carboxymethylcellulose and compound 4,
The composition being made of hydroxypropyl methylcellulose and compound 8,
The composition being made of low-substituted hydroxypropyl cellulose and compound 1,
The composition being made of hydroxypropyl methylcellulose and compound 2,
The composition being made of cellulose acetate and compound 8,
The composition being made of hymetellose and compound 2,
The composition being made of microcrystalline cellulose and compound 10,
The composition being made of low-substituted hydroxypropyl methylcellulose and compound 8,
The composition being made of microcrystalline cellulose and compound 8,
The composition being made of low-substituted hydroxypropyl cellulose and compound 2,
The composition being made of hydroxypropyl methylcellulose and compound 4,
The composition being made of low-substituted hydroxypropyl methylcellulose and compound 10,
The composition being made of croscarmellose sodium and compound 6,
The composition being made of ethyl cellulose and compound 10,
The composition being made of cellulose acetate and compound 4,
The composition being made of sodium carboxymethylcellulose and compound 2,
The composition being made of cellacefate and compound 10,
The composition being made of hydroxypropylcellulose and compound 10,
The composition being made of hyetellose and compound 10,
The composition being made of ethyl cellulose and compound 9,
The composition being made of ethyl cellulose and compound 6,
The composition being made of ethyl hydroxy cellulose and compound 6,
The composition being made of ethyl cellulose and compound 8,
The composition being made of hydroxypropyl methylcellulose and compound 6,
The composition being made of ethyl hydroxy cellulose and compound 8,
The composition being made of microcrystalline cellulose and compound 2,
The composition being made of sodium carboxymethylcellulose and compound 6,
The composition being made of croscarmellose sodium and compound 4,
The composition being made of hydroxypropyl methylcellulose and compound 10,
The composition being made of hydroxypropylcellulose and compound 2,
The composition being made of methylcellulose and compound 8,
The composition being made of hydroxypropylcellulose and compound 8,
The composition being made of hyetellose and compound 8.
9. composition according to claim 8, which is characterized in that the composition is selected from one of following composition:
The composition being made of low-substituted hydroxypropyl cellulose and compound 8,
The composition being made of methylcellulose and compound 4,
The composition being made of hymetellose and compound 10,
The composition being made of croscarmellose sodium and compound 8,
The composition being made of sodium carboxymethylcellulose and compound 10,
The composition being made of sodium carboxymethylcellulose and compound 4,
The composition being made of hydroxypropyl methylcellulose and compound 8,
The composition being made of low-substituted hydroxypropyl cellulose and compound 1,
The composition being made of hydroxypropyl methylcellulose and compound 2,
The composition being made of cellulose acetate and compound 8,
The composition being made of hymetellose and compound 2,
The composition being made of microcrystalline cellulose and compound 10,
The composition being made of low-substituted hydroxypropyl methylcellulose and compound 8,
The composition being made of microcrystalline cellulose and compound 8,
The composition being made of low-substituted hydroxypropyl cellulose and compound 2,
The composition being made of hydroxypropyl methylcellulose and compound 4,
The composition being made of low-substituted hydroxypropyl methylcellulose and compound 10,
The composition being made of croscarmellose sodium and compound 6.
10. composition according to claim 9, which is characterized in that the composition is selected from one of following composition:
The composition being made of low-substituted hydroxypropyl cellulose and compound 8,
The composition being made of methylcellulose and compound 4,
The composition being made of hymetellose and compound 10,
The composition being made of croscarmellose sodium and compound 8,
The composition being made of sodium carboxymethylcellulose and compound 10,
The composition being made of sodium carboxymethylcellulose and compound 4,
The composition being made of hydroxypropyl methylcellulose and compound 8,
The composition being made of low-substituted hydroxypropyl cellulose and compound 1,
The composition being made of hydroxypropyl methylcellulose and compound 2.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910050775.2A CN109620961A (en) | 2019-01-20 | 2019-01-20 | The composition being made of morpholone derivative and cellulose derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201910050775.2A CN109620961A (en) | 2019-01-20 | 2019-01-20 | The composition being made of morpholone derivative and cellulose derivative |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110357868A (en) * | 2019-08-09 | 2019-10-22 | 新乡双鹭药业有限公司 | The preparation method of impurity in a kind of synthesis of razaxaban |
| CN111393428A (en) * | 2020-03-27 | 2020-07-10 | 南京国星生物技术研究院有限公司 | Method for preparing rivaroxaban impurity |
| JP2022140430A (en) * | 2021-03-10 | 2022-09-26 | 日本ジェネリック株式会社 | Rivaroxaban-containing tablet |
-
2019
- 2019-01-20 CN CN201910050775.2A patent/CN109620961A/en not_active Withdrawn
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110357868A (en) * | 2019-08-09 | 2019-10-22 | 新乡双鹭药业有限公司 | The preparation method of impurity in a kind of synthesis of razaxaban |
| CN111393428A (en) * | 2020-03-27 | 2020-07-10 | 南京国星生物技术研究院有限公司 | Method for preparing rivaroxaban impurity |
| CN111393428B (en) * | 2020-03-27 | 2022-03-15 | 南京国星生物技术研究院有限公司 | Preparation method of rivaroxaban impurity |
| JP2022140430A (en) * | 2021-03-10 | 2022-09-26 | 日本ジェネリック株式会社 | Rivaroxaban-containing tablet |
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Application publication date: 20190416 |