CN106176642B - A kind of Disket and preparation method thereof for treating respiratory disease - Google Patents
A kind of Disket and preparation method thereof for treating respiratory disease Download PDFInfo
- Publication number
- CN106176642B CN106176642B CN201610566453.XA CN201610566453A CN106176642B CN 106176642 B CN106176642 B CN 106176642B CN 201610566453 A CN201610566453 A CN 201610566453A CN 106176642 B CN106176642 B CN 106176642B
- Authority
- CN
- China
- Prior art keywords
- erdosteine
- hydrate
- disket
- parts
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/30—Hetero atoms other than halogen
- C07D333/36—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
Respiratory disease Erdosteine Disket and preparation method thereof is treated the present invention relates to a kind of.The Disket is made of Erdosteine, hydroxypropyl cellulose, sodium carboxymethyl starch, Macrogol 4000-6000, microcrystalline cellulose 102, crospovidone, magnesium stearate, PVP K30；The Erdosteine is Erdosteine monohydrate, molecular formula C8H11NO4S2·H2O shows characteristic diffraction peak at 3.323,8.484,12.661,21.823,30.645,31.161,33.209,36.161,38.935 with the X-ray powder diffraction collection that the 2 θ ± 0.2 ° angles of diffraction indicate.Test discovery, the dispersion tablet stability is good, bioavilability is high, solve in the prior art Erdosteine dispersible tablet poor solubility, poor compressibility, in production process the problems such as easy sticking.
Description
Technical field
The invention belongs to field of medicine preparations, it is related to a kind of Disket for treating respiratory disease and its preparation side
Method, more specifically to a kind of Erdosteine Disket and preparation method thereof.
Background technique
Phlegm is the product of respiratory inflammation, can stimulate respiratory mucosa, causes cough and asthma, and can aggravate to infect.It is anxious
When chronic bronchitis or chronic lung diseases respiratory failure, if patient's thick sputum is spent high or forms phlegm bolt, it can block and exhale
It inhales road and causes to suffocate.Therefore, using viscous phlegm regulator, make patient's phlegm dissolving, thinning, viscosity reduces, and accelerates respiratory tract viscous
Film ciliary movement improves transport function, has a very important significance.
This is smooth etc. for the viscous phlegm regulator listed at present such as bromhexine, mesna, carboxylic first, all has different degrees of viscous
Phlegm adjustment effect, but its pharmacology or clinically there are some defects.The sulfydryl to dissociate in molecular structure can adsorb gastrointestinal tract and glue egg
It is white, gastrointestinal tract local damage can be generated after oral, side effect is larger, can weaken penicillin, cephalosporin analog antibiotic, erythromycin, four
The antibacterial activity of ring element etc., unsuitable drug combination be not high to the improvement effect of certain respiration parameters such as phlegm viscosity etc..
Erdosteine is a kind of pro-drug, and non-free closed sulfydryl is had in structure, to local mucoprotein without
Active function generates three metabolites containing free sulfhydryl groups through metabolism after oral and plays pharmacological action, thus it is oral after
Without obvious gastrointestinal side effect.It is demonstrated experimentally that Erdosteine cylinder metabolism-ure can make two sulphur of mucoprotein in bronchial secretion
Key fracture, and change secretion composition and rheological property, sputum viscosity is reduced, suppressed respiratory function, this product energy are improved
Free radical is removed, the oxidation deactivation that effective protection a1- antitrypsin is induced from cigarette, dirt is prevented to lung elastance albumen
And the damage of neutrophil leucocyte.This product can also obviously increase IgA/ albumin, lactoferrin/albumin ratio, weaken part
Inflammation, enhancing and improvement antibiotic are conducive to the treatment of the various inflammation of respiratory tract to the osmosis of tunica mucosa bronchiorum.Foreign countries face
Bed researches show that: compared with similar product such as this smooth, ambroxol of acetylcysteine, carboxylic first, this product is to acute and chronic bronchitis
Inflammation has a good effect, more effective to the improvement of certain respiratory function parameters, and drug accumulation does not occur for large dosage administration,
Liver and kidney function moderate obstacle is to this product characteristics of pharmacokinetics without substantially changeing.
Dispersible tablet is also known as water dispersion tablet, and referring in water can rapid evenly dispersed tablet.Except with the steady of conventional tablet
Outside the advantages that qualitative good, easy to carry, convenient to take, there are also the higher advantage of bioavilability, it can directly swallow, chew clothes or throwing
Enter and is taken after dispersing in water, particularly suitable for swallowing difficult patient, and it is in good taste, improve the compliance of patient.
Such as " dispersion tablet recipe, process characteristic and its progress " (" drug assessment " the 3rd phase of volume 5 in 2005) discloses a variety of
It is suitble to prepare the auxiliary material of dispersible tablet, is collapsed as low-substituted hydroxypropyl cellulose, microcrystalline cellulose, croscarmellose sodium can be used as
Agent is solved to use.It is mentioned that low-substituted hydroxypropyl cellulose optimum amount is 2~5%.
In addition, " Chinese pharmaceutic adjuvant " (Chemical Industry Press, version in 2006, the chief editor such as Luo Mingsheng) discloses carboxymethyl
Sodium starch is best using outer add mode effect, and microcrystalline cellulose is generally not suitable for using as disintegrating agent.
The dissolubility of Erdosteine is poor, and it is low in the intracorporal effective bioavailability of people to be made general formulation, therefore, we
It is made into dispersible tablet in patent CN101606931B, improves the water solubility of drug to a certain extent, but there is also
Defect, such as: lactose price is more expensive, and microcrystalline cellulose hygroscopicity height causes preparation stability undesirable etc..
There are many patents to prepare Erdosteine preparation by studying new crystal-form compound at present, achieve it is certain at
Effect, but result is still undesirable.Such as:
CN104788421A discloses a kind of Erdosteine compound and preparation method thereof for treating respiratory inflammation, the strategic point
It is as shown in Figure 3 to take charge of the X-ray powder diffraction spectrogram that smooth compound is obtained using Cu-K alpha ray measurement more.
CN104873495A discloses a kind of erdosteine composition for treating respiratory inflammation, by Erdosteine, lactose,
Microcrystalline cellulose, hydroxypropyl methylcellulose, polyoxyethylene sorbitan monoleate, purified water, silica are made, and the Erdosteine is novel crystal forms
Compound, the X-ray powder diffraction spectrogram obtained using Cu-K alpha ray measurement are as shown in Figure 4.
CN104983693A discloses a kind of drug erdosteine composition granule for treating respiratory tract infection, more by strategic point
It takes charge of smooth, calcium carbonate, sucrose, citric acid, lemon yellow, purified water, magnesium stearate to be made, the Erdosteine is novel crystal forms chemical combination
Object, the X-ray powder diffraction spectrogram obtained using Cu-K alpha ray measurement are as shown in Figure 5.
CN105055348A discloses a kind of drug erdosteine composition tablet for treating respiratory inflammation and its preparation
Method, the composition tablet is by Erdosteine, sodium starch glycolate, lactose, L-HPC21,95% ethyl alcohol, magnesium stearate peppermint
Essence is made, and the Erdosteine is crystal compound, is composed using the X-ray powder diffraction that Cu-K alpha ray measurement obtains
Figure is as shown in Figure 6.
CN105078901A discloses a kind of drug erdosteine composition dry suspensoid agent for treating respiratory disease, by
Erdosteine, sucrose, xylitol, disodium hydrogen phosphate, propylene glycol alginate, Sucralose, purified water are made, and the strategic point is more
Taking charge of smooth is crystal compound, and the X-ray powder diffraction spectrogram obtained using Cu-K alpha ray measurement is as shown in Figure 7.
CN105106172A discloses a kind of drug erdosteine composition capsule for treating respiratory inflammation, by E Duosi
Smooth, starch goes the double hydrogen guaiaretic acids of first, 95% ethyl alcohol, PVP K30, talcum powder to be made, and the Erdosteine is novel crystal forms
Compound, the X-ray powder diffraction spectrogram obtained using Cu-K alpha ray measurement are as shown in Figure 8.
CN105193750A discloses a kind of drug erdosteine composition tablet for treating respiratory inflammation, by E Duosi
Smooth, lactose, crospovidone, zinc oxide, 95% ethyl alcohol, Macrogol 6000, magnesium stearate are made, and the Erdosteine is
Crystal compound, the X-ray powder diffraction spectrogram obtained using Cu-K alpha ray measurement are as shown in Figure 9.
CN105232445A discloses a kind of drug erdosteine composition dry suspensoid agent for treating respiratory disease, by
Erdosteine, sorbierite, potassium metaphosphate, Arabic gum, glycyrrhizin are made, and the Erdosteine is crystal compound,
The X-ray powder diffraction spectrogram obtained using Cu-K alpha ray measurement is as shown in Figure 10.
CN105232473A discloses a kind of drug erdosteine composition granule for treating respiratory tract infection, more by strategic point
It takes charge of smooth, sucrose, lactitol, vanillic aldehyde, purified water to be made, the Erdosteine is crystal compound, uses Cu-K alpha ray
It is as shown in figure 11 to measure obtained X-ray powder diffraction spectrogram.
As it is known by the man skilled in the art that the polymorph of drug has become drug research process and drug into yield and quality control
The important component that must can lack in system and detection process.New drug compound bioactivity is facilitated to the research of drug polymorph
Selection, help to improve bioavilability, promote clinical efficacy, facilitate the selection and design of drug administration approach, and
The determination of pharmaceutical preparation technology parameter, to improve pharmaceutical production quality.Same drug crystalline form is different, and bioavilability may
Significant difference.Same drug, certain crystalline forms may have higher bioactivity than other crystalline forms.
The present invention has carried out a large amount of experimental study on the basis of document disclosed above, proposes strategic point of the present invention
Take charge of smooth dispersible tablet and preparation method thereof, wherein Erdosteine is Erdosteine hydrate, completely not with the crystal form of the prior art more
Together.
Summary of the invention
The purpose of the present invention is to provide a kind of drug combination preparations of new treatment respiratory disease (especially to divide
Discrete piece agent) and preparation method thereof, and the crystal form and preparation process of Erdosteine hydrate are provided, to solve Erdosteine dissolution
Spend poor, poor compressibility, in production process the problems such as easy sticking.
The first purpose of the invention is to provide a kind of Diskets and preparation method thereof for treating respiratory disease, adopt
Technical solution is as follows:
A kind of Disket for treating respiratory disease, by Erdosteine, hydroxypropyl cellulose, carboxymethyl starch
Sodium, Macrogol 4000-6000, microcrystalline cellulose 102, crospovidone, magnesium stearate, PVP K30 composition.
Wherein, the Erdosteine which uses is Erdosteine hydrate, is indicated with the 2 θ ± 0.2 ° angles of diffraction
X-ray powder diffraction collection 3.323 °, 8.484 °, 12.661 °, 21.823 °, 30.645 °, 31.161 °, 33.209 °,
Characteristic diffraction peak is shown at 36.161 °, 38.935 °.
Preferably, in parts by weight, Erdosteine Disket of the present invention is by 10 parts of Erdosteine hydrates, 1-3 parts of hydroxyls
Propyl cellulose, 0.5-1.0 part sodium carboxymethyl starch, 1-1.5 parts of Macrogol 4000s -6000,3-4 parts of microcrystalline celluloses 102,
1-3 parts of crospovidone, 0.1-0.2 parts of magnesium stearates, 0.2-0.5 parts of PVP K30 compositions.
It is further preferred that in parts by weight, Erdosteine Disket of the present invention is by 10 parts of Erdosteine hydrates, 2
Part hydroxypropyl cellulose, 0.7 part of sodium carboxymethyl starch, 1.2 parts of Macrogol 4000s -6000,3.6 parts of microcrystalline celluloses 102,
1.5 parts of crospovidone, 0.15 part of magnesium stearate, 0.3 part of PVP K30 composition.
Preferably, Erdosteine Disket of the present invention is prepared to use following preparation method:
(1) supplementary material is stocked up: being weighed the Erdosteine hydrate of recipe quantity, hydroxypropyl cellulose, sodium carboxymethyl starch, is gathered
Ethylene glycol 4000-6000, microcrystalline cellulose 102, crospovidone, magnesium stearate, PVP K30, by Erdosteine hydrate
Crushing sieves with 100 mesh sieve, and hydroxypropyl cellulose, sodium carboxymethyl starch crushed 120 meshes respectively, by microcrystalline cellulose 102, gathers
Ethylene glycol 4000-6000 crushed 80 meshes；Crospovidone be crushed into 60 meshes；Prepare 5% PVP K30 ethanol；
(2) mixing granulation: Erdosteine hydrate that step (1) is got ready, hydroxypropyl cellulose, sodium carboxymethyl starch,
Macrogol 4000-6000, microcrystalline cellulose 102 are added in wet mixing pelletizer, the dry-mixed 5-15min of speed of agitator 60rpm；
Prepared 5% PVP K30 ethanol is added at one time after dry-mixed in 1min；60rpm wet mixing 5min, wet mixing
0.5min is cut by cutting revolving speed 900rpm when 4.5min, wet granular is made；Wet granular obtained is transferred in ebullated dryer,
Temperature control 60-70 DEG C bakings 15-35 minute, shutdown, clear filter bag, blowing, obtained dry particl；
(3) whole grain total mix: pelletizing machine is added in dry particl obtained by upper step and carries out whole grain, adds the crosslinking of recipe quantity
Povidone, magnesium stearate, 15rpm mixing 15min；
(4) tabletting: supplementary material is uniformly mixed, and carries out tabletting, is examined, packing.
A second object of the present invention is to provide a kind of Erdosteine hydrate crystal and its preparation process, the technologies of use
Scheme is as follows:
The present invention provides a kind of new Erdosteine hydrate crystal, and each Erdosteine hydrate contains 1 crystallization water,
Its molecular formula is C8H11NO4S2·H2O, and its X-ray powder diffraction spectrogram such as Fig. 1 for being obtained using Cu-K alpha ray measurement
It is shown.
Pass through heat differential-thermogravimetric TG-DTA analysis, Erdosteine hydrate weightlessness 6.5- within the scope of 80-120 DEG C
6.8wt%.
Preferably, which prepares with the following method:
(1) Erdosteine crude product is ground up, sieved, is dissolved into 25-35 DEG C of acetone ethanol mixed solution, obtains E Duosi
Smooth lysate, the volume of the mixed solution are 6-8 times of Erdosteine crude product quality；
(2) add active carbon decoloring 20-30 minutes of Erdosteine crude product quality 0.02%-0.1%, filtering；
(3) -15 DEG C~5 DEG C of physiological saline is added dropwise under conditions of stirring, the volume of physiological saline is Erdosteine dissolution
2-4 times of liquid product, is at the uniform velocity added dropwise in 0.5-1.5h, and the stirring rate is 20-25rmp；
(4) -15 DEG C~5 DEG C are cooled to after being added dropwise to complete to continue to stir 0.5-2h under the stirring rate of 10-15rmp, it is quiet
It sets 3-5h and white crystal, filtering is precipitated；
(5) vacuum drying obtains Erdosteine hydrate crystal after successively being washed with distilled water, ethyl acetate.
Preferably, in the step (1) in the mixed solution of acetone ethanol, the volume ratio of acetone and ethyl alcohol is 5:1-3.
Preferably, the physiological saline volume being added dropwise under stirring conditions in the step (3) is Erdosteine lysate
3 times of volume；The temperature of physiological saline is -10 DEG C；Stirring rate when physiological saline is added is 23rmp.
Preferably, -10 DEG C are cooled to after being added dropwise to complete in step (4) to continue to stir 1h under the stirring rate of 12rmp.
The present invention has the advantage that and has the active effect that
(1) a kind of Erdosteine hydrate different from the prior art has been used in technical solution provided by the invention, has been shown
Write the stability and dissolution rate for improving Erdosteine.
(2) in technical solution provided by the invention, Erdosteine is first prepared into monohydrate, test discovery, the hydration
Object has good mobility, can uniformly mix with other auxiliary materials, and prepared Erdosteine Disket infiltration rate is fast,
Bioavilability is high.
(3) technical solution provided by the invention, preparation process is fairly simple, easy to operate, and solving Erdosteine can
The problem of pressure property difference, can effectively prevent sticking in later period tableting processes, moreover it is possible to improve the solubility of dispersible tablet, be suitble to industrialization
Mass production.
Detailed description of the invention
Fig. 1 is the X-ray powder diffraction spectrogram of Erdosteine hydrate of the present invention
Fig. 2 is the thermogravimetric analysis figure of Erdosteine hydrate of the present invention
Fig. 3 is the X-ray powder diffraction spectrogram of Erdosteine compound disclosed in patent CN104788421A
Fig. 4 is the X-ray powder diffraction spectrogram of Erdosteine crystal compound disclosed in patent CN104873495A
Fig. 5 is the X-ray powder diffraction spectrogram of Erdosteine crystal compound disclosed in patent CN104983693A
Fig. 6 is the X-ray powder diffraction spectrogram of Erdosteine crystal compound disclosed in patent CN105055348A
Fig. 7 is the X-ray powder diffraction spectrogram of Erdosteine crystal compound disclosed in patent CN105078901A
Fig. 8 is the X-ray powder diffraction spectrogram of Erdosteine crystal compound disclosed in patent CN105106172A
Fig. 9 is the X-ray powder diffraction spectrogram of Erdosteine crystal compound disclosed in patent CN105193750A
Figure 10 is the X-ray powder diffraction spectrogram of Erdosteine crystal compound disclosed in patent CN105232445A
Figure 11 is the X-ray powder diffraction spectrogram of Erdosteine crystal compound disclosed in patent CN105232473A
Specific embodiment
Beneficial effects of the present invention are now further described by following embodiment, embodiment is only used for the purpose of illustration,
It does not limit the scope of the invention, simultaneously for done according to the present invention aobvious of the technical field of the invention those of ordinary skill
The change and modification being clear to are also contained within the scope of the invention.The technology contents of the not detailed description of the present invention are known skill
Art.
Embodiment 1: the preparation of Erdosteine hydrate
(1) Erdosteine crude product 100g is taken, the temperature of 500ml acetone and 200ml ethyl alcohol composition is dissolved into after being ground up, sieved
To obtain Erdosteine lysate in 30 DEG C of mixed solutions；
(2) add active carbon decoloring 25 minutes of 0.05g, filtering；
(3) -10 DEG C of temperature of 3 times of volumes of Erdosteine lysate are at the uniform velocity added dropwise in stirring rate under conditions of being 23rmp
Physiological saline is added dropwise in 1h；
(4) it is cooled to -10 DEG C after being added dropwise to complete to continue to stir 1h under the stirring rate of 12rmp, stands 4h and white is precipitated
Crystal, filtering；
(5) vacuum drying obtains Erdosteine hydrate crystal 98.75g after successively being washed with distilled water, ethyl acetate.
It is measured with powder x-ray diffraction measuring method, is existed with the X-ray powder diffraction collection that the 2 θ ± 0.2 ° angles of diffraction indicate
It is shown at 3.323 °, 8.484 °, 12.661 °, 21.823 °, 30.645 °, 31.161 °, 33.209 °, 36.161 °, 38.935 °
Characteristic diffraction peak.
Elemental analysis:
Measured value: C 35.9368%, H 4.8962%, N 5.2435%, O 29.9312%, S 23.9783%.
Theoretical value: C 35.9437%, H 4.9017%, N 5.2396%, O 29.9253%, S 23.9897%.
Elemental analysis result and theoretical value are almost the same.
It uses Cattell aquametry measurement moisture content for 6.75wt%, coincide substantially with theoretical value.
It is measured using thermogravimetric analysis, as a result as shown in Fig. 2, crystal water content is 6.74wt%, is coincide substantially with theoretical value.
Embodiment 2: the preparation of Erdosteine hydrate
(1) Erdosteine crude product 100g is taken, the temperature of 500ml acetone and 100ml ethyl alcohol composition is dissolved into after being ground up, sieved
To obtain Erdosteine lysate in 25 DEG C of mixed solutions；
(2) add active carbon decoloring 20 minutes of 0.1g, filtering；
(3) 5 DEG C of temperature of life of 4 times of volumes of Erdosteine lysate is at the uniform velocity added dropwise in stirring rate under conditions of being 20rmp
Salt water is managed, is added dropwise in 1.5h；
(4) it is cooled to 5 DEG C after being added dropwise to complete to continue to stir 2h under the stirring rate of 10rmp, stands 5h and white crystalline substance is precipitated
Body, filtering；
(5) vacuum drying obtains Erdosteine hydrate crystal 98.52g after successively being washed with distilled water, ethyl acetate.
It is measured with powder x-ray diffraction measuring method, is existed with the X-ray powder diffraction collection that the 2 θ ± 0.2 ° angles of diffraction indicate
It is shown at 3.323 °, 8.484 °, 12.661 °, 21.823 °, 30.645 °, 31.161 °, 33.209 °, 36.161 °, 38.935 °
Characteristic diffraction peak.
Elemental analysis:
Measured value: C 35.9513%, H 4.9127%, N 5.2305%, O 29.9128%, S 23.9931%.
Theoretical value: C 35.9437%, H 4.9017%, N 5.2396%, O 29.9253%, S 23.9897%.
Elemental analysis result and theoretical value are almost the same.
Embodiment 3: the preparation of Erdosteine hydrate
(1) Erdosteine crude product 100g is taken, the temperature of 500ml acetone and 300ml ethyl alcohol composition is dissolved into after being ground up, sieved
To obtain Erdosteine lysate in 35 DEG C of mixed solutions；
(2) add active carbon decoloring 30 minutes of 0.02g, filtering；
(3) -15 DEG C of temperature of 2 times of volumes of Erdosteine lysate are at the uniform velocity added dropwise in stirring rate under conditions of being 25rmp
Physiological saline is added dropwise in 0.5h；
(4) it is cooled to -15 DEG C after being added dropwise to complete to continue to stir 0.5h under the stirring rate of 15rmp, it is white to stand 3h precipitation
Color crystal, filtering；
(5) vacuum drying obtains Erdosteine hydrate crystal 98.67g after successively being washed with distilled water, ethyl acetate.
It is measured with powder x-ray diffraction measuring method, is existed with the X-ray powder diffraction collection that the 2 θ ± 0.2 ° angles of diffraction indicate
It is shown at 3.323 °, 8.484 °, 12.661 °, 21.823 °, 30.645 °, 31.161 °, 33.209 °, 36.161 °, 38.935 °
Characteristic diffraction peak.
Elemental analysis:
Measured value: C 35.9492%, H 4.9156%, N 5.2287%, O 29.9162%, S 23.9918%.
Theoretical value: C 35.9437%, H 4.9017%, N 5.2396%, O 29.9253%, S 23.9897%.
Elemental analysis result and theoretical value are almost the same.
Embodiment 4: Erdosteine dispersible tablet
Preparation process:
(1) supplementary material is stocked up: being weighed the Erdosteine hydrate of recipe quantity, hydroxypropyl cellulose, sodium carboxymethyl starch, is gathered
Ethylene glycol 4000-6000, microcrystalline cellulose 102, crospovidone, magnesium stearate, PVP K30, by Erdosteine hydrate
Crushing sieves with 100 mesh sieve, and hydroxypropyl cellulose, sodium carboxymethyl starch crushed 120 meshes respectively, by microcrystalline cellulose 102, gathers
Ethylene glycol 4000-6000 crushed 80 meshes, and crospovidone crushed 60 meshes, prepare 5% PVP K30 ethanol；
(2) mixing granulation: Erdosteine hydrate that step (1) is got ready, hydroxypropyl cellulose, sodium carboxymethyl starch,
Macrogol 4000-6000, microcrystalline cellulose 102 are added in wet mixing pelletizer, the dry-mixed 10min of speed of agitator 60rpm；It is dry
Prepared 5% PVP K30 ethanol is added at one time in 1min after mixed；60rpm wet mixing 5min, wet mixing
0.5min is cut by cutting revolving speed 900rpm when 4.5min, wet granular is made；Wet granular obtained is transferred in ebullated dryer,
Temperature control is dried 25 minutes at 65 DEG C, is shut down, clear filter bag, blowing, and dry particl is made；
(3) whole grain total mix: pelletizing machine is added in dry particl obtained by upper step and carries out whole grain, adds the crosslinking of recipe quantity
Povidone, magnesium stearate, 15rpm mixing 15min；
(4) tabletting: supplementary material is uniformly mixed, and carries out tabletting, is examined, packing.
Embodiment 5: Erdosteine dispersible tablet
Preparation process:
(1) supplementary material is stocked up: being weighed the Erdosteine hydrate of recipe quantity, hydroxypropyl cellulose, sodium carboxymethyl starch, is gathered
Ethylene glycol 4000-6000, microcrystalline cellulose 102, crospovidone, magnesium stearate, PVP K30, by Erdosteine hydrate
Crushing sieves with 100 mesh sieve, and hydroxypropyl cellulose, sodium carboxymethyl starch crushed 120 meshes respectively, by microcrystalline cellulose 102, gathers
Ethylene glycol 4000-6000 crushed 80 meshes, and crospovidone crushed 60 meshes, prepare 5% PVP K30 ethanol；
(2) mixing granulation: Erdosteine hydrate that step (1) is got ready, hydroxypropyl cellulose, sodium carboxymethyl starch,
Macrogol 4000-6000, microcrystalline cellulose 102 are added in wet mixing pelletizer, the dry-mixed 15min of speed of agitator 60rpm；It is dry
Prepared 5% PVP K30 ethanol is added at one time in 1min after mixed；60rpm wet mixing 5min, wet mixing
0.5min is cut by cutting revolving speed 900rpm when 4.5min, wet granular is made；Wet granular obtained is transferred in ebullated dryer,
Temperature control is dried 15 minutes at 60 DEG C, is shut down, clear filter bag, blowing, and dry particl is made；
(3) whole grain total mix: pelletizing machine is added in dry particl obtained by upper step and carries out whole grain, adds the crosslinking of recipe quantity
Povidone, magnesium stearate, 15rpm mixing 15min；
(4) tabletting: supplementary material is uniformly mixed, and carries out tabletting, is examined, packing.
Embodiment 6: Erdosteine dispersible tablet
Preparation process:
(1) supplementary material is stocked up: being weighed the Erdosteine hydrate of recipe quantity, hydroxypropyl cellulose, sodium carboxymethyl starch, is gathered
Ethylene glycol 4000-6000, microcrystalline cellulose 102, crospovidone, magnesium stearate, PVP K30, by Erdosteine hydrate
Crushing sieves with 100 mesh sieve, and hydroxypropyl cellulose, sodium carboxymethyl starch crushed 120 meshes respectively, by microcrystalline cellulose 102, gathers
Ethylene glycol 4000-6000 crushed 80 meshes, and crospovidone crushed 60 meshes, prepare 5% PVP K30 ethanol；
(2) mixing granulation: Erdosteine hydrate that step (1) is got ready, hydroxypropyl cellulose, sodium carboxymethyl starch,
Macrogol 4000-6000, microcrystalline cellulose 102 are added in wet mixing pelletizer, the dry-mixed 5min of speed of agitator 60rpm；It is dry
Prepared 5% PVP K30 ethanol is added at one time in 1min after mixed；60rpm wet mixing 5min, wet mixing
0.5min is cut by cutting revolving speed 900rpm when 4.5min, wet granular is made；Wet granular obtained is transferred in ebullated dryer,
Temperature control is dried 35 minutes at 70 DEG C, is shut down, clear filter bag, blowing, and dry particl is made；
(3) whole grain total mix: pelletizing machine is added in dry particl obtained by upper step and carries out whole grain, adds the crosslinking of recipe quantity
Povidone, magnesium stearate, 15rpm mixing 15min；
(4) tabletting: supplementary material is uniformly mixed, and carries out tabletting, is examined, packing.
Embodiment 7: Erdosteine dispersible tablet
Preparation process is the same as embodiment 4.
Embodiment 8: Erdosteine dispersible tablet
Preparation process is the same as embodiment 4.
Embodiment 9: Erdosteine dispersible tablet
Preparation process is the same as embodiment 4.
Embodiment 10: Erdosteine dispersible tablet
Preparation process is the same as embodiment 4.
Comparative example 1: Erdosteine dispersible tablet (commercially available Erdosteine)
Preparation process is the same as embodiment 4.
Comparative example 2: Erdosteine dispersible tablet (commercially available Erdosteine)
Preparation process is the same as embodiment 4.
Comparative example 3: Erdosteine dispersible tablet (CN101606931 embodiment 1)
Preparation process: recipe quantity microcrystalline cellulose, low-substituted hydroxypropyl cellulose are crossed into 80 meshes, lactose, acesulfame potassium, carboxylic
Methyl starch sodium crosses 120 meshes.Erdosteine and low-substituted hydroxypropyl cellulose are crushed with ball mill after mixing, mistake
Sodium carboxymethyl starch is added in 100 meshes, dry-mixed using high-speed mixing granulating machine, and revolving speed is 45 turns/min, mixes 10min, is added
Wet mixing is carried out after dehydrated alcohol 20ml, revolving speed is 30 turns/min, mixes 3min, then 2min, wet granular obtained are cut in wet mixing
It is transferred in ebullated dryer, temperature control is dried 20~25 minutes at 65 DEG C, is shut down, clear filter bag, blowing, dry particl whole grain.It is whole
Three-dimensional mixer is added with suction feeding in particle after grain, and microcrystalline cellulose mixing is added, and mixing machine revolving speed is 35 turns/min,
15min is mixed, lactose, acesulfame potassium and magnesium stearate is added and continuess to mix, revolving speed is 30 turns/min, mixes 10min, and mixing is equal
Even medicinal powder carries out tabletting, and tabletting hardness is 3N, packs after the substrate examination pressed is qualified to obtain the final product.
The present invention also provides following experimental examples, to further illustrate to product of the present invention:
The related substance detection of experimental example 1, Erdosteine hydrate of the present invention
This experimental example detects the related substance in Erdosteine hydrate crystal prepared by embodiment 1-3, this
Experiment is instructed former according to 2010 editions second annex of Chinese Pharmacopoeia, VIII P residual solvent measuring method, Ⅺ Ⅹ F drug impurity analysis of annex
It then carries out, the result is shown in tables 1:
Testing result of the table 1 in relation to substance
| Hydrate | Acetone | Ethyl alcohol | Ethyl acetate | Other are in relation to substance |
| Embodiment 1 | 0.04% | 0.02% | 0.02% | 0.54% |
| Embodiment 2 | 0.03% | 0.01% | 0.05% | 0.61% |
| Embodiment 3 | 0.03% | 0.02% | 0.04% | 0.57% |
The mobility investigation of experimental example 2, Erdosteine hydrate crystal of the present invention
This experimental example investigates the mobility of sample by measuring the angle of repose of sample, and the specific method is as follows: taking sample
Grain, flows into circular surface plate from fixed small funnel, until obtaining highest cone, measure cone height H and
Radius R calculates angle of repose α by tan α=H/R, and angle of repose is bigger, and mobility is poorer, and as a result see Table 2 for details.
The mobility of 2 each sample of table
| Sample 1 | Sample 2 | Sample 3 | Sample 4 | Sample 5 | |
| H | 2.03cm | 2.12cm | 2.10cm | 3.15cm | 3.24cm |
| R | 3cm | 3cm | 3cm | 3cm | 3cm |
| α | 35° | 36° | 35° | 46° | 47° |
Wherein, sample 1 is 1 product of embodiment；
Sample 2 is 2 product of embodiment；
Sample 3 is 3 product of embodiment；
Sample 4 is the Erdosteine compound prepared referring to patent CN104788421A embodiment 1；
Sample 5 is commercially available Erdosteine bulk pharmaceutical chemicals, is purchased from Xi'an Hai Xin pharmaceutical Co. Ltd.
As seen from Table 2, compared with the Erdosteine compound of the prior art, Erdosteine hydrate of the present invention has excellent
Mobility, be conducive to the accuracy for improving packing, and while mix with other compositions be easily mixed it is uniform.
The stability test of experimental example 3, Erdosteine hydrate of the present invention
1, accelerated test
Each a batch of sample of Example 1-3 preparation, is placed under conditions of 40 ± 2 DEG C of Yu Wendu, relative humidity 75 ± 5%
6 months, character, related substance, labelled amount is measured by sampling respectively at 0,1,2,3,6 the end of month, the results are shown in Table 3.
3 accelerated test result of table (40 ± 2 DEG C of temperature, relative humidity 75 ± 5%)
As seen from Table 3, Erdosteine hydrate of the present invention is put under conditions of 40 ± 2 DEG C of temperature, relative humidity 75 ± 5%
It sets 6 months, related content of material is low, and each index has no significant change, and this product quality stability is good.
2, long term test
Sample two batches prepared by Example 1 place 6 under conditions of 25 ± 2 DEG C of Yu Wendu, relative humidity 60 ± 5%
Month, character, related substance, labelled amount is measured by sampling respectively at 0,3,6,9,12,18,24 the end of month, the results are shown in Table 4.
4 long-term test results of table (25 ± 2 DEG C of temperature, relative humidity 60 ± 5%)
As seen from Table 4, Erdosteine hydrate of the present invention is put under conditions of 25 ± 2 DEG C of temperature, relative humidity 60 ± 5%
24 months stabilizations are set, each index has no significant change.
The water solubility of experimental example 4, Erdosteine crystal compound of the present invention
Sample prepared by Example 1-3 carries out soluble test, result and the (purchase of commercially available Erdosteine bulk pharmaceutical chemicals
From Xi'an Hai Xin pharmaceutical Co. Ltd) it compares, it the results are shown in Table 5.
Specific test method:
Suitable distilled water is added in the low capacity bottle with constant temperature jacket, Erdosteine is added at 20 DEG C to no longer
Until dissolution, starts magnetic stirrer, persistently stirred under constant temperature, system is in the shape of two-phase coexistent always during the experiment
State, the solubility of the concentration of Erdosteine as at this temperature in the liquid phase of system after 70 minutes.It is sampled after 2 hours point
Analysis, takes average value similar in adjacent two times result as measured value of experiment, before sampling, in order to be sufficiently separated solid-liquid, stops stirring
After mixing, not molten Erdosteine is deposited to the bottom of low capacity bottle, a small amount of upper clear supernate is extracted with syringe, with 0.45 micron
Filter filtering, sample is taken from filtrate, the content of Erdosteine is measured by HPLC.
The water solubility of the Erdosteine hydrate of the present invention of table 5
| Sample | Embodiment 1 | Embodiment 2 | Embodiment 3 | It is commercially available |
| For the first time | 16.99mg/ml | 16.91mg/ml | 16.78mg/ml | 1.41mg/ml |
| Second | 16.87mg/ml | 16.93mg/ml | 16.85mg/ml | 1.43mg/ml |
| Average value | 16.93mg/ml | 16.92mg/ml | 16.82mg/ml | 1.42mg/ml |
As can be seen from Table 5, the water solubility of Erdosteine hydrate of the present invention mentions significantly compared with commercially available Erdosteine
It is high.
Experimental example 5, Erdosteine Disket dissolution determination of the present invention test
1, in water, hydrochloric acid solution (pH=1.0), phosphate buffer (pH=5.8), phosphate buffer (pH=6.8)
The dissolution rate of middle measurement Disket of the present invention.
Dissolution conditions: it 75 turns/min, volume 1000ml, is measured according to spectrophotometry, measures wavelength 290nm.When measurement
Between 90min, the results are shown in Table 6.
Dissolution rate of the Disket of each embodiment of table 6 preparation in four kinds of media
2, Erdosteine dissolution determination is tested:
Sample is taken, according to dissolution method (two annex of Chinese Pharmacopoeia version in 2010, Ⅹ the second method of C), with 0.2% 12
The phosphate buffer of sodium alkyl sulfate is dissolution medium, and revolving speed is every point 75 turns of kind, is operated according to methods, through 10,20,30 minutes
When, solution 10ml is taken, filters, subsequent filtrate is taken, as test solution.It separately takes Erdosteine reference substance appropriate, 11 μ g/ is made
Ml, as reference substance solution.By external standard method with calculated by peak area every dissolution rate.Limit is 80%, Ying Fuhe of labelled amount
Regulation.
The dissolution determination result of the Disket of each embodiment of table 7 preparation
Find out from table 6,7:
The result of embodiment 4-10 illustrates, due to having used E Duositan hydrate prepared by the present invention, these embodiments
The Disket of preparation, dissolution is quickly；
The result of comparative example 1,2 illustrates, uses commercially available Erdosteine, the dispersible tablet of simulation prescription preparation of the present invention
Agent, drug-eluting are poor；
Comparative example 3 illustrate, using commercially available Erdosteine, be different from the present invention prescription preparation Disket, drug
Dissolution makes moderate progress, but improves limited.
In conclusion the present invention has obtained unexpected technical effect.
Experimental example 6, Erdosteine Disket appearance of the present invention are investigated
8 Disket appearance of table is investigated
As seen from Table 8, comparative example 1,2 simulates prescription of the present invention using commercially available Erdosteine and suppresses Disket, piece
Face is coarse, there is sticking phenomenon；Comparative example 3 is added to lactose (having excipient effect, good fluidity) as filler, compacting point
Discrete piece agent, it is unilateral good.
This test further demonstrates superiority of the invention: Erdosteine being prepared into hydrate, without adding lactose
The problem that poor compressibility can be solved effectively prevent sticking in later period tableting processes, moreover it is possible to improve the solubility of Disket.
Experimental example 7: Erdosteine Disket of the present invention draws moist investigation
It is moist that this experimental example has investigated drawing for the Disket of Erdosteine hydrate crystal provided by the invention preparation, this
Experiment is carried out according to 2010 editions second annex of Chinese Pharmacopoeia, Ⅺ Ⅹ J drug draws moist test guideline, the results are shown in Table 9.
Drawing for 9 Disket of table is moist
| Sample 1 | Sample 2 | Sample 3 | Sample 4 | Sample 5 | Sample 6 | Sample 7 | Sample 8 | |
| Draw wet percentage weight increase | 3.5% | 3.6% | 3.6% | 3.8% | 3.7% | 3.5% | 3.6% | 13.8% |
Wherein, sample 1 is 4 product of embodiment；
Sample 2 is 5 product of embodiment；
Sample 3 is 6 product of embodiment；
Sample 4 is 7 product of embodiment；
Sample 5 is 8 product of embodiment；
Sample 6 is 9 product of embodiment；
Sample 7 is 10 product of embodiment；
Sample 8 is the product of comparative example 3.
As seen from Table 9, the Disket that prepared by Erdosteine hydrate crystal provided by the invention draws wet weight gain percentage
Rate is small, and hygroscopicity is small.
The stability test of experimental example eight, Erdosteine Disket of the present invention
1) accelerated test study on the stability:
Disket prepared by embodiment 4-10 and comparative example 1-3 is placed under same packaging be placed in 40 DEG C/
Progressive shape, dissolution rate, related object are distinguished in storage 6 months in the climatic chamber of RH75% when 0 month and 6th month
The investigation of matter, content.It is measured in relation to substance and content with HPLC method, the results are shown in Table 10.
The Erdosteine Disket accelerated test study on the stability result of the present invention of table 10
As shown in table 10, during accelerated test, the appearance character of sample and content do not become substantially in each test
Change.But the dissolution rate of Disket prepared by comparative example obviously becomes smaller, related substance obviously becomes larger；And it is of the invention
The dissolution of Disket does not change substantially, and the increase in relation to substance is also much smaller, illustrates dispersion prepared by the present invention
Tablet can be improved the stability of drug, extend the shelf life of preparation.Control in relation to substance is conducive to control the bad of drug
Reaction.
2) long term test study on the stability:
By Disket prepared by embodiment 4-10 and comparative example 1-3 in the case where simulation lists terms of packing, in room
It under temperature, was sampled respectively at the 12nd, 18,24 month, is investigated by the project and method of pharmacopeia in 2010, the results are shown in Table 11.
The Erdosteine Disket long-term test results of the present invention of table 11
As shown in table 11, Erdosteine Disket of the present invention and the sample of comparative example example preparation are being placed at room temperature for 24
A month test, the results show that the appearance character of Erdosteine Disket of the present invention, labelled amount, Related substances separation and other
Inspection item is not substantially change, illustrates that Erdosteine Disket of the present invention is basicly stable.
Claims (10)
1. a kind of Disket for treating respiratory disease, which is characterized in that the Disket is by Erdosteine, hydroxypropyl
Base cellulose, Macrogol 4000-6000, microcrystalline cellulose 102, crospovidone, magnesium stearate, gathers sodium carboxymethyl starch
Tie up ketone K30 composition；
The Erdosteine is Erdosteine hydrate, is existed with the X-ray powder diffraction collection that the 2 θ ± 0.2 ° angles of diffraction indicate
It is shown at 3.323 °, 8.484 °, 12.661 °, 21.823 °, 30.645 °, 31.161 °, 33.209 °, 36.161 °, 38.935 °
Characteristic diffraction peak；
Each Erdosteine hydrate contains 1 crystallization water, molecular formula C8H11NO4S2·H2O。
2. the Disket for the treatment of respiratory disease as described in claim 1, which is characterized in that in parts by weight, described
Disket by 10 parts of Erdosteine hydrates, 1-3 parts of hydroxypropyl celluloses, 0.5-1.0 parts of sodium carboxymethyl starches, 1-1.5
Part Macrogol 4000-6000,3-4 parts of microcrystalline celluloses 102,1-3 parts of crospovidone, 0.1-0.2 parts of magnesium stearates, 0.2-
0.5 part of PVP K30 composition.
3. the Disket for the treatment of respiratory disease as claimed in claim 2, which is characterized in that in parts by weight, described
Disket by 10 parts of Erdosteine hydrates, 2 parts of hydroxypropyl celluloses, 0.7 part of sodium carboxymethyl starch, 1.2 parts of poly- second two
Alcohol 4000-6000,3.6 parts of microcrystalline celluloses, 102,1.5 parts of crospovidone, 0.15 part of magnesium stearate, 0.3 part of PVP K30
Composition.
4. a kind of preparation method for the Disket for preparing treatment respiratory disease a method according to any one of claims 1-3,
It is characterized in that including the following steps:
(1) supplementary material is stocked up: weighing the Erdosteine hydrate, hydroxypropyl cellulose, sodium carboxymethyl starch, poly- second two of recipe quantity
Alcohol 4000-6000, microcrystalline cellulose 102, crospovidone, magnesium stearate, PVP K30；Erdosteine hydrate is crushed
It sieves with 100 mesh sieve；Hydroxypropyl cellulose, sodium carboxymethyl starch be crushed into 120 meshes respectively；By microcrystalline cellulose 102, poly- second two
Alcohol 4000-6000 crushed 80 meshes respectively；Crospovidone be crushed into 60 meshes；Prepare 5% PVP K30 ethanol；
(2) mixing granulation: Erdosteine hydrate, hydroxypropyl cellulose, the sodium carboxymethyl starch, poly- second that step (1) is got ready
Glycol 4000-6000, microcrystalline cellulose 102 are added in wet mixing pelletizer, the dry-mixed 5-15min of speed of agitator 60rpm；It is dry-mixed
After prepared 5% PVP K30 ethanol is added at one time in 1min；60rpm wet mixing 5min, wet mixing 4.5min
When by cutting revolving speed 900rpm cut 0.5min, be made wet granular；Wet granular obtained is transferred in ebullated dryer, temperature control
System 60-70 DEG C bakings 15-35 minute, shutdown, clear filter bag, blowing, obtained dry particl；
(3) whole grain total mix: being added pelletizing machine for dry particl obtained by upper step and carry out whole grain, adds the poly- dimension of crosslinking of recipe quantity
Ketone, magnesium stearate, 15rpm mixing 15min；
(4) tabletting: supplementary material is uniformly mixed, and carries out tabletting, is examined, packing.
5. a kind of Erdosteine hydrate described in claim 1, which is characterized in that the X- obtained using Cu-K alpha ray measurement
Ray powder diffractogram is as shown in Figure 1.
6. Erdosteine hydrate as claimed in claim 5, which is characterized in that it is analyzed by hot weight-differential heat TG-DTA,
Weightlessness 6.5-6.8wt% within the scope of 80-120 DEG C.
7. a kind of preparation method of Erdosteine hydrate described in claim 1, which is characterized in that the preparation method includes
Following steps:
(1) Erdosteine crude product is ground up, sieved, is dissolved into 25-35 DEG C of acetone ethanol mixed solution, it is molten obtains Erdosteine
Liquid is solved, the volume of the mixed solution is 6-8 times of Erdosteine crude product quality；
(2) add active carbon decoloring 20-30 minutes of Erdosteine crude product quality 0.02%-0.1%, filtering；
(3) -15 DEG C~5 DEG C of physiological saline is added dropwise under conditions of stirring, the volume of physiological saline is that Erdosteine dissolves liquid
Long-pending 2-4 times is at the uniform velocity added dropwise in 0.5-1.5h, and the stirring rate is 20-25rmp；
(4) it is cooled to -15 DEG C~5 DEG C after being added dropwise to complete to continue to stir 0.5-2h under the stirring rate of 10-15rmp, stands 3-
White crystal, filtering is precipitated in 5h；
(5) vacuum drying obtains Erdosteine hydrate crystal after successively being washed with distilled water, ethyl acetate.
8. the preparation method of Erdosteine hydrate as claimed in claim 7, which is characterized in that acetone in the step (1)
In the mixed solution of ethyl alcohol, the volume ratio of acetone and ethyl alcohol is 5:1-3.
9. the preparation method of Erdosteine hydrate as claimed in claim 7, which is characterized in that stirred in the step (3)
The physiological saline volume being added dropwise under conditions of mixing is 3 times of Erdosteine lysate volume；The temperature of physiological saline is -10 DEG C；
Stirring rate when physiological saline is added is 23rmp.
10. the preparation method of Erdosteine hydrate as claimed in claim 7, which is characterized in that be added dropwise in the step (4)
- 10 DEG C are cooled to after the completion to continue to stir 1h under the stirring rate of 12rmp.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610566453.XA CN106176642B (en) | 2016-07-19 | 2016-07-19 | A kind of Disket and preparation method thereof for treating respiratory disease |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610566453.XA CN106176642B (en) | 2016-07-19 | 2016-07-19 | A kind of Disket and preparation method thereof for treating respiratory disease |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106176642A CN106176642A (en) | 2016-12-07 |
| CN106176642B true CN106176642B (en) | 2019-08-13 |
Family
ID=57494000
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610566453.XA Active CN106176642B (en) | 2016-07-19 | 2016-07-19 | A kind of Disket and preparation method thereof for treating respiratory disease |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106176642B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107157976A (en) * | 2017-07-03 | 2017-09-15 | 北京北朋科技有限公司 | Application of the compound of thioether acids structure in medicament for resisting platelet aggregation is prepared |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4411909A (en) * | 1981-03-19 | 1983-10-25 | Refarmed, Recherches Pharmaceutiques Et Medicales, S.A. | [(2-Oxo-3-tetrahydrothienylcarbamoyl)-alkylthio] acetic acids, their salts and esters, a process for preparation thereof and the pharmaceutical compositions containing same |
| WO2009062659A2 (en) * | 2007-11-16 | 2009-05-22 | Edmond Pharma S.R.L. | Polymorphs of enantiopure erdosteine |
| CN101606931A (en) * | 2009-08-06 | 2009-12-23 | 山东罗欣药业股份有限公司 | A kind of erdosteine composition and preparation method thereof |
| CN101941963A (en) * | 2010-04-22 | 2011-01-12 | 浙江康乐药业股份有限公司 | Synthesis method of erdosteine |
| CN104873495A (en) * | 2015-05-15 | 2015-09-02 | 苗怡文 | Erdosteine composition for treating respiratory tract inflammation |
-
2016
- 2016-07-19 CN CN201610566453.XA patent/CN106176642B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4411909A (en) * | 1981-03-19 | 1983-10-25 | Refarmed, Recherches Pharmaceutiques Et Medicales, S.A. | [(2-Oxo-3-tetrahydrothienylcarbamoyl)-alkylthio] acetic acids, their salts and esters, a process for preparation thereof and the pharmaceutical compositions containing same |
| WO2009062659A2 (en) * | 2007-11-16 | 2009-05-22 | Edmond Pharma S.R.L. | Polymorphs of enantiopure erdosteine |
| CN101606931A (en) * | 2009-08-06 | 2009-12-23 | 山东罗欣药业股份有限公司 | A kind of erdosteine composition and preparation method thereof |
| CN101941963A (en) * | 2010-04-22 | 2011-01-12 | 浙江康乐药业股份有限公司 | Synthesis method of erdosteine |
| CN104873495A (en) * | 2015-05-15 | 2015-09-02 | 苗怡文 | Erdosteine composition for treating respiratory tract inflammation |
Non-Patent Citations (1)
| Title |
|---|
| 厄多司坦的合成;李飞等;《中国医药工业杂志》;20011220;第32卷(第12期);第533-534页 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106176642A (en) | 2016-12-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US20190381051A1 (en) | Pharmaceutical formulation of palbociclib and a preparation method thereof | |
| CN102600132A (en) | Oral preparation containing amisulpride | |
| CN104788421B (en) | A kind of erdosteine compound treating respiratory inflammation and preparation method thereof | |
| CN106176642B (en) | A kind of Disket and preparation method thereof for treating respiratory disease | |
| EA018636B1 (en) | Drug delivery system for administration of a water soluble, cationic and amphiphilic pharmaceutically active substance | |
| CN105828827A (en) | Solid preparation comprising tofogliflozin and method for producing same | |
| TWI788557B (en) | Solid dosage form having excellent stability | |
| CN105435239B (en) | Mei Suoshuli Film coated tablets and preparation method thereof | |
| EP3395371B1 (en) | Drug inclusion compound, preparation thereof, and preparation method therefor | |
| CN105367551A (en) | Dabigatran etexilate glycolate, preparation method and applications thereof | |
| CN114377147A (en) | Alvatripopa clathrate compound, composition and preparation method thereof | |
| US20080014263A1 (en) | Amorphous eprosartan mesylate and process for the preparation thereof | |
| CN106589022A (en) | Roxithromycin compound as well as preparation method and pharmaceutical composition thereof | |
| CN104873495A (en) | Erdosteine composition for treating respiratory tract inflammation | |
| EP3395346B1 (en) | Oral preparation and preparation method therefor | |
| JPWO2019208540A1 (en) | Solid formulation with excellent stability | |
| CN105348261A (en) | Dabigatran etexilate pyruvate, preparation method and applications thereof | |
| CN105440017A (en) | Dabigatran etexilate vanillate and preparation method and application thereof | |
| CN114948969B (en) | Pharmaceutical composition comprising a crystalline form of a compound and fumaric acid, process for the preparation thereof and use thereof | |
| CN114716417B (en) | Bulk drug of compound and fumaric acid in crystal form, pharmaceutical composition and application thereof | |
| CN104983693A (en) | Medicine erdosteine composition granules for treating respiratory tract infection | |
| CN106187991B (en) | A kind of compound and preparation method thereof for treating respiratory disease | |
| CN105232473A (en) | Pharmaceutical erdosteine composite granules for treating respiratory tract infection | |
| CN106606786A (en) | Pharmaceutical composition containing isavuconazole | |
| CN105348259A (en) | Dabigatran etexilate oxaloacetate, preparation method and applications thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |