CN106176642A - A kind of dispersible tablet treating respiratory system disease and preparation method thereof - Google Patents
A kind of dispersible tablet treating respiratory system disease and preparation method thereof Download PDFInfo
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- CN106176642A CN106176642A CN201610566453.XA CN201610566453A CN106176642A CN 106176642 A CN106176642 A CN 106176642A CN 201610566453 A CN201610566453 A CN 201610566453A CN 106176642 A CN106176642 A CN 106176642A
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- erdosteine
- hydrate
- dispersible tablet
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- 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
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- 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
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- 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
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- 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
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- 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
The present invention relates to one and treat respiratory system disease erdosteine dispersible tablet and preparation method thereof.This dispersible tablet is made up of erdosteine, hydroxypropyl cellulose, carboxymethyl starch sodium, Macrogol 4000 6000, microcrystalline Cellulose 102, polyvinylpolypyrrolidone, magnesium stearate, PVP K30；Described erdosteine is erdosteine monohydrate, and its molecular formula is C8H11NO4S2·H2O, shows characteristic diffraction peak with the X ray powder diffraction that the 2 θ ± 0.2 ° angles of diffraction represent at 3.323,8.484,12.661,21.823,30.645,31.161,33.209,36.161,38.935.Test finds, this dispersible tablet good stability, bioavailability are high, solves in prior art in erdosteine dispersible tablet poor solubility, poor compressibility, production process the problems such as easy sticking.
Description
Technical field
The invention belongs to field of medicine preparations, relate to a kind of dispersible tablet treating respiratory system disease and preparation side thereof
Method, more particularly, it relates to a kind of erdosteine dispersible tablet and preparation method thereof.
Background technology
Expectorant is the product of respiratory inflammation, can stimulate respiratory mucosa, causes cough and asthma, and can increase the weight of to infect.Anxious
When chronic bronchitis or chronic lung diseases respiratory failure, as patient's thick sputum spends height or forms expectorant bolt, can block and exhale
Inhale road and cause suffocating.Therefore, using viscous expectorant regulator, make patient's phlegm dissolving, thinning, viscosity reduces, and accelerates respiratory tract and glues
Film ciliary movement, improves transport function, and tool is of great significance.
At present this is smooth etc. for viscous expectorant regulator such as the bromhexine, mesna of listing, carboxylic first, is respectively provided with gluing in various degree
Expectorant regulation effect, but its pharmacology or there are some defects clinically.Sulfydryl free in molecular structure can adsorb gastrointestinal tract and glue egg
In vain, oral after can produce gastrointestinal tract local damage, side effect is relatively big, can weaken penicillin, cephalosporins, erythromycin, four
The antibacterial activity of ring element etc., unsuitable drug combination, the most high to the improvement effect of some respiration parameter such as expectorant viscosity etc..
Erdosteine is a kind of prodrug, with the sulfydryl of closing of non-free in its structure, to local mucin without
Active function, produces three metabolites containing free sulfhydryl groups through metabolism after being administered orally and plays pharmacological action, thus after being administered orally
Without obvious gastrointestinal side effect.It is demonstrated experimentally that erdosteine cylinder metabolism-ure can make mucinous two sulfur in bronchial secretion
Bond fission, and change secretions composition and rheological property, reduce sputum viscosity, improve downtrod respiratory function, this product energy
Removing free radical, effectively protection a1-antitrypsin is from cigarette, the oxidation deactivation of dirt induction, prevents elastance of lung albumen
And the damage of neutrophilic granulocyte.This product can also substantially increase IgA/ albumin, lactoferrin/albuminous ratio, weakens local
Inflammation, strengthens and improves the antibiotic osmosis to bronchial mucosa, the beneficially treatment of the various inflammation of respiratory tract.Abroad face
Bed research display: comparing with like product such as acetylcysteine, this smooth, ambroxol of carboxylic first etc., this product is to acute and chronic bronchitis
Inflammation has good curative effect, and to the improvement of some respiratory function parameter more effectively, heavy dose of administration does not occurs drug accumulation,
This product characteristics of pharmacokinetics is changed by Liver and kidney function moderate obstacle without obvious.
Dispersible tablet is also known as water dispersion tablet, and referring to can rapid homodisperse tablet in water.Except having the steady of conventional tablet
Qualitative good, be easy to carry, outside the advantage such as taking convenience, the advantage that also bioavailability is higher, can directly swallow, chew clothes or throw
Enter in water and take after dispersion, be particularly suitable for swallowing the patient of difficulty, and in good taste, improve the compliance of patient.
As " dispersible tablet prescription, process characteristic and progress thereof " (" drug assessment " the 3rd phase of volume 5 in 2005) discloses multiple
Being suitable for preparing the adjuvant of dispersible tablet, such as low-substituted hydroxypropyl cellulose, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose can conduct
Disintegrating agent uses.It is mentioned that low-substituted hydroxypropyl cellulose optimum amount is 2～5%.
Additionally, " China's pharmaceutic adjuvant " (Luo Mingsheng etc. edits for Chemical Industry Press, version in 2006) discloses carboxymethyl
Starch Sodium uses outer add mode effect best, and microcrystalline Cellulose is generally not suitable for using as disintegrating agent.
The dissolubility of erdosteine is poor, makes the general formulation effective bioavailability in human body low, therefore, and we
In patent CN101606931B, it is made into dispersible tablet, improves the water solublity of medicine to a certain extent, but there is also
Defect, such as: lactose is expensive, microcrystalline Cellulose hygroscopicity height causes preparation stability undesirable.
There are many patents to prepare erdosteine preparation by studying new crystal-form compound at present, achieve certain one-tenth
Effect, but result is the most undesirable.Such as:
CN104788421A discloses a kind of erdosteine compound treating respiratory inflammation and preparation method thereof, this strategic point
The X-ray powder diffractogram that the smooth compound use Cu-K alpha ray measurement of many departments obtains is as shown in Figure 3.
CN104873495A discloses a kind of erdosteine composition treating respiratory inflammation, by erdosteine, lactose,
Microcrystalline Cellulose, hypromellose, polyoxyethylene sorbitan monoleate, purified water, silicon dioxide are made, and described erdosteine is novel crystal forms
Compound, uses the X-ray powder diffractogram that Cu-K alpha ray measurement obtains as shown in Figure 4.
CN104983693A discloses a kind of medicine erdosteine composition granule treating respiratory tract infection, many by strategic point
Taking charge of smooth, calcium carbonate, sucrose, citric acid, lemon yellow, purified water, magnesium stearate to make, described erdosteine is novel crystal forms chemical combination
Thing, uses the X-ray powder diffractogram that Cu-K alpha ray measurement obtains as shown in Figure 5.
CN105055348A discloses a kind of medicine erdosteine composition tablet treating respiratory inflammation and preparation thereof
Method, described composition tablet is by erdosteine, sodium starch glycolate, lactose, L-HPC21,95% ethanol, magnesium stearate Herba Menthae
Essence is made, and described erdosteine is crystal compound, uses the X-ray powder diffraction spectrum that Cu-K alpha ray measurement obtains
Figure is as shown in Figure 6.
CN105078901A discloses a kind of medicine erdosteine composition dry suspension treating respiratory system disease, by
Erdosteine, sucrose, xylitol, disodium hydrogen phosphate, propylene glycol alginate, sucralose, purified water are made, and described strategic point is many
Take charge of smooth for crystal compound, use the X-ray powder diffractogram that Cu-K alpha ray measurement obtains as shown in Figure 7.
CN105106172A discloses a kind of medicine erdosteine composition capsule treating respiratory inflammation, by E Duosi
Smooth, starch, nor-pair of hydrogen guaiaretic acid, 95% ethanol, PVP K30, Pulvis Talci are made, and described erdosteine is novel crystal forms
Compound, uses the X-ray powder diffractogram that Cu-K alpha ray measurement obtains as shown in Figure 8.
CN105193750A discloses a kind of medicine erdosteine composition tablet treating respiratory inflammation, by E Duosi
Smooth, lactose, polyvinylpolypyrrolidone, zinc oxide, 95% ethanol, polyethylene glycol 6000, magnesium stearate are made, and described erdosteine is
Crystal compound, uses the X-ray powder diffractogram that Cu-K alpha ray measurement obtains as shown in Figure 9.
CN105232445A discloses a kind of medicine erdosteine composition dry suspension treating respiratory system disease, by
Erdosteine, sorbitol, potassium metaphosphate, arabic gum, glycyrrhizin are made, and described erdosteine is crystal compound,
Use the X-ray powder diffractogram that Cu-K alpha ray measurement obtains as shown in Figure 10.
CN105232473A discloses a kind of medicine erdosteine composition granule treating respiratory tract infection, many by strategic point
Taking charge of smooth, sucrose, lactose, vanillin, purified water to make, described erdosteine is crystal compound, uses Cu-K alpha ray
Measure the X-ray powder diffractogram obtained as shown in figure 11.
As it is known by the man skilled in the art that the polymorph of medicine has become as drug research process and becomes yield and quality control with medicine
The important component part must lacked during system and detection.Research polymorphic to medicine contributes to new drug compound biological activity
Selection, be favorably improved bioavailability, promote clinical efficacy, contribute to selection and the design of drug administration approach, and
The determination of pharmaceutical preparation technology parameter, thus improve pharmaceutical production quality.Same medicine crystal form is different, and its bioavailability may
Significant difference.Same medicine, some crystal form may possess higher biological activity than other crystal forms.
The present invention has carried out substantial amounts of experimental study on the basis of document disclosed above, it is proposed that strategic point of the present invention
Taking charge of smooth dispersible tablet and preparation method thereof, wherein erdosteine is erdosteine hydrate more, with the crystal formation of prior art the most not
With.
Summary of the invention
The drug combination preparation that it is an object of the invention to provide a kind of new treatment respiratory system disease (especially divides
Discrete piece agent) and preparation method thereof, and crystal formation and the preparation technology of erdosteine hydrate are provided, thus solve erdosteine and dissolve
Spend in poor, poor compressibility, production process the easily problem such as sticking.
First purpose of the present invention is to provide a kind of dispersible tablet treating respiratory system disease and preparation method thereof, adopts
Technical scheme as follows:
A kind of dispersible tablet treating respiratory system disease, it is by erdosteine, hydroxypropyl cellulose, carboxymethyl starch
Sodium, Macrogol 4000-6000, microcrystalline Cellulose 102, polyvinylpolypyrrolidone, magnesium stearate, PVP K30 form.
Wherein, the erdosteine that this dispersible tablet uses is erdosteine hydrate, represents with the 2 θ ± 0.2 ° angles of diffraction
X-ray powder diffraction spectrum 3.323 °, 8.484 °, 12.661 °, 21.823 °, 30.645 °, 31.161 °, 33.209 °,
36.161 °, show characteristic diffraction peak at 38.935 °.
Preferably, in parts by weight, erdosteine dispersible tablet of the present invention is by 10 parts of erdosteine hydrates, 1-3 part hydroxyl
Propyl cellulose, 0.5-1.0 part carboxymethyl starch sodium, 1-1.5 part Macrogol 4000-6000,3-4 part microcrystalline Cellulose 102,
1-3 part polyvinylpolypyrrolidone, 0.1-0.2 part magnesium stearate, 0.2-0.5 part PVP K30 form.
It is further preferred that in parts by weight, erdosteine dispersible tablet of the present invention by 10 parts of erdosteine hydrates, 2
Part hydroxypropyl cellulose, 0.7 part of carboxymethyl starch sodium, 1.2 parts of Macrogol 4000s-6000,3.6 parts of microcrystalline Cellulose 102,
1.5 parts of polyvinylpolypyrrolidone, 0.15 part of magnesium stearate, 0.3 part of PVP K30 composition.
Preferably, prepare erdosteine dispersible tablet of the present invention and have employed following preparation method:
(1) supplementary material is got the raw materials ready: weighs the erdosteine hydrate of recipe quantity, hydroxypropyl cellulose, carboxymethyl starch sodium, gather
Ethylene glycol 4000-6000, microcrystalline Cellulose 102, polyvinylpolypyrrolidone, magnesium stearate, PVP K30, by erdosteine hydrate
Pulverized 100 mesh sieves, hydroxypropyl cellulose, carboxymethyl starch sodium were pulverized 120 mesh sieves respectively, by microcrystalline Cellulose 102, gathered
Ethylene glycol 4000-6000 pulverized 80 mesh sieves；Polyvinylpolypyrrolidone was pulverized 60 mesh sieves；Prepare 5% PVP K30 ethanol；
(2) mixing granulation: erdosteine hydrate that step (1) is got ready, hydroxypropyl cellulose, carboxymethyl starch sodium,
Macrogol 4000-6000, microcrystalline Cellulose 102 are added in wet mixing pelletizer, and speed of agitator 60rpm is dry mixed 5-15min；
The 5% PVP K30 ethanol that after end is dry mixed, disposable addition has prepared in 1min；60rpm wet mixing 5min, wet mixing
Cut 0.5min by cutting rotating speed 900rpm during 4.5min, prepare wet granular；Prepared wet granular is proceeded in ebullated dryer,
Temperature controls to dry 15-35 minute at 60-70 DEG C, shuts down, clear filter bag, blowing, prepares dry granule；
(3) granulate always mixes: the dry granule obtained by upper step is added pelletizing machine and carries out granulate, add the crosslinking of recipe quantity
Polyvidone, magnesium stearate, 15rpm mixing 15min；
(4) tabletting: supplementary material mix homogeneously, carries out tabletting, inspection, subpackage.
Second object of the present invention is to provide a kind of erdosteine hydrate crystal and preparation technology, the technology of employing
Scheme is as follows:
The present invention provides a kind of new erdosteine hydrate crystal, and each erdosteine hydrate contains 1 water of crystallization,
Its molecular formula is C8H11NO4S2·H2O, and X-ray powder diffractogram such as Fig. 1 that its use Cu-K alpha ray measurement obtains
Shown in.
Being analyzed by heat differential-thermogravimetric TG-DTA, this erdosteine hydrate is weightless 6.5-in the range of 80-120 DEG C
6.8wt%.
Preferably, this erdosteine hydrate is adopted and is prepared with the following method:
(1) grinding of erdosteine crude product is sieved, be dissolved in the acetone ethanol mixed solution of 25-35 DEG C, obtain E Duosi
Smooth lysate, the volume of described mixed solution is 6-8 times of erdosteine crude product quality；
(2) add activated carbon decolorizing 20-30 minute of erdosteine crude product quality 0.02%-0.1%, filter；
(3) dripping-15 DEG C～the normal saline of 5 DEG C under conditions of stirring, the volume of normal saline is that erdosteine dissolves
Long-pending 2-4 times of liquid, at the uniform velocity drips complete in 0.5-1.5h, described stir speed (S.S.) is 20-25rmp；
(4) it is cooled to-15 DEG C～5 DEG C after being added dropwise to complete under the stir speed (S.S.) of 10-15rmp, continues stirring 0.5-2h, quiet
Put 3-5h and separate out white crystal, filter；
(5) wash final vacuum successively by distilled water, ethyl acetate and be dried acquisition erdosteine hydrate crystal.
Preferably, in described step (1) in the mixed solution of acetone ethanol, acetone is 5:1-3 with the volume ratio of ethanol.
Preferably, in described step (3), under conditions of stirring, the normal saline volume of dropping is erdosteine lysate
3 times of volume；The temperature of normal saline is-10 DEG C；Described stir speed (S.S.) when adding normal saline is 23rmp.
Preferably, it is cooled to-10 DEG C after step (4) being added dropwise to complete under the stir speed (S.S.) of 12rmp, continues stirring 1h.
The present invention has the advantage that and has the active effect that
(1) technical scheme that the present invention provides employs a kind of erdosteine hydrate being different from prior art, aobvious
Write stability and the dissolution that improve erdosteine.
(2) in the technical scheme that the present invention provides, erdosteine being first prepared as monohydrate, test finds, this hydration
Thing has good mobility, it is possible to uniformly mix with other adjuvants, and prepared erdosteine dispersible tablet infiltration rate is fast,
Bioavailability is high.
(3) technical scheme that the present invention provides, its preparation process is fairly simple, easy to operate, and solving erdosteine can
A difficult problem for pressure property difference, can effectively prevent sticking in later stage tableting processes, moreover it is possible to improve the dissolubility of dispersible tablet, is suitable for industrialization
Big production.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffractogram 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 diffractogram of erdosteine compound disclosed in patent CN104788421A
Fig. 4 is the X-ray powder diffractogram of erdosteine crystal compound disclosed in patent CN104873495A
Fig. 5 is the X-ray powder diffractogram of erdosteine crystal compound disclosed in patent CN104983693A
Fig. 6 is the X-ray powder diffractogram of erdosteine crystal compound disclosed in patent CN105055348A
Fig. 7 is the X-ray powder diffractogram of erdosteine crystal compound disclosed in patent CN105078901A
Fig. 8 is the X-ray powder diffractogram of erdosteine crystal compound disclosed in patent CN105106172A
Fig. 9 is the X-ray powder diffractogram of erdosteine crystal compound disclosed in patent CN105193750A
Figure 10 is the X-ray powder diffractogram of erdosteine crystal compound disclosed in patent CN105232445A
Figure 11 is the X-ray powder diffractogram of erdosteine crystal compound disclosed in patent CN105232473A
Detailed description of the invention
Now further describing beneficial effects of the present invention by following example, embodiment is only used for the purpose of illustration,
Do not limit the scope of the invention, simultaneously for the technical field of the invention those of ordinary skill according to showing that the present invention is done
And within the change being clear to and modification are also contained in the scope of the invention.The technology contents of the most detailed description of the present invention is known skill
Art.
Embodiment 1: the preparation of erdosteine hydrate
(1) take erdosteine crude product 100g, grind and after sieving, be dissolved into 500ml acetone and the temperature of 200ml ethanol composition
It is in the mixed solution of 30 DEG C, obtains erdosteine lysate；
(2) add the activated carbon decolorizing 25 minutes of 0.05g, filter；
(3) temperature-10 DEG C of 3 times of volumes of erdosteine lysate is at the uniform velocity dripped under conditions of stir speed (S.S.) is 23rmp
Normal saline, in 1h, dropping is complete；
(4) it is cooled to-10 DEG C after being added dropwise to complete under the stir speed (S.S.) of 12rmp, continues stirring 1h, stand 4h and separate out white
Crystal, filters；
(5) wash final vacuum successively by distilled water, ethyl acetate and be dried acquisition erdosteine hydrate crystal 98.75g.
Measure by powder X-ray diffraction algoscopy, exist with the X-ray powder diffraction spectrum that the 2 θ ± 0.2 ° angles of diffraction represent
3.323 °, 8.484 °, 12.661 °, 21.823 °, 30.645 °, 31.161 °, 33.209 °, 36.161 °, show at 38.935 °
Characteristic diffraction peak.
Elementary 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%.
Elementary analysis result is basically identical with theoretical value.
Using Ka Shi aquametry to measure moisture is 6.75wt%, the most identical with theoretical value.
Employing thermogravimetric analysis measures, and result is as in figure 2 it is shown, crystal water content is 6.74wt%, the most identical with theoretical value.
Embodiment 2: the preparation of erdosteine hydrate
(1) take erdosteine crude product 100g, grind and after sieving, be dissolved into 500ml acetone and the temperature of 100ml ethanol composition
It is in the mixed solution of 25 DEG C, obtains erdosteine lysate；
(2) add the activated carbon decolorizing 20 minutes of 0.1g, filter；
(3) life of the temperature 5 DEG C of 4 times of volumes of erdosteine lysate is at the uniform velocity dripped under conditions of stir speed (S.S.) is 20rmp
Reason saline, in 1.5h, dropping is complete；
(4) it is cooled to 5 DEG C after being added dropwise to complete under the stir speed (S.S.) of 10rmp, continues stirring 2h, stand 5h and separate out white brilliant
Body, filters；
(5) wash final vacuum successively by distilled water, ethyl acetate and be dried acquisition erdosteine hydrate crystal 98.52g.
Measure by powder X-ray diffraction algoscopy, exist with the X-ray powder diffraction spectrum that the 2 θ ± 0.2 ° angles of diffraction represent
3.323 °, 8.484 °, 12.661 °, 21.823 °, 30.645 °, 31.161 °, 33.209 °, 36.161 °, show at 38.935 °
Characteristic diffraction peak.
Elementary 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%.
Elementary analysis result is basically identical with theoretical value.
Embodiment 3: the preparation of erdosteine hydrate
(1) take erdosteine crude product 100g, grind and after sieving, be dissolved into 500ml acetone and the temperature of 300ml ethanol composition
It is in the mixed solution of 35 DEG C, obtains erdosteine lysate；
(2) add the activated carbon decolorizing 30 minutes of 0.02g, filter；
(3) temperature-15 DEG C of 2 times of volumes of erdosteine lysate is at the uniform velocity dripped under conditions of stir speed (S.S.) is 25rmp
Normal saline, in 0.5h, dropping is complete；
(4) it is cooled to-15 DEG C after being added dropwise to complete under the stir speed (S.S.) of 15rmp, continues stirring 0.5h, stand 3h and separate out white
Color crystal, filters；
(5) wash final vacuum successively by distilled water, ethyl acetate and be dried acquisition erdosteine hydrate crystal 98.67g.
Measure by powder X-ray diffraction algoscopy, exist with the X-ray powder diffraction spectrum that the 2 θ ± 0.2 ° angles of diffraction represent
3.323 °, 8.484 °, 12.661 °, 21.823 °, 30.645 °, 31.161 °, 33.209 °, 36.161 °, show at 38.935 °
Characteristic diffraction peak.
Elementary 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%.
Elementary analysis result is basically identical with theoretical value.
Embodiment 4: erdosteine dispersible tablet
Preparation technology:
(1) supplementary material is got the raw materials ready: weighs the erdosteine hydrate of recipe quantity, hydroxypropyl cellulose, carboxymethyl starch sodium, gather
Ethylene glycol 4000-6000, microcrystalline Cellulose 102, polyvinylpolypyrrolidone, magnesium stearate, PVP K30, by erdosteine hydrate
Pulverized 100 mesh sieves, hydroxypropyl cellulose, carboxymethyl starch sodium were pulverized 120 mesh sieves respectively, by microcrystalline Cellulose 102, gathered
Ethylene glycol 4000-6000 pulverized 80 mesh sieves, and polyvinylpolypyrrolidone was pulverized 60 mesh sieves, prepared 5% PVP K30 ethanol；
(2) mixing granulation: erdosteine hydrate that step (1) is got ready, hydroxypropyl cellulose, carboxymethyl starch sodium,
Macrogol 4000-6000, microcrystalline Cellulose 102 are added in wet mixing pelletizer, and speed of agitator 60rpm is dry mixed 10min；Dry
The 5% PVP K30 ethanol that after mixed end, disposable addition has prepared in 1min；60rpm wet mixing 5min, wet mixing
Cut 0.5min by cutting rotating speed 900rpm during 4.5min, prepare wet granular；Prepared wet granular is proceeded in ebullated dryer,
Temperature controls to dry 25 minutes at 65 DEG C, shuts down, clear filter bag, blowing, prepares dry granule；
(3) granulate always mixes: the dry granule obtained by upper step is added pelletizing machine and carries out granulate, add the crosslinking of recipe quantity
Polyvidone, magnesium stearate, 15rpm mixing 15min；
(4) tabletting: supplementary material mix homogeneously, carries out tabletting, inspection, subpackage.
Embodiment 5: erdosteine dispersible tablet
Preparation technology:
(1) supplementary material is got the raw materials ready: weighs the erdosteine hydrate of recipe quantity, hydroxypropyl cellulose, carboxymethyl starch sodium, gather
Ethylene glycol 4000-6000, microcrystalline Cellulose 102, polyvinylpolypyrrolidone, magnesium stearate, PVP K30, by erdosteine hydrate
Pulverized 100 mesh sieves, hydroxypropyl cellulose, carboxymethyl starch sodium were pulverized 120 mesh sieves respectively, by microcrystalline Cellulose 102, gathered
Ethylene glycol 4000-6000 pulverized 80 mesh sieves, and polyvinylpolypyrrolidone was pulverized 60 mesh sieves, prepared 5% PVP K30 ethanol；
(2) mixing granulation: erdosteine hydrate that step (1) is got ready, hydroxypropyl cellulose, carboxymethyl starch sodium,
Macrogol 4000-6000, microcrystalline Cellulose 102 are added in wet mixing pelletizer, and speed of agitator 60rpm is dry mixed 15min；Dry
The 5% PVP K30 ethanol that after mixed end, disposable addition has prepared in 1min；60rpm wet mixing 5min, wet mixing
Cut 0.5min by cutting rotating speed 900rpm during 4.5min, prepare wet granular；Prepared wet granular is proceeded in ebullated dryer,
Temperature controls to dry 15 minutes at 60 DEG C, shuts down, clear filter bag, blowing, prepares dry granule；
(3) granulate always mixes: the dry granule obtained by upper step is added pelletizing machine and carries out granulate, add the crosslinking of recipe quantity
Polyvidone, magnesium stearate, 15rpm mixing 15min；
(4) tabletting: supplementary material mix homogeneously, carries out tabletting, inspection, subpackage.
Embodiment 6: erdosteine dispersible tablet
Preparation technology:
(1) supplementary material is got the raw materials ready: weighs the erdosteine hydrate of recipe quantity, hydroxypropyl cellulose, carboxymethyl starch sodium, gather
Ethylene glycol 4000-6000, microcrystalline Cellulose 102, polyvinylpolypyrrolidone, magnesium stearate, PVP K30, by erdosteine hydrate
Pulverized 100 mesh sieves, hydroxypropyl cellulose, carboxymethyl starch sodium were pulverized 120 mesh sieves respectively, by microcrystalline Cellulose 102, gathered
Ethylene glycol 4000-6000 pulverized 80 mesh sieves, and polyvinylpolypyrrolidone was pulverized 60 mesh sieves, prepared 5% PVP K30 ethanol；
(2) mixing granulation: erdosteine hydrate that step (1) is got ready, hydroxypropyl cellulose, carboxymethyl starch sodium,
Macrogol 4000-6000, microcrystalline Cellulose 102 are added in wet mixing pelletizer, and speed of agitator 60rpm is dry mixed 5min；Dry
The 5% PVP K30 ethanol that after mixed end, disposable addition has prepared in 1min；60rpm wet mixing 5min, wet mixing
Cut 0.5min by cutting rotating speed 900rpm during 4.5min, prepare wet granular；Prepared wet granular is proceeded in ebullated dryer,
Temperature controls to dry 35 minutes at 70 DEG C, shuts down, clear filter bag, blowing, prepares dry granule；
(3) granulate always mixes: the dry granule obtained by upper step is added pelletizing machine and carries out granulate, add the crosslinking of recipe quantity
Polyvidone, magnesium stearate, 15rpm mixing 15min；
(4) tabletting: supplementary material mix homogeneously, carries out tabletting, inspection, subpackage.
Embodiment 7: erdosteine dispersible tablet
Preparation technology is with embodiment 4.
Embodiment 8: erdosteine dispersible tablet
Preparation technology is with embodiment 4.
Embodiment 9: erdosteine dispersible tablet
Preparation technology is with embodiment 4.
Embodiment 10: erdosteine dispersible tablet
Preparation technology is with embodiment 4.
Comparative example 1: erdosteine dispersible tablet (commercially available erdosteine)
Preparation technology is with embodiment 4.
Comparative example 2: erdosteine dispersible tablet (commercially available erdosteine)
Preparation technology is with embodiment 4.
Comparative example 3: erdosteine dispersible tablet (CN101606931 embodiment 1)
Preparation technology: recipe quantity microcrystalline Cellulose, low-substituted hydroxypropyl cellulose are crossed 80 mesh sieves, lactose, acesulfame potassium, carboxylic
Methyl starch sodium crosses 120 mesh sieves.To pulverize with ball mill after erdosteine and low-substituted hydroxypropyl cellulose mix homogeneously, mistake
100 mesh sieves, add carboxymethyl starch sodium, use high-speed mixing granulating machine to be dry mixed, and rotating speed is 45 turns/min, mixes 10min, adds
Carrying out wet mixing after dehydrated alcohol 20ml, rotating speed is 30 turns/min, mixes 3min, then wet mixing cutting 2min, prepared wet granular
Proceeding in ebullated dryer, temperature controls to dry 20～25 minutes at 65 DEG C, shuts down, clear filter bag, blowing, dry granule granulate.Whole
Granule suction feeding after Li adds three-dimensional mixer, adds microcrystalline Cellulose mixing, and mixer rotating speed is 35 turns/min,
Mixing 15min, adds lactose, acesulfame potassium and magnesium stearate and continues mixing, and rotating speed is 30 turns/min, mixes 10min, and mixing is all
Even medicated powder carries out tabletting, and tabletting hardness is 3N, the qualified rear packaging of substrate examination that presses and get final product.
Present invention also offers following experimental example, so that product of the present invention to be further illustrated:
Experimental example 1, erdosteine hydrate of the present invention have related substance to detect
The related substance that has in erdosteine hydrate crystal prepared by embodiment 1-3 is detected by this experimental example, this
Test and instruct former according to 2010 editions second annex VIII P residual solvent algoscopy of Chinese Pharmacopoeia, annex Ⅺ Ⅹ F medicine impurity analysis
Then carrying out, it the results are shown in Table 1:
Table 1 has the testing result of related substance
| Hydrate | Acetone | Ethanol | Ethyl acetate | Other have related 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% |
Experimental example 2, the mobility of erdosteine hydrate crystal of the present invention are investigated
This experimental example is by measuring the mobility investigating sample angle of repose of sample, and concrete grammar is as follows: take sample
Grain, flows in the surface plate of circle from fixing little funnel, until obtain the highest cone, measure cone height H and
Radius R, calculates α angle of repose by tan α=H/R, and angle of repose is the biggest, and mobility is the poorest, the results detailed in Table 2.
The mobility of table 2 each sample
| 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 embodiment 1 product；
Sample 2 is embodiment 2 product；
Sample 3 is embodiment 3 product；
Sample 4 is the erdosteine compound with reference to patent CN104788421A embodiment 1 preparation；
Sample 5 is commercially available erdosteine crude drug, purchased from Xi'an Hai Xin pharmaceutical Co. Ltd.
As seen from Table 2, compared with the erdosteine compound of prior art, erdosteine hydrate of the present invention has excellence
Mobility, be conducive to improving the accuracy of subpackage, and be easily mixed uniform when mix with other compositions.
Experimental example 3, the stability test of erdosteine hydrate of the present invention
1, accelerated test
Sample prepared by Example 1-3 is each a collection of, places under conditions of temperature 40 ± 2 DEG C, relative humidity 75 ± 5%
6 months, respectively at 0,1,2,3,6 the end of month sampling and measuring character, have related substance, labelled amount, the results are shown in Table 3.
Table 3 accelerated test result (temperature 40 ± 2 DEG C, relative humidity 75 ± 5%)
As seen from Table 3, erdosteine hydrate of the present invention is put under conditions of temperature 40 ± 2 DEG C, relative humidity 75 ± 5%
Putting 6 months, relevant content of material is low, and each index has no significant change, and this product quality stability is good.
2, long term test
Two batches, the sample of Example 1 preparation, places 6 under conditions of temperature 25 ± 2 DEG C, relative humidity 60 ± 5%
Month, respectively at 0,3,6,9,12,18,24 the end of month sampling and measuring character, have related substance, labelled amount, the results are shown in Table 4.
Table 4 long-term test results (temperature 25 ± 2 DEG C, relative humidity 60 ± 5%)
As seen from Table 4, erdosteine hydrate of the present invention is put under conditions of temperature 25 ± 2 DEG C, relative humidity 60 ± 5%
Putting 24 months and stablize, each index has no significant change.
Experimental example 4, the water solublity of erdosteine crystal compound of the present invention
Sample prepared by Example 1-3, carries out soluble test, and its result (is purchased with commercially available erdosteine crude drug
From Xi'an Hai Xin pharmaceutical Co. Ltd) contrast, the results are shown in Table 5.
Concrete test method:
In the low capacity bottle with constant temperature jacket, add appropriate distilled water, at 20 DEG C, add erdosteine to no longer
Till dissolving, starting magnetic stirrer, continuously stirred under constant temperature, in experimentation, system is in the shape of two-phase coexistent all the time
State, the dissolubility at a temperature of the concentration of erdosteine is this in the liquid phase of system after 70 minutes.It is sampled after 2 hours point
Analysis, takes the close meansigma methods of adjacent two times result as measured value of experiment, before sampling, in order to make solid-liquid be sufficiently separated, stops stirring
After mixing, the most molten erdosteine is deposited to the bottom of low capacity bottle, extracts a small amount of upper clear supernate with syringe, with 0.45 micron
Filter filters, and takes sample, measured the content of erdosteine by HPLC from filtrate.
The water solublity of table 5 erdosteine of the present invention hydrate
| Sample | Embodiment 1 | Embodiment 2 | Embodiment 3 | Commercially available |
| For the first time | 16.99mg/ml | 16.91mg/ml | 16.78mg/ml | 1.41mg/ml |
| For the second time | 16.87mg/ml | 16.93mg/ml | 16.85mg/ml | 1.43mg/ml |
| Meansigma methods | 16.93mg/ml | 16.92mg/ml | 16.82mg/ml | 1.42mg/ml |
As can be seen from Table 5, the water solublity of erdosteine hydrate of the present invention, compared with commercially available erdosteine, carries significantly
High.
Experimental example 5, erdosteine dispersible tablet dissolution determination of the present invention are tested
1, at water, hydrochloric acid solution (pH=1.0), phosphate buffer (pH=5.8), phosphate buffer (pH=6.8)
The dissolution of middle mensuration dispersible tablet of the present invention.
Dissolution conditions: 75 turns/min, volume 1000ml, according to spectrophotometry, measure wavelength 290nm.During mensuration
Between 90min, the results are shown in Table 6.
Dispersible tablet prepared by each embodiment of table 6 dissolution in four kinds of media
2, erdosteine dissolution determination experiment:
Take sample, according to dissolution method (Chinese Pharmacopoeia two annex Ⅹ C the second methods of version in 2010), with 0.2% 12
The phosphate buffer of alkyl sodium sulfate was dissolution medium, and rotating speed is every point of kind 75 turns, operates in accordance with the law, through 10,20,30 minutes
Time, take solution 10ml, filter, take subsequent filtrate, as need testing solution.Separately take erdosteine reference substance appropriate, make 11 μ g/
Ml, as reference substance solution.By external standard method with the dissolution of calculated by peak area every.Limit is the 80% of labelled amount, should meet
Regulation.
The dissolution determination result of dispersible tablet prepared by each embodiment of table 7
Find out from table 6,7:
The result explanation of embodiment 4-10, owing to employing E Duositan hydrate prepared by the present invention, these embodiments
The dispersible tablet of preparation, dissolution is quickly；
The result explanation of comparative example 1,2, uses dispersible tablet prepared by commercially available erdosteine, simulation prescription of the present invention
Agent, drug-eluting is poor；
Comparative example 3 illustrates, uses dispersible tablet prepared by commercially available erdosteine prescription different from the present invention, medicine
Dissolution makes moderate progress, but improves limited.
In sum, the present invention has obtained unforeseeable technique effect.
Experimental example 6, erdosteine dispersible tablet outward appearance of the present invention are investigated
Table 8 dispersible tablet outward appearance is investigated
As seen from Table 8, comparative example 1,2 uses commercially available erdosteine to simulate prescription of the present invention compacting dispersible tablet, sheet
Face is coarse, has sticking phenomenon；Comparative example 3 with the addition of lactose (having excipient effect, good fluidity) as filler, compacting point
Discrete piece agent, unilateral well.
This test demonstrates the superiority of the present invention further: erdosteine is prepared as hydrate, it is not necessary to add lactose
A difficult problem for poor compressibility can be solved, later stage tableting processes effectively prevents sticking, moreover it is possible to improve the dissolubility of dispersible tablet.
Experimental example 7: erdosteine dispersible tablet of the present invention draws moist investigation
It is moist that this experimental example has investigated drawing of the dispersible tablet prepared of erdosteine hydrate crystal that the present invention provides, this
Experiment is drawn moist test direction principle according to 2010 editions second annex Ⅺ Ⅹ J medicine of Chinese Pharmacopoeia and is carried out, and the results are shown in Table 9.
Drawing of table 9 dispersible tablet 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 embodiment 4 product；
Sample 2 is embodiment 5 product；
Sample 3 is embodiment 6 product；
Sample 4 is embodiment 7 product；
Sample 5 is embodiment 8 product；
Sample 6 is embodiment 9 product；
Sample 7 is embodiment 10 product；
Sample 8 is the product of comparative example 3.
As seen from Table 9, the dispersible tablet prepared of erdosteine hydrate crystal that the present invention provides draw wet weightening finish percentage
Rate is little, and hygroscopicity is little.
Experimental example eight, the stability test of erdosteine dispersible tablet of the present invention
1) accelerated test study on the stability:
Dispersible tablet prepared by embodiment 4-10 and comparative example 1-3 is placed under same packaging be placed in 40 DEG C/
Storage 6 months in the climatic chamber of RH75%, difference Progressive symmetric erythrokeratodermia shape, dissolution, relevant thing when 0 month and 6th month
Matter, the investigation of content.There are related substance and content HPLC method to be measured, the results are shown in Table 10.
Table 10 erdosteine of the present invention dispersible tablet accelerated test study on the stability result
As shown in table 10, during accelerated test, in each test, appearance character and the content of sample substantially become
Change.But the dissolution of the dispersible tablet prepared by comparative example substantially diminishes, related substance is had substantially to become big；And the present invention
The dissolution of dispersible tablet does not substantially change, and the increase having related substance is the most much smaller, and the dispersion prepared by the present invention is described
Tablet can improve the stability of medicine, extends the shelf life of preparation.Have related substance controls beneficially to control the bad of medicine
Reaction.
2) long term test study on the stability:
By the dispersible tablet prepared by embodiment 4-10 and comparative example 1-3 under simulation listing terms of packing, in room
Under temperature, respectively at the 12nd, 18, sampling in 24 months, project and method by pharmacopeia in 2010 are investigated, and the results are shown in Table 11.
Table 11 erdosteine of the present invention dispersible tablet long-term test results
As shown in table 11, the sample that prepared by erdosteine dispersible tablet of the present invention and comparative example's example places 24 in room temperature
Individual month test, result shows, the appearance character of erdosteine dispersible tablet of the present invention, labelled amount, Related substances separation and other
Inspection project does not all occur substantially to change, and illustrates that erdosteine dispersible tablet of the present invention is basicly stable.
Claims (10)
1. the dispersible tablet treating respiratory system disease, it is characterised in that described dispersible tablet is by erdosteine, hydroxypropyl
Base cellulose, carboxymethyl starch sodium, Macrogol 4000-6000, microcrystalline Cellulose 102, polyvinylpolypyrrolidone, magnesium stearate, poly-
Dimension ketone K30 composition；Described erdosteine is erdosteine hydrate, the X-ray powder diffraction represented with the 2 θ ± 0.2 ° angles of diffraction
Collection of illustrative plates 3.323 °, 8.484 °, 12.661 °, 21.823 °, 30.645 °, 31.161 °, 33.209 °, 36.161 °, at 38.935 °
Show characteristic diffraction peak.
2. the dispersible tablet treating respiratory system disease as claimed in claim 1, it is characterised in that in parts by weight, described
Dispersible tablet by 10 parts of erdosteine hydrates, 1-3 part hydroxypropyl cellulose, 0.5-1.0 part carboxymethyl starch sodium, 1-1.5
Part Macrogol 4000-6000,3-4 part microcrystalline Cellulose 102,1-3 part polyvinylpolypyrrolidone, 0.1-0.2 part magnesium stearate, 0.2-
0.5 part of PVP K30 composition.
3. the dispersible tablet treating respiratory system disease as claimed in claim 2, it is characterised in that in parts by weight, described
Dispersible tablet by 10 parts of erdosteine hydrates, 2 parts of hydroxypropyl celluloses, 0.7 part of carboxymethyl starch sodium, 1.2 parts of poly-second two
Alcohol 4000-6000,102,1.5 parts of polyvinylpolypyrrolidone of 3.6 parts of microcrystalline Cellulose, 0.15 part of magnesium stearate, 0.3 part of PVP K30
Composition.
4. prepare a preparation method for the dispersible tablet for the treatment of respiratory system disease as described in claim 1-3 is arbitrary, its
It is characterised by comprising the steps:
(1) supplementary material is got the raw materials ready: weigh the erdosteine hydrate of recipe quantity, hydroxypropyl cellulose, carboxymethyl starch sodium, poly-second two
Alcohol 4000-6000, microcrystalline Cellulose 102, polyvinylpolypyrrolidone, magnesium stearate, PVP K30；Erdosteine hydrate is pulverized
Cross 100 mesh sieves；Hydroxypropyl cellulose, carboxymethyl starch sodium were pulverized 120 mesh sieves respectively；By microcrystalline Cellulose 102, poly-second two
Alcohol 4000-6000 pulverized 80 mesh sieves respectively；Polyvinylpolypyrrolidone was pulverized 60 mesh sieves；Prepare 5% PVP K30 ethanol；
(2) mixing granulation: erdosteine hydrate that step (1) is got ready, hydroxypropyl cellulose, carboxymethyl starch sodium, poly-second
Glycol 4000-6000, microcrystalline Cellulose 102 are added in wet mixing pelletizer, and speed of agitator 60rpm is dry mixed 5-15min；It is dry mixed
The 5% PVP K30 ethanol that after end, disposable addition has prepared in 1min；60rpm wet mixing 5min, wet mixing 4.5min
Time by cutting rotating speed 900rpm cut 0.5min, prepare wet granular；Prepared wet granular is proceeded in ebullated dryer, temperature control
Make and dry 15-35 minute at 60-70 DEG C, shut down, clear filter bag, blowing, prepare dry granule；
(3) granulate always mixes: the dry granule obtained by upper step is added pelletizing machine and carries out granulate, adds the poly-dimension of crosslinking of recipe quantity
Ketone, magnesium stearate, 15rpm mixing 15min；
(4) tabletting: supplementary material mix homogeneously, carries out tabletting, inspection, subpackage.
5. the erdosteine hydrate described in a claim 1, it is characterised in that each erdosteine hydrate contains 1
Water of crystallization, its molecular formula is C8H11NO4S2·H2O, and X-ray powder diffraction spectrum that its use Cu-K alpha ray measurement obtains
Figure is as shown in Figure 1.
6. erdosteine hydrate as claimed in claim 5, it is characterised in that analyzed by heat differential-thermogravimetric TG-DTA,
Weightless 6.5-6.8wt% in the range of 80-120 DEG C.
7. the preparation method of the erdosteine hydrate described in a claim 1, it is characterised in that described preparation method includes
Following steps:
(1) grinding of erdosteine crude product is sieved, be dissolved in the acetone ethanol mixed solution of 25-35 DEG C, obtain erdosteine molten
Solving liquid, the volume of described mixed solution is 6-8 times of erdosteine crude product quality；
(2) add activated carbon decolorizing 20-30 minute of erdosteine crude product quality 0.02%-0.1%, filter；
(3) dripping-15 DEG C～the normal saline of 5 DEG C under conditions of stirring, the volume of normal saline is that erdosteine dissolves liquid
Long-pending 2-4 times, at the uniform velocity drips complete in 0.5-1.5h, described stir speed (S.S.) is 20-25rmp；
(4) it is cooled to-15 DEG C～5 DEG C after being added dropwise to complete under the stir speed (S.S.) of 10-15rmp, continues stirring 0.5-2h, stand 3-
5h separates out white crystal, filters；
(5) wash final vacuum successively by distilled water, ethyl acetate and be dried acquisition erdosteine hydrate crystal.
8. the preparation method of erdosteine hydrate as claimed in claim 7, it is characterised in that acetone in described step (1)
In the mixed solution of ethanol, acetone is 5:1-3 with the volume ratio of ethanol.
9. the preparation method of erdosteine hydrate as claimed in claim 7, it is characterised in that described step is being stirred in (3)
3 times that normal saline volume is erdosteine lysate volume dripped under conditions of mixing；The temperature of normal saline is-10 DEG C；
Described stir speed (S.S.) when adding normal saline is 23rmp.
10. the preparation method of erdosteine hydrate as claimed in claim 7, it is characterised in that dropping in described step (4)
It is cooled to-10 DEG C after completing under the stir speed (S.S.) of 12rmp, continues stirring 1h.
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| WO2019007015A1 (en) * | 2017-07-03 | 2019-01-10 | 北京北朋科技有限公司 | Application of compound of thioether acid structure in preparing anti-platelet aggregation drugs |
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