CN106913550A - A kind of preparation method of eslicarbazepine acetate piece - Google Patents
A kind of preparation method of eslicarbazepine acetate piece Download PDFInfo
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- CN106913550A CN106913550A CN201710140262.1A CN201710140262A CN106913550A CN 106913550 A CN106913550 A CN 106913550A CN 201710140262 A CN201710140262 A CN 201710140262A CN 106913550 A CN106913550 A CN 106913550A
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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
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
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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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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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
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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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
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
Abstract
The present invention relates to a kind of preparation method of eslicarbazepine acetate piece, the raw material composition of the eslicarbazepine acetate piece is：The weight portion of eslicarbazepine acetate 400, the weight portion of Ac-Di-Sol 28~32, the weight portion of PVP 34~36, the weight portion of magnesium stearate 3~4；Wherein, 16 weight portions are added in Ac-Di-Sol, it is balance of additional；Add 18 weight portions in PVP, it is balance of additional；The preparation method includes：I. the crushing of active component, the mixing of II. granulation materials, III. granulations, IV. is dried, V. whole grains, the additional auxiliary material mixing of VI., VII. compressing tablets.
Description
Technical field
The invention belongs to pharmaceutics field, and in particular to a kind of preparation method of eslicarbazepine acetate piece.
Background technology
Eslicarbazepine acetate (eslicarbazepine acetate, ESL), also known as ESL,
Chemical name (S) -10- acetyl group -10,11 dihydro -5H- dibenzo [b, f] azatropylidene -5- formamides, shown in structural formula as I.Its
For with or not with secondary generalized seizures adults with epilepsy partial seizures auxiliary treatment.ESL is tied in chemistry
It is similar to carbamazepine and Oxcarbazepine on structure, it is advantageous that it is avoided that the formation of toxic metabolites such as epoxides, together
When reduce the ratio of non-active ingredient in metabolin, reduce adverse reaction rate, improve pharmacological activity.I~III phases face
Bed experiment display, ESL is for by the partial hair of adult epilepsy invalid after 1~3 kind of medicine (including carbamazepine etc.) treatment
The patient of work has good validity and tolerance.Because security is good, psychoneural side effect is low, acetic acid Ai Sili cassies
It is flat that there are wide market prospects.
Eslicarbazepine acetate piece is in October, 2009 in European Initial Public Offering, trade nameWithIn November, 2013 is ratified to be listed in the U.S. through FDA, trade nameAt present, the kind in China still
Do not go public.Due to bearing the excessive risk and high cost of new drug development, the price that original grinds medicine is all costly.It is expected that original is ground
If eslicarbazepine acetate piece in Discussion on Chinese Listed, its price also can be high.For the epilepsy for needing Long-term taking medicine
For patient, heavier economic pressures can be undoubtedly brought, or even because economic cause cannot enjoy the benefit of new drug.
Imitation medicine is to reduce patient medication financial burden most direct and effective means.In order to ensure the drug safety of patient
With it is effective, imitation medicine must grind medicine in the being consistent property of aspect such as bioactivity with original.Active component is all in the form of preparation
Patient is bestowed, the property and quality of preparation influence active component Absorption And Metabolism process in vivo, and then influence the life of preparation
Thing activity.Therefore, imitation medicine will grind medicine in every quality index of preparation close to original first.For tablet
Speech, the dissolved corrosion of active component is one of important inspection target.And the various factors and link in tablet manufacture are all
Tablet dissolution can be influenceed, such as prescription composition, the physical behavior of active component, the selection of auxiliary material, the addition manner of auxiliary material are (with activity
Pelletize together interior of composition plus, or additional after granulation and interior plus/additional ratio), granulation mode (wet granulation
Or dry granulation), the mode (stirring at low speed or high-speed stirred), the compressing tablet that mix when pressure etc..In other words, piece
The specific dissolved corrosion of agent is the result and macro manifestations of above-mentioned many factors comprehensive function.
Specification in only disclosePiece contains eslicarbazepine acetate and following without work
Property composition：PVP (adhesive), Ac-Di-Sol (disintegrant) and magnesium stearate (lubricant), but without open
The specific consumption of each auxiliary material, does not disclose the specific preparation method and technique of tablet yet.
Although being also related to the report of the prescription composition of eslicarbazepine acetate piece, its prescription group in the prior art
Chengdu withThere is larger difference.Such as the middle promulgated by the State Council of publication number CN 105560251A (publication date on May 11st, 2016)
A kind of bright patent application " eslicarbazepine acetate pharmaceutical composition ", the auxiliary material composition of disclosed eslicarbazepine acetate piece
For pregelatinized starch, microcrystalline cellulose (filler), Ac-Di-Sol (disintegrant), magnesium stearate (lubricant) and
80% ethanol solution (adhesive)；And it thinks that the release in vitro of medicine can be improved using the pregelatinized starch of special ratios
The stability of degree and preparation.
The content of the invention
It is an object of the invention to provide a kind of preparation method of eslicarbazepine acetate piece.By side of the present invention
The eslicarbazepine acetate piece that method is prepared, its dissolved corrosion withPiece is basically identical.
In order to realize above-mentioned technique effect, present invention employs following technical scheme：
A kind of preparation method of eslicarbazepine acetate piece, the raw material of the eslicarbazepine acetate piece constitutes and is：
The weight portion of eslicarbazepine acetate 400, the weight portion of Ac-Di-Sol 28~32, the weight portion of PVP 34~36,
The weight portion of magnesium stearate 3~4；Wherein, 16 weight portions are added in Ac-Di-Sol, it is balance of additional；Add in PVP
18 weight portions, it is balance of additional；
The preparation method comprises the following steps：
I. the crushing of active component
Eslicarbazepine acetate is by mechanical crushing so that 80 μm and the μ of D (4,3) ＜ 40 of 20 μm of particle diameter D50 ＜, D90 ＜
M, crosses 40~60 mesh sieves, and the eslicarbazepine acetate after being pulverized and sieved is standby；
II. the mixing of granulation material
According to weight portion, by step I obtain pulverize and sieve after eslicarbazepine acetate, it is interior plus cross-linked carboxymethyl
The PVP mixing of sodium cellulosate and Nei Jia, obtains material of pelletizing；
III. pelletize
The additional PVP water of the weight portion is configured to the PVP slurry of weight percent concentration 12%~15%
Liquid, is added to the granulation material that step II is obtained, and is well mixed, and obtains wet granular；
IV. dry
The wet granular that step III is obtained is dried to moisture≤3.0% at 50~65 DEG C, obtains dry particl；
V. whole grain
The dry particl that step IV is obtained is crossed into 24 mesh sieve whole grains, the dry particl after whole grain is obtained；
VI. additional auxiliary material mixing
It is dry after the whole grain that the additional Ac-Di-Sol of the weight portion, magnesium stearate and step V are obtained
Particle mixes, and obtains compressing tablet material；
VII. compressing tablet
The compressing tablet materials result that step VI is obtained, 15~18kN of compression force, 16~20kgf of tablet hardness.
Preferably, the raw material composition of the eslicarbazepine acetate piece is：The weight portion of eslicarbazepine acetate 400,
The weight portion of Ac-Di-Sol 28, the weight portion of PVP 35, the wherein weight portion of magnesium stearate 4, cross-linked carboxymethyl fiber
Add 16 weight portions in plain sodium, it is balance of additional, 18 weight portions are added in PVP, it is balance of additional.
It is also preferred that in the step I, eslicarbazepine acetate is crushed by Universalpulverizer or beater grinder.
It is furthermore preferred that in the step I, eslicarbazepine acetate is crushed with beater grinder, each loading amount is 400~
During 500g, crush 3~4 seconds every time, be repeated 3 times so that 80 μm and 40 μm of D (4,3) ＜ of 20 μm of particle diameter D50 ＜, D90 ＜, cross 40
~60 mesh sieves, the eslicarbazepine acetate after being pulverized and sieved is standby.
Preferably, the acetic acid Chinese mugwort after what I was obtained in the step II, the step of first take weight portion described in 1/3 pulverize and sieve
Department's licarbazepine, mixes with the Ac-Di-Sol and the PVP of Nei Jia that add in the weight portion；Add surplus
Eslicarbazepine acetate mixing after what remaining step I was obtained pulverize and sieve.
It is furthermore preferred that in the step II, being blended in three-dimensional mixer is carried out.
As one preferred embodiment, the operation that possesses of the step II is：
Eslicarbazepine acetate after what the step of first taking weight portion described in 1/3 I was obtained pulverize and sieve, with the weight
Part it is interior plus Ac-Di-Sol and the PVP of Nei Jia mix 5~10min in three-dimensional mixer, rotating speed 20~
25rpm；Add residue step I obtain pulverize and sieve after eslicarbazepine acetate mix 5~10min, rotating speed 20
~25rpm, obtains material of pelletizing.
Preferably, in the step III, carried out in high-shearing granulation machine.
It is also preferred that in the step III, the stir speed (S.S.) of the high-shearing granulation machine is 20~30Hz；More preferably
It is 25Hz.
It is also preferred that in the step III, the addition speed of the PVP slurry is 300~1200g/min；It is more excellent
Elect 400~1200g/min, most preferably 400~600g/min as.
It is also preferred that in the step III, when the PVP slurry is added, the shear rate of high-shearing granulation machine
It is 1200~1700rpm, more preferably 1500rpm；The PVP slurry is added and finished, 2800~3200rpm, more preferably
3000rpm high speed shears 30 seconds~1 minute, more preferably 30~40 seconds.
As one preferred embodiment, the concrete operations of the step III are：
The additional PVP water of the weight portion is configured to the PVP of weight percent concentration 12%~15%
Slurry；The granulation material that step II is obtained is placed in high-shearing granulation machine, opens the high-shearing granulation machine, stirring speed
Stirred 30 seconds~1 minute under rate 25Hz, 1500rpm shear rate, material is formed vortex, with the speed of 400~600g/min
After adding the PVP slurry, addition to finish, stirred 30~40 seconds under 3000rpm shear rates；Shut down, agitation discharging is obtained
To wet granular.
Preferably, in the step IV, drying temperature is 60~65 DEG C.
It is also preferred that in the step IV, moisture≤2% of dry particl.
Preferably, in the step VI, the additional Ac-Di-Sol of the weight portion, magnesium stearate and step
Dry particl after the whole grain that V is obtained mixes 4~6min, 20~25rpm of rotating speed in three-dimensional mixer.
Preferably, in the step VII, compression force is 15~17kN.
Preferably, in above-mentioned preparation method, the PVP is 30 POVIDONE K 30 BP/USP -29/32.
Preferably, the eslicarbazepine acetate piece for being prepared by above-mentioned preparation method, every Ai Sili containing acetic acid
Oxcarbazepine 400mg, average piece weighs 465~472mg.
In description of the invention, the composition of the eslicarbazepine acetate tablet recipe, " weight portion " of each component is represented
When each component relative usage proportion relation, rather than its determination mass unit.According to actual conditions, 1 weight portion can be with table
Show any mass number.
" interior plus " and " additional " described in description of the invention is separation to pelletize, auxiliary material (including disintegrant is crosslinked
Sodium carboxymethylcellulose, adhesive PVP) mix with active component eslicarbazepine acetate before granulation then for " interior plus "；
" additional " refers to auxiliary material (including disintegrant Ac-Di-Sol, adhesive PVP and magnesium stearate lubricant) in system
Grain is added after neutralizing granulation.
Above-mentioned preparation method by enlarged experiment to 5000/batches (every contain eslicarbazepine acetate 400mg), even if
The sample-loading amount of equipment increases to the 70% of maximum sample-loading amount during compressing tablet, and still compressibility is good for compressing tablet material, the acetic acid for preparing
Eslicarbazepine piece any surface finish, disintegration time about 15min is molten in the acid medium (SGF environment) of pH1.2
Go out curve withPiece is basically identical.Illustrate that preparation method of the invention (prescription and formulation parameters) is to stablize feasible
, it is adapted to industrialized production.
Brief description of the drawings
The present invention will be further described below in conjunction with the accompanying drawings.
Fig. 1 is the matched curve of compression force and tablet hardness that embodiment 9 is set up, wherein " --- " represents regression curve,
" --- -- " represents 95% confidential interval, " --- --- -- " represent 95% forecast interval.
Specific embodiment
The present invention provides a kind of preparation method of eslicarbazepine acetate piece, the original of the eslicarbazepine acetate piece
Expect that composition is：The weight portion of eslicarbazepine acetate 400, the weight portion of Ac-Di-Sol 28~32, PVP 34~
36 weight portions, the weight portion of magnesium stearate 3~4；Wherein, Jia 16~20 weight portions in Ac-Di-Sol, it is balance of outer
Plus；Add 18 weight portions in PVP, it is balance of additional；
The preparation method comprises the following steps：
I. the crushing of active component
Eslicarbazepine acetate is crushed with beater grinder, when each loading amount is 400~500g, 3~4 is crushed every time
Second, it is repeated 3 times so that 80 μm and 40 μm of D (4,3) ＜ of 20 μm of particle diameter D50 ＜, D90 ＜, 40 mesh sieves are crossed, after being pulverized and sieved
Eslicarbazepine acetate, it is standby；
II. the mixing of granulation material
Eslicarbazepine acetate after what the step of first taking weight portion described in 1/3 I was obtained pulverize and sieve, with the weight
Part it is interior plus Ac-Di-Sol and the PVP of Nei Jia mix 5~10min in three-dimensional mixer, rotating speed 20~
25rpm；Add residue step I obtain pulverize and sieve after eslicarbazepine acetate mix 5~10min, rotating speed 20
~25rpm, obtains material of pelletizing；
III. pelletize
The additional PVP water of the weight portion is configured to the PVP of weight percent concentration 12%~15%
Slurry；The granulation material that step II is obtained is placed in high-shearing granulation machine, opens the high-shearing granulation machine, stirring speed
Stirred 30 seconds~1 minute under rate 25Hz, 1500rpm shear rate, material is formed vortex, with the speed of 400~600g/min
After adding the PVP slurry, addition to finish, stirred 30~40 seconds under 3000rpm shear rates；Shut down, agitation discharging is obtained
To wet granular；
IV. dry
The wet granular that step III is obtained is dried to moisture≤2.0% at 60~65 DEG C, obtains dry particl；
V. whole grain
The dry particl that step IV is obtained is crossed into 24 mesh sieve whole grains, the dry particl after whole grain is obtained；
VI. additional auxiliary material mixing
Dry after the whole grain that the additional Ac-Di-Sol of the weight portion, magnesium stearate and step V are obtained
Grain mixes 4~6min, 20~25rpm of rotating speed in three-dimensional mixer, obtains material before compressing tablet；
VII. compressing tablet
The compressing tablet materials result that step VI is obtained, 15~17kN of compression force, 16~20kgf of tablet hardness.
Preferably, the raw material composition of the eslicarbazepine acetate piece is：The weight portion of eslicarbazepine acetate 400,
The weight portion of Ac-Di-Sol 28~32, the weight portion of PVP 34~36, the weight portion of magnesium stearate 4, wherein being crosslinked carboxylic
Add 16 weight portions in sodium carboxymethylcellulose pyce, it is balance of additional, 18 weight portions are added in PVP, it is balance of additional.
It is also preferred that the PVP is 30 POVIDONE K 30 BP/USP -29/32.
Preferably, described every 400mg containing eslicarbazepine acetate of eslicarbazepine acetate piece, every weight 465~
472mg, the prescription of monolithic constitutes and is：
Eslicarbazepine acetate 400mg, 28~32mg of Ac-Di-Sol, 34~36mg of PVP, tristearin
Jia 16~20mg in sour 3~4mg of magnesium, wherein Ac-Di-Sol, it is balance of additional, 18mg, surplus are added in PVP
For additional.
The present invention is illustrated referring to specific embodiment.It will be appreciated by those skilled in the art that these embodiments are only
For illustrating the present invention, it limits the scope of the present invention never in any form.
Experimental technique in following embodiments, unless otherwise specified, is conventional method.Medicine used in following embodiments
Material raw material, reagent material etc., unless otherwise specified, are commercially available purchase product.Wherein, active component, auxiliary material and portion of reagent
Purchase situation is as follows：
(1) original grinds product information
(2) supplementary material inventory
| Composition | Lot number | Producer |
| Eslicarbazepine acetate | 196-4-1041-11A | Jiangsu Vcare PharmaTech Co., Ltd. |
| 30 POVIDONE K 30 BP/USP -29/32 | D001695710 | ISP companies of the U.S. |
| Ac-Di-Sol | TN14826925 | FMC Corp. of the U.S. |
| Magnesium stearate | 140508 | Huainan, Anhui mountains and rivers pharmaceutic adjuvant Co., Ltd |
(3) equipment list
| Title | Producer | Key equipment parameter |
| JA5003B electronic balances | German Sai Duolisi | Max：120g；D=0.1mg |
| KF30001 electronic balances | Kaifeng Group Co., Ltd | Max：3000g；D=0.1g |
| FW400 Universalpulverizers | Tianjin Stettlen Instrument Ltd. | - |
| GHL-10 efficient wet mixer-granulators | Changzhou Hua Yang drying equipments factory | Controllable rotating speed and controllable cutting 1500rpm |
| DHG-9240A heated-air circulation ovens | The upper grand experimental facilities Co., Ltd of Nereid | 50℃-200℃ |
| YK-100 oscillating granulators | Changzhou Hua Yang drying equipments factory | - |
| SYH5-10 three-dimensional motion mixers | Changzhou Hua Yang drying equipments factory | - |
| ZP10A tablet press machines | Traditional Chinese medicines dragon is vertical | 10 punchings |
Dissolution and disintegration time of the tablet in the acid medium of pH=1.2 are according to as follows in following embodiments and comparative example
Method is determined：
(1) dissolution (pH=1.2)
This product is taken, according to dissolution method (four methods of general rule 0931 of Chinese Pharmacopoeia version in 2015), with pH1.2 hydrochloric acid solutions
(potassium chloride 3.728g, plus 1.0mol/L hydrochloric acid solution 85ml, are diluted with water to 1000ml, shake up, and obtain final product.) 900ml is for molten
Go out medium, rotating speed is 50 turns per minute, is operated in accordance with the law.When 5,10,15,30,45,60,90 minutes, solution 10ml is taken,
Filtration, precision measures subsequent filtrate 1ml, puts in 10ml measuring bottles, and scale is diluted to dissolution medium, shakes up, and filters, and takes subsequent filtrate work
It is need testing solution.Another to take eslicarbazepine acetate reference substance about 20mg, accurately weighed, in putting 50ml measuring bottles, plus acetonitrile is about
5ml makes dissolving, then is diluted to scale with dissolution medium, shakes up；Precision measures 1ml, puts in 10ml measuring bottles, is diluted with dissolution medium
To scale, shake up, filter, take subsequent filtrate as reference substance solution.According to the chromatographic condition under assay, precision is measured for examination
Product solution and each 20 μ l of reference substance solution, are injected separately into liquid chromatograph, record chromatogram.
(2) disintegration time
This product 6 is taken, according to disintegration time limited inspection technique (four methods of general rule 0921 of Chinese Pharmacopoeia version in 2015), disintegration is put respectively
In the glass tube of instrument hanging basket, start disintegration tester and checked that each all should all dissolve in 15 minutes.Can not be complete if any 1
Full disintegration, should separately take 6 retrials, all should meet regulation.
Embodiment 1Eslicarbazepine acetate pieceDisintegration time and the measure of dissolution
According to the method described above, determineDisintegration time in the acid medium of pH=1.2 and dissolution, knot
Fruit is shown in Table 1.
Table 1Disintegration time and the measurement result of dissolution
As eslicarbazepine acetate piece prepared by the basis for playing bioactivity, the present invention, in disintegration time and molten
Go out aspect should try one's best withPiece is consistent.
Embodiment 2The research of eslicarbazepine acetate grinding mode and preferably
Inventor's research finds that eslicarbazepine acetate is by after crushing, electrostatic agglomeration phenomenon is serious, is not suitable for into one
Step treatment after sieving, it is necessary to go to reunite.The present embodiment have studied crushing and sieving mode to the compressing tablet of particle after granulation and
The influence of dissolution.
The prescription composition of the eslicarbazepine acetate piece of the present embodiment is as follows, wherein 0.1g=1 weight portions:
Prepared by following steps：
According to above-mentioned prescription, prepare 6 parts of supplementary materials, numbering is 1~6；According still further to the crushing shown in table 2 and sieving mode point
Other places reason eslicarbazepine acetate, the eslicarbazepine acetate after being pulverized and sieved, measure heap density and particle diameter (D10,
D50, D90 and D (4,3)), it is standby；Eslicarbazepine acetate after pulverizing and sieving is mixed with interior plus auxiliary material at PE bags, is shifted
The shake granulation manually into cutting mixer, additional 30 POVIDONE K 30 BP/USP -29/32 is configured to the slurry of 12% (w/w), point 3 additions；
Finish, stir about 30s is transferred to 60 DEG C of baking 30min in pallet, takes out 24 mesh whole grains and adds additional cross-linked carboxymethyl
Sodium cellulosate and magnesium stearate, 11mm circle scrobicula stampings, piece weigh about 467mg/ pieces, average hardness about 16kgf.
The dissolution measurement result of 1~6 group of pelletization, compressing tablet situation and the tablet for preparing, is shown in Table 2 and table 3.
The tablet that 2 1~6 groups of table prepares situation
Tablet dissolution (pH=1.2) measurement result of 3 1~6 groups of preparations of table
Although such as dissolution of the particle diameter of the data display active ingredients particles of table 3 to tablet does not make significant difference, particle diameter
There is significant impact to production process：Table 2 shows that eslicarbazepine acetate processes (40 mesh~100 through Ordinary pulverization sieving
Mesh), the particle heterogeneity for obtaining of pelletizing, heap density is low, poor compressibility；Particle bulk density is improved after crossing 160 mesh or 200 mesh sieves,
But it is still below the particle of mechanical crushing；Although compressibility is also improved, still not as good as the particle of mechanical crushing.And it is above-mentioned
Particle prepared by the material that result of the test seems prompting only D90≤40 μm just has compressibility.
To sum up, eslicarbazepine acetate should use mechanical crushing, can use Universalpulverizer, beater grinder etc.；Examine
Consider the requirement of industrialized production, be preferably able to the beater grinder that a large amount of continuous offers meet Particle size requirements.
In order to investigate the influence of beater grinder rotating speed and screen cloth diameter to preparation, following experiment has been carried out again：
Prepare 2 parts of supplementary materials according to the prescription composition described in the present embodiment, the recipe quantity is expanded into 50 times prepares the 3rd part
Supplementary material, numbering is 7,8 and 9 respectively, and every group of eslicarbazepine acetate is crushed with beater grinder respectively, beater grinder
Rotating speed and crush after screen cloth diameter it is as shown in table 4.Measure pulverize and sieve after eslicarbazepine acetate particle diameter (D10,
D50, D90 and D (4,3))；Eslicarbazepine acetate after pulverizing and sieving is mixed with interior plus auxiliary material at PE bags, outer addition polymerization dimension
Ketone K-29/32 is configured to the slurry of 12.5% (w/w), and each group granulation mode is as shown in table 4；The softwood for obtaining is transferred in pallet
60 DEG C of baking 30min, take out 24 mesh whole grains and add additional Ac-Di-Sol and magnesium stearate, 11mm circle scrobicula punching presses
Piece, piece weighs about 467mg/ pieces, average hardness about 16kgf.
The tablet that 4 7~9 groups of table is prepared and dissolution situation
The result of table 4 shows：Eslicarbazepine acetate is crushed using beater grinder, the active component particle diameter is to screen cloth
Aperture is more sensitive, and after screen cloth is replaced by 0.25mm arrow shapeds screen cloth (60 mesh) from 0.4mm round-hole meshes (40 mesh), D90 has significantly
Decline.Even so, the tablet dissolution that 3 groups are prepared is similar, and tablet all is ground close to original, illustrated in beater grinder
Eslicarbazepine acetate is crushed under normal revolution (2500~4000rpm), 40~60 mesh sieves are crossed, effect is suitable.In addition, early stage
Study particle obtained in thinking 40 μm of materials of D90 ＜ and just possess compressibility, but 7 and 8 groups of eslicarbazepine acetate through hammer
After formula pulverizer is crushed, about 60 μm of D90 can still prepare that compressibility is good, the preferable tablet of dissolved corrosion.
Finally determine that acetic acid licarbazepine uses mechanical crushing according to above-mentioned result of the test, preferably use beater grinder powder
Broken, particle diameter makees following control：20 μm of 80 μm of D90 ＜, D50 ＜, 40 μm of D (4,3) ＜, cross 40~60 mesh sieves after crushing.
Embodiment 3The research of disintegrant consumption and feed postition method
The prescription of eslicarbazepine acetate piece prepared by the present invention constitutes simple, the cross-linked carboxymethyl fiber of water-insoluble
Plain sodium be disintegrant, water miscible 30 POVIDONE K 30 BP/USP -29/32 be adhesive, influence of the disintegrant to disintegration and the dissolution of tablet compared with
Greatly, the present embodiment to the consumption and feed postition (interior plus/additional ratio) of disintegrant study and preferred.
The crushing of 1500g eslicarbazepine acetates beater grinder is taken, when each loading amount is 400~500g, per wheat-middlings
Broken 3~4 seconds, it is repeated 3 times so that 80 μm and 40 μm of D (4,3) ＜ of 20 μm of particle diameter D50 ＜, D90 ＜, crosses 40 mesh sieves, is crushed
Eslicarbazepine acetate after sieving, for the preparation of tablet；Supplementary material is weighed according to weight portion shown in 5~table of table 7, wherein
1 weight portion=0.2g；Eslicarbazepine acetate after pulverizing and sieving is mixed with interior plus auxiliary material at PE bags, cutting is transferred to and is stirred
Shake granulation manually in machine is mixed, additional 30 POVIDONE K 30 BP/USP -29/32 is configured to the slurry of 12% (w/w), point 3 additions；Finish, stir
About 30s is transferred to 60 DEG C of baking 30min in pallet, takes out 24 mesh whole grains and adds additional Ac-Di-Sol and stearic acid
Magnesium, 11mm circle scrobicula stampings, piece weighs about 467mg/ pieces, average hardness about 16kgf, every group of each preparation 200.
The dissolution of each group tablet is determined, 5~table 7 is the results are shown in Table.
The disintegrant consumption of table 5 and feed postition research packet and dissolution measurement result (I)
*：API is eslicarbazepine acetate, similarly hereinafter；
a：" disintegrant " is Ac-Di-Sol, similarly hereinafter；
b：" adhesive " is 30 POVIDONE K 30 BP/USP -29/32, similarly hereinafter.
The disintegrant consumption of table 6 and feed postition research packet and dissolution measurement result (II)
The disintegrant consumption of table 7 and feed postition research packet and dissolution measurement result (III)
The result of table 5~7 is shown, in unit formulation with disintegrant between 16~20mg, total amount is prepared between 28~32mg
Its dissolution of the tablet for obtaining grinds that piece is basically identical with original, and similarity is good；It is 16mg with disintegrant that especially unit formulation is interior, additional
Tablet of the disintegrant between 12~16mg.
The auxiliary material of eslicarbazepine acetate piece of the invention is that disintegrant Ac-Di-Sol and adhesive are poly-
Dimension ketone, stator again under, the consumption of adhesive PVP is adjusted with the consumption of disintegrant.By the consumption of above-mentioned disintegrant, really
The total consumption of unit formulation of adhesive PVP is determined for 34~36mg, interior plus 18mg, additional 16~18mg.
Embodiment 4Added binding agents add slurry concentration research and preferably
The present embodiment adds slurry concentration to be studied to added binding agents.
The crushing of 150g eslicarbazepine acetates beater grinder is taken, is crushed 3~4 seconds every time, be repeated 3 times so that grain
80 μm and 40 μm of D (4,3) ＜ of 20 μm of footpath D50 ＜, D90 ＜, crosses 40 mesh sieves, the acetic acid Ai Sili cassies after being pulverized and sieved
It is flat, for the preparation of tablet；Supplementary material is weighed according to weight portion shown in table 8, wherein 1 weight portion=0.1g；After pulverizing and sieving
Eslicarbazepine acetate mix at PE bags with disintegrant and adhesive with interior, be transferred to cutting mixer in manually shake system
Grain, the slurry of 30 POVIDONE K 30 BP/USP -29/32 of additional various concentrations, divides 3 additions respectively.Adhesive stirs 30s after adding, according to softwood
Situation crosses 65 DEG C of baking 30min after the wet whole grain of 24 mesh sieves, or directly spreads in pallet, 65 DEG C of baking 30min without whole grain.Take out dry
Grain, 24 mesh whole grains add additional disintegrant (Ac-Di-Sol) and magnesium stearate, 10.5mm circle scrobicula punching presses
Piece, piece weighs about 467mg/ pieces, 18~20kgf of hardness.Preparation amount：100.
The added binding agents of table 8 add slurry concentration studies
*；Slurry concentration is weight percentage concentration (w/w)
Upper table shows that tablet formulation is identical, and added binding agents slurry concentration has significantly to granulation and the dissolution of tablet
Influence.Specifically, when added binding agents slurry concentration is 10%, material is viscous glutinous blocking, it is necessary to through overly moist whole grain, obtained piece is molten
Go out to grind piece with original and have larger difference；The slurry of concentration 12% and 15%, material can sieve with after convection drying, without wet whole grain,
And piece disintegration and dissolution phenomenon are completely the same obtained in two slurry concentrations, and piece is ground closely with original.It is therefore preferable that outer addition polymerization
Dimension ketone water is configured to the slurry of 12%~15% (weight percent concentration).
Embodiment 5Added binding agents slurry add slurry speed research and preferably
In pilot scale and industrialized production, granulation is using the granulator of Large Copacity, the addition speed of added binding agents slurry
Formation to particle in pelletization can have an impact.Therefore, it is determined that eslicarbazepine acetate tablet recipe of the present invention
On the basis of, the present embodiment adds speed to be studied additional binder paste.
The crushing of 3700g eslicarbazepine acetates beater grinder is taken, each pack amount is 400~500g, per wheat-middlings
Broken 3~4 seconds, it is repeated 3 times so that 80 μm and 40 μm of D (4,3) ＜ of 20 μm of particle diameter D50 ＜, D90 ＜, crosses 40 mesh sieves, is crushed
Eslicarbazepine acetate after sieving, for the preparation of tablet；Supplementary material is weighed according to weight portion shown in table 9, wherein 1 weight
Part=3g；Eslicarbazepine acetate after 1/3 is pulverized and sieved mixes with disintegrant and adhesive with interior at PE bags, adds
Remaining API mixing 3min, is then transferred to be pelletized in high-shearing granulation machine.Stir speed (S.S.) 25Hz (about 450rpm) low sheraing
Under rotating speed (1500rpm) plus slurry, plus slurry speed as shown in table 9, plus slurry finish after continue high shear (3000rpm) 40s, shut down,
Take out particle and be transferred to pallet, 65 DEG C of baking 30min；Dry particl is taken out, 24 mesh whole grains add additional disintegrant (cross-linked carboxymethyl
Sodium cellulosate) and magnesium stearate, 10.5mm circle scrobicula stampings, piece weighs about 467mg/ pieces, 18~20kgf of hardness.Preparation amount：
3000.
The influence of table 9 plus slurry speed to tablet dissolution
In identical under additional disintegrant, three kinds add the dissolution of slurry rate processing substantially similar, therefore 300g/min~
The slurry speed that adds of 1200g/min can use.But the dissolution rate of the treatment of 300g/min is compared with 400g/min's and 1200g/min
Treatment is slow；Accordingly, it is preferred that plus slurry speed is 400g/min~1200g/min.
Embodiment 6The research of lubricant quantity and preferably
The present embodiment is studied the consumption of lubricant.
The crushing of 1250g eslicarbazepine acetates beater grinder is taken, is crushed 3~4 seconds every time, be repeated 3 times so that grain
80 μm and 40 μm of D (4,3) ＜ of 20 μm of footpath D50 ＜, D90 ＜, crosses 40 mesh sieves, the acetic acid Ai Sili cassies after being pulverized and sieved
It is flat, for the preparation of tablet；Supplementary material is weighed according to weight portion shown in table 10, wherein 1 weight portion=1g；To pulverize and sieve respectively
Eslicarbazepine acetate afterwards mixes with disintegrant and adhesive with interior at PE bags, be transferred to cutting mixer in shake manually
Granulation, the binder paste of additional 12% (w/w), point 3 additions.Adhesive stirs 30s after adding, softwood is direct without whole grain
Spread in pallet, 65 DEG C of baking 30min.Take out dry particl, 24 mesh whole grains, respectively according to the (crosslinking of the additional disintegrant of consumption shown in table 9
Sodium carboxymethylcellulose) and magnesium stearate, 10.5mm circle scrobicula stampings, piece weighs about 467mg/ pieces, 18~20kgf of hardness.
Preparation amount：1000.
Influence of the lubricant quantity of table 10 to tablet
The record of table 10 shows, when the consumption of lubricant is 4mg/ pieces, punch die has white film layer after can overcoming compressing tablet
Problem.It is therefore preferable that the consumption of lubricant is 4mg/ pieces.
Embodiment 7Granulating process is studied and preferred
1. wet granulation stir speed (S.S.)
Pilot scale and industrialized production use high-shearing granulation machine wet granulation, general to require shearing line rate ＞ 5m/
S, the high-shearing granulation machine rotating speed of embodiment of the present invention is adjusted with Hz units, diameter of stirring paddle 30cm, according to high shear
It is required that, rotating speed is not less than 360rpm, >=20Hz.It is 20~30Hz (the machine maximum (top) speed 35Hz) by this determination stir speed (S.S.), it is excellent
Select 25Hz.
2. shear rate
Study tour plus slurry open the necessity of high shear after finishing.Specific process of the test and result are as follows：
The crushing of 2500g eslicarbazepine acetates beater grinder is taken, each pack amount is 400~500g, per wheat-middlings
Broken 3~4 seconds, it is repeated 3 times so that 80 μm and 40 μm of D (4,3) ＜ of 20 μm of particle diameter D50 ＜, D90 ＜, crosses 40 mesh sieves, is crushed
Eslicarbazepine acetate after sieving, for the preparation of tablet；Supplementary material is weighed according to weight portion shown in table 11, wherein 1 weight
Amount part=3g；The eslicarbazepine acetate after pulverizing and sieving is mixed with disintegrant and adhesive with interior at PE bags respectively, is turned
Move to granulation in high-shearing granulation machine.Add slurry (12% 30 POVIDONE K 30 BP/USP -29/32), plus slurry under stir speed (S.S.) 25Hz (about 450rpm)
Speed 400g/min, plus slurry and add slurry to finish post processing according to being carried out table 11 Suo Shi；Wet granular is transferred to pallet, 65 DEG C of bakings
30min.Dry particl is taken out, 24 mesh whole grains add additional disintegrant (Ac-Di-Sol) and magnesium stearate, 10.5mm
Circular scrobicula stamping, piece weighs about 467mg/ pieces, 18~20kgf of hardness.Preparation amount：3000.
Influence of the high-shearing granulation machine shear rate of table 11 to tablet
Only low sheraing during compared to granulation, has no the agglomeration of softwood under high shear, particle diameter increase, after granulation dissolution compared with
Only the sample of low sheraing is raised.The unlatching of high shear improves adhesive in the homogeneous of storeroom beneficial to the further dispersion of material
Property.In the case where control slurry adding amount is appropriate, open what high shear was a need for.Preferably, after adding slurry to finish at low shear,
High shear is opened to stir 30 seconds~1 minute, more preferably 30~40 seconds.
Embodiment 8The research of whole grain
Many using dry whole grain in the preparation process of general tablet, some process modifications also occur in that wet whole grain.The present embodiment
Whether investigate needs wet whole grain.
The crushing of 2500g eslicarbazepine acetates beater grinder is taken, each pack amount is 400~500g, per wheat-middlings
Broken 3~4 seconds, it is repeated 3 times so that 80 μm and 40 μm of D (4,3) ＜ of 20 μm of particle diameter D50 ＜, D90 ＜, crosses 40 mesh sieves, is crushed
Eslicarbazepine acetate after sieving, for the preparation of tablet；Supplementary material is weighed according to weight portion shown in table 12, wherein 1 weight
Amount part=3g；Eslicarbazepine acetate after 1/3 is pulverized and sieved respectively mixes with disintegrant and adhesive with interior at PE bags,
Remaining eslicarbazepine acetate mixing 3min is subsequently adding, is transferred in high-shearing granulation machine, according to table 12 Suo Shi points
Do not pelletized, whole grain, drying.The mesh whole grain of dry particl 24, adds additional disintegrant (Ac-Di-Sol) and tristearin
Sour magnesium, 11mm circle scrobicula stampings, piece weighs about 467mg/ pieces, 16~20kgf of hardness.Preparation amount：3000/batches.
Influence of the high-shearing granulation machine shear rate of table 12 to tablet
The data display of upper table, the treatment of " low sheraing rotating speed adds the wet whole grain of slurry+particle ", dissolution rate compared with " plus slurry after height cut
Cut rotating speed+convection drying " granulation after dissolution it is low.In addition, it is long to form 2~3mm during through wet whole grain, after partial material sieving
Short strip shape.To sum up, wet whole grain may bring the moist degree of the decline of dissolution, material may further to influence whole grain mistake
The squeezing effect of journey, and then influence dissolution.Therefore, then preferred feed of the present invention is carried out dry whole without wet whole grain convection drying
Grain.So can both simplify operation, it is cost-effective, influence of the operating error to product quality performance can be avoided again.
Embodiment 9The research of piece hardness and compression force
1. a hardness research
After measured, the former hardness ＞ 20kgf for grinding piece, for the difference for avoiding granulation particle compressibility causes piece hardness to reach
Compression force is excessive during 20kgf, and the present embodiment has investigated the dissolution difference of 16~18kgf of piece hardness and 20kgf.
The crushing of 2500g eslicarbazepine acetates beater grinder is taken, each pack amount is 400~500g, per wheat-middlings
Broken 3~4 seconds, it is repeated 3 times so that 80 μm and 40 μm of D (4,3) ＜ of 20 μm of particle diameter D50 ＜, D90 ＜, crosses 40 mesh sieves, is crushed
Eslicarbazepine acetate after sieving, for the preparation of tablet；Supplementary material is weighed according to weight portion shown in table 13, wherein 1 weight
Amount part=3g；Eslicarbazepine acetate after 1/3 is pulverized and sieved mixes with disintegrant and adhesive with interior at PE bags, then
Remaining eslicarbazepine acetate mixing 3min is added, granulation in high-shearing granulation machine is transferred to.Stir speed (S.S.) 25Hz is (about
450rpm) add under low sheraing rotating speed (1500rpm) and starch (12%w/w binder pastes), plus slurry speed is as shown in table 13.Plus starched
Bi Hou, continues high shear (3000rpm) 40s, shuts down, and particle spreads on pallet 65 DEG C and dries 1h, takes out 24 mesh whole grains, adds
Additional disintegrant (Ac-Di-Sol) and magnesium stearate, 11mm circle scrobicula stampings, piece weigh about 467mg/ pieces, firmly
Degree is as shown in table 13.Total lot amount 3000.
Influence of 13 hardness of table to dissolution
The different prescription of two batches finds, tablet hardness≤20kN (16~20kN), tablet is 5,10, the dissolution of 15min
Degree is significantly higher than the tablet of hardness ＞ 20kN.It is therefore preferable that tablet hardness control of the invention is in 16~20kN.
2. the investigation of compression force
Research find, the particle that preparation method of the present invention is prepared pressure be 13~17kN when, the piece of compacting
Agent hardness rises rapidly, and compression force is increased afterwards, and piece hardness ascensional range is reduced, and excessively after pressure (＞ 18kN), piece stretching is strong
Degree is reduced on the contrary.Fig. 1 is shown in the matched curve of compression force and tablet hardness.Take into account compressing tablet can between progressive and piece porosity it is homogeneous
Property, it was initially believed that compression force is the most suitable in 15~18kN.
In order to verify, carried out the preparation of 3 batch tablets, the prescription of unit formulation with the group 2 in table 13,200 every batch,
Preparation method is for example preceding " a 1. hardness research ", and difference is compression force and piece hardness, it is specific as shown in table 14.Investigate different
Compressing tablet situation and piece dissolution situation under compression force, the results are shown in Table 14.
The different compression force lower sheeting phenomenons of table 14 and dissolution situation
*：Undetermined
Result shows：Tablet dissolution is ground closer to original under pressure 15-17kN；And compression force increases so that dissolution is in 5-
30min declines 3-5%.
Embodiment 10It is prepared by the pilot scale of eslicarbazepine acetate piece
The pilot-scale production of 2 batches 5000/batches is carried out, the weight portion of supplementary material is shown in Table 15 in prescription, wherein 1 weight portion
=5g；Prepared by following steps：
I. the crushing of active component
Eslicarbazepine acetate is crushed with beater grinder, when each loading amount is 400~500g, 3~4 is crushed every time
Second, it is repeated 3 times so that 80 μm and 40 μm of D (4,3) ＜ of 20 μm of particle diameter D50 ＜, D90 ＜, 40 mesh sieves are crossed, after being pulverized and sieved
Eslicarbazepine acetate, it is standby；
II. the mixing of granulation material
Eslicarbazepine acetate after what the step of first taking weight portion described in 1/3 I was obtained pulverize and sieve, with the weight
Part it is interior plus Ac-Di-Sol and the PVP of Nei Jia mix 5~8min in three-dimensional mixer, rotating speed 20~
25rpm；Add residue step I obtain pulverize and sieve after eslicarbazepine acetate mix 8~10min, rotating speed 20
~25rpm, obtains material of pelletizing；
III. pelletize
The additional 30 POVIDONE K 30 BP/USP -29/32 of the weight portion is configured to the PVP of weight percent concentration 12% with water
Slurry；The granulation material that step II is obtained is placed in high-shearing granulation machine, opens the high-shearing granulation machine, stirring speed
Stirred 40 seconds~1 minute under rate 25Hz, 1500rpm shear rate, material is formed vortex, respectively with 400g/min and 600g/
After the speed of min adds the PVP slurry, addition to finish, stirred 30~40 seconds under 3000rpm shear rates；Shut down, stir
Dynamic discharging, obtains wet granular；
IV. dry
The wet granular that step III is obtained is dried 1 hour at 65 DEG C, and moisture ＜ 2.0% obtains dry particl；
V. whole grain
The dry particl that step IV is obtained is crossed into 24 mesh sieve whole grains, the dry particl after whole grain is obtained；
VI. additional auxiliary material mixing
Dry after the whole grain that the additional Ac-Di-Sol of the weight portion, magnesium stearate and step V are obtained
Grain mixes 4~6min, 20~25rpm of rotating speed in three-dimensional mixer, obtains material before compressing tablet；
VII. compressing tablet
The compressing tablet materials result that step VI is obtained, 16~17kN of compression force, 16~18kgf of tablet hardness；Every batch is obtained
5000, average every weight 467mg, 400mg containing eslicarbazepine acetate.
The eslicarbazepine acetate piece pilot scale of table 15
The pilot scale of numbering 20160616, compressing tablet sample-loading amount increases to the 70% of equipment, the tablet dissolution for preparing with dress
The pilot scale (20151123) of sample amount 40% is basically identical, and the dissolution for grinding piece with original is closely.Illustrate preparation method of the invention
(prescription and formulation parameters) are stabilizations, are adapted to industrialized production.
In a word, the invention provides a kind of preparation method of eslicarbazepine acetate piece.By studying influence preparation
Each processing step, including supplementary material composition and consumption, auxiliary material order of addition, granulating process, whole grain technique, tablet forming technique
Deng, the eslicarbazepine acetate piece dissolution for preparing that is grinds piece closely with original, so as to ensure that the tablet with it is former
Grind the bioequivalence and clinical application safety of piece and control effect.
Claims (10)
1. a kind of preparation method of eslicarbazepine acetate piece, the raw material composition of the eslicarbazepine acetate piece is：Vinegar
It is the weight portion of sour eslicarbazepine 400, the weight portion of Ac-Di-Sol 28~32, the weight portion of PVP 34~36, hard
The weight portion of fatty acid magnesium 3~4；Wherein, 16 weight portions are added in Ac-Di-Sol, it is balance of additional；Jia 18 in PVP
Weight portion, it is balance of additional；
The preparation method comprises the following steps：
I. the crushing of active component
Eslicarbazepine acetate is by mechanical crushing so that 80 μm of 20 μm of particle diameter D50 ＜, D90 ＜ and 40 μm of D (4,3) ＜, mistake
40~60 mesh sieves, the eslicarbazepine acetate after being pulverized and sieved is standby；
II. the mixing of granulation material
According to weight portion, by step I obtain pulverize and sieve after eslicarbazepine acetate, it is interior plus cross-linked carboxymethyl fiber
The PVP mixing of plain sodium and Nei Jia, obtains material of pelletizing；
III. pelletize
The additional PVP water of the weight portion is configured to the PVP slurries of weight percent concentration 12%~15%, plus
Enter the granulation material obtained to step II, be well mixed, obtain wet granular；
IV. dry
The wet granular that step III is obtained is dried to moisture≤3.0% at 50~65 DEG C, obtains dry particl；
V. whole grain
The dry particl that step IV is obtained is crossed into 24 mesh sieve whole grains, the dry particl after whole grain is obtained；
VI. additional auxiliary material mixing
Dry particl after the whole grain that the additional Ac-Di-Sol of the weight portion, magnesium stearate and step V are obtained
Mixing, obtains compressing tablet material；
VIII. compressing tablet
The compressing tablet materials result that step VI is obtained, 15~18kN of compression force, 16~20kgf of tablet hardness.
2. preparation method according to claim 1, it is characterised in that the raw material composition of the eslicarbazepine acetate piece
For：The weight portion of eslicarbazepine acetate 400, the weight portion of Ac-Di-Sol 28, the weight portion of PVP 35, stearic acid
Add 16 weight portions in the weight portion of magnesium 4, wherein Ac-Di-Sol, it is balance of additional, 18 weight portions are added in PVP, it is remaining
Measure as additional.
3. preparation method according to claim 1, it is characterised in that in the step I, eslicarbazepine acetate passes through
Universalpulverizer or beater grinder are crushed；
Preferably, in the step I, eslicarbazepine acetate is crushed with beater grinder, and each loading amount is 400~500g
When, crush 3~4 seconds every time, it is repeated 3 times so that 80 μm and 40 μm of D (4,3) ＜ of 20 μm of particle diameter D50 ＜, D90 ＜, cross 40~60
Mesh sieve, the eslicarbazepine acetate after being pulverized and sieved is standby.
4. preparation method according to claim 1, it is characterised in that in the step II, first take weight portion described in 1/3
In eslicarbazepine acetate after what step I was obtained pulverize and sieve, with the weight portion plus cross-linked carboxymethyl cellulose
The PVP mixing of sodium and Nei Jia；Add residue step I obtain pulverize and sieve after eslicarbazepine acetate mixing；
It is furthermore preferred that in the step II, being blended in three-dimensional mixer is carried out；
As one preferred embodiment, the operation that possesses of the step II is：
Eslicarbazepine acetate after what the step of first taking weight portion described in 1/3 I was obtained pulverize and sieve, with the weight portion
It is interior plus Ac-Di-Sol and the PVP of Nei Jia mix 5~10min in three-dimensional mixer, rotating speed 20~
25rpm；Add residue step I obtain pulverize and sieve after eslicarbazepine acetate mix 5~10min, rotating speed 20
~25rpm, obtains material of pelletizing.
5. preparation method according to claim 4, it is characterised in that in the step III, in high-shearing granulation machine
Carry out；
It is also preferred that in the step III, the stir speed (S.S.) of the high-shearing granulation machine is 20~30Hz；More preferably
25Hz；
It is also preferred that in the step III, the addition speed of the PVP slurry is 300~1200g/min；More preferably
400~1200g/min, most preferably 400~600g/min；
It is also preferred that in the step III, when the PVP slurry is added, the shear rate of high-shearing granulation machine is
1200~1700rpm, more preferably 1500rpm；The PVP slurry is added and finished, 2800~3200rpm, more preferably
3000rpm high speed shears 30 seconds~1 minute, more preferably 30~40 seconds；
As one preferred embodiment, the concrete operations of the step III are：
The additional PVP water of the weight portion is configured to the PVP slurry of weight percent concentration 12%~15%；
The granulation material that step II is obtained is placed in high-shearing granulation machine, opens the high-shearing granulation machine, stir speed (S.S.)
Stirred 30 seconds~1 minute under 25Hz, 1500rpm shear rate, material is formed vortex, added with the speed of 400~600g/min
Enter the PVP slurry, after addition is finished, stirred 30~40 seconds under 3000rpm shear rates；Shut down, agitation discharging is obtained
Wet granular.
6. preparation method according to claim 1, it is characterised in that in the step IV, drying temperature is 60~65 DEG C；
Preferably, in the step IV, moisture≤2% of dry particl.
7. preparation method according to claim 1, it is characterised in that in the step VI, the additional friendship of the weight portion
Dry particl after the whole grain that connection sodium carboxymethylcellulose, magnesium stearate are obtained with step V mixes 4 in three-dimensional mixer~
6min, 20~25rpm of rotating speed.
8. preparation method according to claim 1, it is characterised in that in the step VII, compression force is 15~17kN.
9. preparation method according to any one of claim 1 to 8, it is characterised in that the PVP be 30 POVIDONE K 30 BP/USP-
29/32。
10. preparation method according to any one of claim 1 to 9, it is characterised in that prepared by the preparation method
The eslicarbazepine acetate piece for obtaining, every 400mg containing eslicarbazepine acetate, average piece weighs 465~472mg.
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| CN112546006A (en) * | 2020-12-25 | 2021-03-26 | 河北医科大学第二医院 | A pharmaceutical composition for treating neurological diseases, and its preparation method |
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|---|---|---|---|---|
| WO2009054743A1 (en) * | 2007-10-26 | 2009-04-30 | Bial - Portela & Ca., S.A. | Oral dosage forms comprising licarbazξpine acetate |
| CN105560251A (en) * | 2014-10-09 | 2016-05-11 | 天津市汉康医药生物技术有限公司 | Eslicarbazepine acetate pharmaceutical composition |
| EP3103444A1 (en) * | 2015-06-09 | 2016-12-14 | Sanovel Ilac Sanayi ve Ticaret A.S. | Pharmaceutical compositions of lacosamide and eslicarbazepine |
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2017
- 2017-03-10 CN CN201710140262.1A patent/CN106913550B/en active Active
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009054743A1 (en) * | 2007-10-26 | 2009-04-30 | Bial - Portela & Ca., S.A. | Oral dosage forms comprising licarbazξpine acetate |
| CN101848698A (en) * | 2007-10-26 | 2010-09-29 | 比亚尔-珀特拉和Ca股份公司 | The peroral dosage form that contains licarbazepine acetate |
| CN105560251A (en) * | 2014-10-09 | 2016-05-11 | 天津市汉康医药生物技术有限公司 | Eslicarbazepine acetate pharmaceutical composition |
| EP3103444A1 (en) * | 2015-06-09 | 2016-12-14 | Sanovel Ilac Sanayi ve Ticaret A.S. | Pharmaceutical compositions of lacosamide and eslicarbazepine |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112546006A (en) * | 2020-12-25 | 2021-03-26 | 河北医科大学第二医院 | A pharmaceutical composition for treating neurological diseases, and its preparation method |
| CN112546006B (en) * | 2020-12-25 | 2022-10-14 | 河北医科大学第二医院 | A pharmaceutical composition for treating neurological diseases, and its preparation method |
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