CN109010301A - A kind of lacosamide crystal form II tablet and its preparation method and application - Google Patents
A kind of lacosamide crystal form II tablet and its preparation method and application Download PDFInfo
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- CN109010301A CN109010301A CN201811032814.8A CN201811032814A CN109010301A CN 109010301 A CN109010301 A CN 109010301A CN 201811032814 A CN201811032814 A CN 201811032814A CN 109010301 A CN109010301 A CN 109010301A
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- lacosamide
- crystal form
- tablet
- microcrystalline cellulose
- hydroxypropyl cellulose
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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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
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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
- A61K31/16—Amides, e.g. hydroxamic acids
-
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
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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 invention discloses a kind of lacosamide crystal form II tablets and its preparation method and application.The lacosamide crystal form II tablet includes label and based calcium, the label includes the supplementary material of following mass percentage content: lacosamide crystal form II10%~60%, microcrystalline cellulose 10%~60%, lactose 0~40%, crospovidone 3~12%, low-substituted hydroxypropyl cellulose 0~10%, hydroxypropyl cellulose 0.5%~10%, silicified microcrystalline cellulose 0.1%~5% and magnesium stearate 0.3%~3%.One-step palletizing is carried out using fluidized bed.The lacosamide crystal form II tablet can be used as antiepileptic.Crystal form II provided by the invention is more convenient for crushing compared with lacosamide raw material and crystal form I, and the micro mist electrostatic crushed is small, it is easier to auxiliary materials and mixing, reduce the loss of drug, manufactured chemical content is high, and dissolution rate is good, and stability is high, and total impurities content is low.
Description
Technical field
The present invention relates to a kind of lacosamide crystal form II tablets and its preparation method and application.
Background technique
Epilepsy (Epilepsy) is the electric discharge of cerebral neuron paroxysmal abnormality, leads to one kind of of short duration cerebral disorder
Chronic disease.The common the nervous system disease of world wide, is only second to cerebrovascular disease and occupies the in nervous system common disease the 2nd
Position.According to statistics, which is 0.3%~0.7% in developed country, and developing country is then up to 1.5%~3.5%；
China's illness rate is about 0.5%, about 6,000,000 people of existing epileptic patient, and there are about 65~700,000 new cases appearance every year.Wherein about
75% can get satisfactory effect by a conventional line antiepileptic, and about 25% is intractable epilepsy, national intractable epilepsy
There are about 1,500,000 or more.China's epileptic patient number is numerous, and concentrates based on 20 years old teenager and children below.It is caused
Residual rate and the death rate are also higher, it has also become are worth social the problem of paying attention to.
Lacosamide is a kind of novel nmda receptor Glycine site binding antagonists, belongs to new class functionality amino
Acid is the antiepileptic with completely new double mechanism effect.Its alternative promotion sodium channel, which slowly inactivates and adjusts, to be collapsed
It reacts mediating proteins -2 (CRMP-2), and CRMP-2 may slow down the nerve for even preventing epileptic attack and mitigation diabetes
Pain.The mechanism of action of this product is different from other antiepileptics listed, and the patient of symptom is unable to control using existing drug
This product can be used.
Lacosamide pieceGerman subsidiary by Belgium when excellent than company (UCB Pharma)
The preparation of Schwarz BioSciences company research and development.EMEA (European Drug Administration) shows the report of evaluating of lacosamide
Show that lacosamide poor fluidity, raw material become abnormal loose after crushed, electrostatic is big, and supplementary material is easy to cause object when mixing
Material is layered, and is also easy to produce a large amount of dust in production process.
The Chinese patent literature of Publication No. CN102885796A disclose a kind of scheme for lacosamide piece for treating epilepsy and its
Preparation method, the invention prepare tablet with conventional method again after wrapping up using common inclusion material scheme for lacosamide.It should
Clathrate process in method is needed using the special installations such as grinder, experience dissolution, grinding and drying steps, and not only technique is numerous
It is trivial, and take a long time, commercialized application is difficult to realize under pharmaceutical industry current condition at home.
The Chinese patent literature of Publication No. CN104784134A discloses a kind of scheme for lacosamide solid pharmaceutical preparation and its preparation
Method, the preparation process will be added using wet granulation inside and outside silica and disintegrating agent, and operational sequence is more, and due to colloidal state
Silica dioxide granule is thin, generates a large amount of dust in process of production, is unfavorable for mass production.
The Chinese patent literature of Publication No. CN103561727A discloses a kind of original for using crystal form I to prepare for bulk pharmaceutical chemicals
Triturate, and it is clear compared to heteromorphs (II) and (III), and heteromorphs (I) possess many advantages such as manufacture and processing, quilt
It is considered the form of thermodynamicaHy most stable.
Studies in China person is absorbed in the exploitation of I crystal form of lacosamide mostly, and still, different crystal forms may cause drug absorption
The difference of rate and degree.Therefore need to study the II crystal form lacosamide piece and its preparation work of a kind of suitable technology production
Skill.
Summary of the invention
Lacosamide is there are poor fluidity in the prior art, and raw material becomes abnormal loose after crushed, and electrostatic is big, supplementary material
It is easy to cause material layering when mixing, the defect of a large amount of dust is also easy to produce in production process.It is to be solved by this invention
Technical problem is to seek a kind of effect more preferably lacosamide medicinal crystal-form, and provides a kind of completely new lacosamide crystal form
II tablet and preparation method and application.Crystal form II provided by the invention easily facilitates powder compared with lacosamide raw material and crystal form I
Broken, the micro mist electrostatic crushed is small, it is easier to auxiliary materials and mixing, reduce the loss of drug, manufactured chemical content is high, molten
Out-degree is good, and stability is high, and total impurities content is low.
The present invention provides a kind of lacosamide crystal form II tablets comprising label and based calcium, the label packet
Include the supplementary material of following mass percentage content: lacosamide crystal form II 10%~60%, filler 20%~60%, disintegration
Agent 5%~20%, adhesive 0.5%~10%, glidant 0.1%~5% and lubricant 0.3%~3%.
In the present invention, the filler can be filler commonly used in the art, preferably lactose, microcrystalline cellulose,
One or more of combinations of pregelatinized starch, mannitol, starch and dextrin；Further preferably microcrystalline cellulose and/or cream
Sugar.
In the present invention, the disintegrating agent can be disintegrating agent commonly used in the art, preferably cross-linked carboxymethyl cellulose
One or more of combinations of sodium, crospovidone, sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose；Further preferably hand over
Join povidone and/or low-substituted hydroxypropyl cellulose, more preferably crospovidone and low-substituted hydroxypropyl cellulose, crospovidone
Mass ratio with low-substituted hydroxypropyl cellulose can be (0.5~3): 1.
In the present invention, described adhesive can be adhesive commonly used in the art, preferably hydroxypropyl cellulose, hydroxypropyl
One or more of combinations of ylmethyl cellulose, starch slurry and crospovidone；Further preferably hydroxypropyl cellulose.
In the present invention, the glidant can be glidant commonly used in the art, preferably silicified microcrystalline cellulose and/or
Talcum powder；Further preferably silicified microcrystalline cellulose.When the glidant is silicified microcrystalline cellulose, the silicified microcrystalline
Cellulose contains 94% microcrystalline cellulose and 6% superfine silica gel powder.
In the present invention, the lubricant can be lubricant commonly used in the art, preferably magnesium stearate, stearic acid,
The combination of one or more of hydrogenated vegetable oil, sodium stearyl fumarate and polyethylene glycols；Further preferably magnesium stearate.
Preferably, the label includes the supplementary material of following mass percentage content: lacosamide crystal form II10%~
60% (such as 40%), microcrystalline cellulose 10%~60% (such as 12.1%, 45.6%, 46.1%, 49.6%), lactose 0~
40% (such as 0,38.0%), crospovidone 3~12% (such as 3.0%, 11.9%), low-substituted hydroxypropyl cellulose 0~
10% (such as 0,4.9%, 5.0%, 9.0%), hydroxypropyl cellulose 0.5%~10% (such as 0,1.2%), silicified microcrystalline are fine
Tie up plain 0.1%~5% (such as 0.66%) and magnesium stearate 0.3%~3% (such as 0.5%).
As a preferred solution of the present invention, the label includes the supplementary material of following mass percentage content: drawing is examined
Husky amine crystal form II 39%~41% (such as 40%), microcrystalline cellulose 49%~50% (such as 49.6%), crospovidone 3
~4% (such as 3.0%), low-substituted hydroxypropyl cellulose 4~5% (such as 5.0%), hydroxypropyl cellulose 1%~2% (such as
1.2%), silicified microcrystalline cellulose 0.5%~1% (such as 0.66%) and magnesium stearate 0.3%~1% (such as 0.5%).
As a preferred solution of the present invention, the label includes the supplementary material of following mass percentage content: drawing is examined
Husky amine crystal form II 39%~41% (such as 39.7%), microcrystalline cellulose 12%~13% (such as 12.1%), lactose 37%~
38% (such as 38.0%), crospovidone 3~4% (such as 3.0%), low-substituted hydroxypropyl cellulose 4~5% (such as
4.9%), hydroxypropyl cellulose 1%~2% (such as 1.2%), silicified microcrystalline cellulose 0.5%~1% (such as 0.66%) and
Magnesium stearate 0.3%~1% (such as 0.5%).
As a preferred solution of the present invention, the label includes the supplementary material of following mass percentage content: drawing is examined
Husky amine crystal form II 39%~41% (such as 39.7%), microcrystalline cellulose 46%~47% (such as 46.1%), crospovidone
11~12% (such as 11.9%), hydroxypropyl cellulose 1%~2% (such as 1.2%), silicified microcrystalline cellulose 0.5%~1%
(such as 0.66%) and magnesium stearate 0.3%~1% (such as 0.5%).
As a preferred solution of the present invention, the label includes the supplementary material of following mass percentage content: drawing is examined
Husky amine crystal form II 39%~41% (such as 40.0%), microcrystalline cellulose 45%~46% (such as 45.6%), crospovidone
3~4% (such as 3.0%), low-substituted hydroxypropyl cellulose 8~9% (such as 9.0%), hydroxypropyl cellulose 1%~2% (such as
1.2%), silicified microcrystalline cellulose 0.5%~1% (such as 0.66%) and magnesium stearate 0.3%~1% (such as 0.5%).
In the present invention, the film coating layer material can be the coating material of this field routine, preferably, the film packet
Clothing layer material is the gastric solubility coating material of pharmaceutical field routine, such as the Opadry II stomach dissolution type film of Shanghai Ka Lekang production
It is coated pre-mixing agent.
In the present invention, the dosage of the based calcium can be the conventional amount used of this field, preferably, the film coating
The weight of layer is the 2%~4% of the label weight.
The present invention also provides the preparation methods of the lacosamide crystal form II tablet comprising following steps:
(1) described adhesive is made into binder solution；
(2) the lacosamide crystal form II, the filler and the disintegrating agent are placed in fluidised bed granulator and are preheated,
Mixing；
(3) binder solution of step (1) preparation, dry, whole grain are added in fluidised bed granulator；
(4) tabletting after the particle, the glidant and the mix lubricant that obtain step (3), obtains label；
(5) it is coated using the label that the coating material obtains step (4).
Wherein, preferably, the lacosamide crystal form II is through sieving or micronization processes, more preferably, the lacosamide
The partial size of crystal form II is more than 80 mesh.
Wherein, solvent commonly used in the art can be used to be configured to binder solution for described adhesive, and the present invention preferably uses
Water and/or ethyl alcohol are prepared.
Wherein, preferably, described adhesive solution is binder aqueous solution.
Wherein, the concentration of described adhesive solution is concentration commonly used in the art, and the present invention is preferably quality percentage
Specific concentration is 2%~10%.
Wherein, in step (2), the inlet air temperature that fluidised bed granulator is arranged is 60~80 DEG C, intake volume 1000m3/
H~3000m3/ h, so that material maintains preferable fluidized state.
Wherein, in step (3), when temperature of charge in fluidised bed granulator reaches 40 DEG C~50 DEG C, liquid feeding pump is opened, is added
Enter the binder solution of step (1) preparation.
Wherein, in step (3), preferably, the flow velocity of described adhesive solution is 50g/min~200g/min, dry temperature
Degree is 60 DEG C~80 DEG C.More preferably, pelletization spray adhesive solution and continue to stir, after to be bonded dose of aqueous solution has sprayed,
Intake volume and drying temperature are maintained, the drying of material is carried out, moisture is controlled 2%~5%, discharges after drying.
Wherein, in step (4), the equipment that this field routine can be used is mixed, and the present invention preferably uses total mix machine
It is mixed.
Wherein, in step (4), the equipment that this field routine can be used carries out tabletting, and the present invention is preferably using rotation pressure
Piece machine carries out tabletting, controls slice weight and hardness.More preferably, component content difference is within ± 5% in control label, tablet hardness
Control is in 5~7kg.
Wherein, in step (5), the equipment that this field routine can be used is coated, and the present invention preferably uses efficient packet
Clothing pot is coated.
A kind of application the present invention also provides lacosamide crystal form II tablet as antiepileptic.
On the basis of common knowledge of the art, above-mentioned each optimum condition, can any combination to get each preferable reality of the present invention
Example.
Agents useful for same and supplementary material of the present invention are commercially available.
The positive effect of the present invention is that:
(1) lacosamide crystal form II provided by the present invention is easier to be crushed as tablet material, and electrostatic is small after crushing,
It is easy to be uniformly mixed with auxiliary material, the conversion of crystal form does not occur for stable crystal form during preparing preparation.
(2) lacosamide crystal form II tablet of the present invention is by optimization formula, using silicified microcrystalline cellulose as glidant,
Colloidal silicon dioxide is improved in powder surface absorption and insecure, in material transfer and tableting processes, easily cause it is de- mixed,
The phenomenon that leading to layering.
(3) lacosamide crystal form II tablet of the present invention uses fluid-bed marumerization technique, brilliant with lacosamide of the present invention
Medicinal composition tablets quality made of type II is stablized, and simplifies production procedure, improves production efficiency, suitable for commercialization
Production.
Detailed description of the invention
Fig. 1 is the X-ray powder diffraction collection of lacosamide crystal form II；
Fig. 2 is the X-ray diffracting spectrum for the total mix particle that step (3) obtains in embodiment 1；
Fig. 3 is the X-ray diffracting spectrum for the coating tablet that step (4) obtains in embodiment 1.
Specific embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to the reality
It applies among a range.In the following examples, the experimental methods for specific conditions are not specified, according to conventional methods and conditions, or according to quotient
The selection of product specification.
Reagent used in following embodiment is as follows:
Lacosamide crystal form I, purchased from the biochemical pharmaceutcal corporation, Ltd's (lot number 20150530) of Shanghai medicine-feeding first
Lacosamide crystal form II, according to specification [0146] in the Chinese patent literature of Publication No. CN103561727A
Section record be prepared, powder x-ray diffraction method characterizes it, as a result as shown in Figure 1,2 θ=5.3 of the angle of diffraction ±
0.2°、6.8±0.2°、10.8±0.2°、11.1±0.2°、12.7±0.2°、15.6±0.2°、16.3±0.2°、17.5±
0.2°、20.6±0.2°、21.6±0.2°、22.5±0.2°、23.3±0.2°、23.9±0.2°、24.4±0.2°、25.9±
There is characteristic peak at 0.2 °, 27.5 ± 0.2 °.Wherein, powder x-ray diffraction method uses BRUKER-AXS company of Germany
D8ADVANCE X-ray powder diffraction instrument, test condition are as follows: Cu target, K α light sourceOperating voltage
40KV, operating current 40mA, step-length 0.02,0.3 second/step of scanning speed, 1.5 DEG C~60.0 DEG C of scanning angle.
Former trituratePurchased from UCB Canada Inc, specification 50mg, lot number 78260, referring to its FDA
Specification, the Tabules using 50 milligrams of lacosamide cores as activating agent, 10 milligrams of crospovidone as disintegrating agent,
14 milligrams of microcrystalline celluloses, 12.5 milligrams of hydroxypropyl celluloses (low substitution), 1 milligram of hydroxypropyl cellulose, 31.3 milligrams of silication
Microcrystalline cellulose is as filler and adhesive and 1.2 milligrams of magnesium stearates as lubricant.Tablet surface has one layer of NOT function
It can property coating.
Microcrystalline cellulose is 101 type microcrystalline celluloses, is purchased from FMC BioPolymer, lot number P111823753.
Lactose, 200 mesh are purchased from Dai Weilin international trade (Shanghai) Co., Ltd., lot number CX250017.
Low-substituted hydroxypropyl cellulose is purchased from Anhui Shanhe Medicinal Subsidiary Material Co., Ltd., lot number 130702.
Crospovidone is purchased from American International Specialty Products Company, lot number 032301906.
Hydroxypropyl cellulose is purchased from Anhui Shanhe Medicinal Subsidiary Material Co., Ltd., lot number 140503.
Hypromellose is purchased from Dow Chemical, lot number PD340285.
Silicified microcrystalline cellulose is purchased from JRS company of Germany, lot number P9B0K44.
Magnesium stearate is purchased from Anhui Shanhe Medicinal Subsidiary Material Co., Ltd., lot number 130503.
Embodiment 1: lacosamide crystal form II tablet
Core formulation (1000 amounts)
Preparation process:
(1) hydroxypropyl cellulose is prepared into the binder aqueous solution of 5wt%, it is spare.
(2) by it is more than 80 mesh of recipe quantity lacosamide crystal form II, microcrystalline cellulose, low-substituted hydroxypropyl cellulose and
Crospovidone is put into fluidised bed granulator, is opened fluidised bed granulator and is preheated, and setting inlet air temperature is 60 DEG C, air inlet
Air quantity is in 2000m3/ h when temperature of charge reaches 42 DEG C, opens liquid feeding pump so that material maintains preferable fluidized state, if
Binder aqueous solution flow velocity is set in 180g/min, pelletization spray adhesive aqueous solution persistently stirs.To be bonded dose of aqueous solution
It after having sprayed, maintains intake volume and temperature of charge constant, carries out the drying of material, control material moisture 2%~5%, dry knot
It discharges after beam.
(3) the above-mentioned particle after 20 meshes excessively is mixed with silicified microcrystalline cellulose and magnesium stearate in total mix machine
It is even.Carry out tabletting using rotary pelleting machine, control in label component content difference within ± 5%, tablet hardness control 5~
7kg。
(4) using the Opadry II stomach dissolved film coating pre-mix dose of Shanghai Ka Lekang production as coating material, using efficient
Coating pan is coated, wherein the weight of based calcium is the 3% of label weight.
The X-ray diffracting spectrum for the total mix particle that the present embodiment step (3) obtains is as shown in Figure 2；Step (4) obtains
The X-ray diffracting spectrum of coating tablet as shown in figure 3, the results show that during preparing preparation stable crystal form, crystalline substance does not occur
The conversion of type.
Embodiment 2: lacosamide crystal form II tablet
Core formulation (1000 amounts)
Preparation process:
(1) hydroxypropyl cellulose is prepared into the binder aqueous solution of 5wt%, it is spare.
(2) lacosamide crystal form II, lactose, microcrystalline cellulose, low substituted hydroxy-propyls more than 80 mesh of recipe quantity is fine
Dimension element, crospovidone are put into fluidised bed granulator, are opened fluidised bed granulator and are preheated, and setting inlet air temperature is 60
DEG C, intake volume is in 2000m3/ h so that material maintains preferable fluidized state, when temperature of charge reaches 42 DEG C, open into
Binder aqueous solution flow velocity is arranged in 180g/min in liquid pump, and pelletization spray adhesive aqueous solution persistently stirs.To be bonded dose
It after aqueous solution has sprayed, maintains intake volume and temperature of charge constant, carries out the drying of material, control material moisture 2%~5%,
It discharges after drying.
(3) the above-mentioned particle after 20 meshes excessively is mixed with silicified microcrystalline cellulose and magnesium stearate in total mix machine
It is even.Carry out tabletting using rotary pelleting machine, control in label component content difference within ± 5%, tablet hardness control 5~
7kg。
(4) using the Opadry II stomach dissolved film coating pre-mix dose of Shanghai Ka Lekang production as coating material, using efficient
Coating pan is coated, wherein the weight of based calcium is the 3% of label weight.
Embodiment 3: lacosamide crystal form II tablet
Core formulation (1000 amounts)
Preparation process:
(1) hydroxypropyl cellulose is prepared into the binder aqueous solution of 5wt%, it is spare.
(2) lacosamide crystal form II more than 80 mesh of recipe quantity, microcrystalline cellulose, crospovidone are put into fluidized bed
It in granulator, opens fluidised bed granulator and is preheated, setting inlet air temperature is 60 DEG C, and intake volume is in 2000m3/ h, so that
Material maintains preferable fluidized state, when temperature of charge reaches 42 DEG C, opens liquid feeding pump, setting binder aqueous solution flow velocity exists
180g/min, pelletization spray adhesive aqueous solution persistently stir.After to be bonded dose of aqueous solution has sprayed, maintain intake volume and
Temperature of charge is constant, carries out the drying of material, controls material moisture 2%~5%, discharges after drying.
(3) the above-mentioned particle after 20 meshes excessively is mixed with silicified microcrystalline cellulose and magnesium stearate in total mix machine
It is even.Carry out tabletting using rotary pelleting machine, control in label component content difference within ± 5%, tablet hardness control 5~
7kg。
(4) using the Opadry II stomach dissolved film coating pre-mix dose of Shanghai Ka Lekang production as coating material, using efficient
Coating pan is coated, wherein the weight of based calcium is the 3% of label weight.
Embodiment 4: lacosamide crystal form II tablet
Core formulation (1000 amounts)
Preparation process:
(1) hydroxypropyl cellulose is prepared into the binder aqueous solution of 5wt%, it is spare.
(2) by it is more than 80 mesh of recipe quantity lacosamide crystal form II, microcrystalline cellulose, low-substituted hydroxypropyl cellulose,
Crospovidone is put into fluidised bed granulator, is opened fluidised bed granulator and is preheated, and setting inlet air temperature is 60 DEG C, air inlet
Air quantity is in 2000m3/ h when temperature of charge reaches 42 DEG C, opens liquid feeding pump so that material maintains preferable fluidized state, if
Binder aqueous solution flow velocity is set in 180g/min, pelletization spray adhesive aqueous solution persistently stirs.To be bonded dose of aqueous solution
It after having sprayed, maintains intake volume and temperature of charge constant, carries out the drying of material, control material moisture 2%~5%, dry knot
It discharges after beam.
(3) the above-mentioned particle after 20 meshes excessively is mixed with silicified microcrystalline cellulose and magnesium stearate in total mix machine
It is even.Carry out tabletting using rotary pelleting machine, control in label component content difference within ± 5%, tablet hardness control 5~
7kg。
(4) using the Opadry II stomach dissolved film coating pre-mix dose of Shanghai Ka Lekang production as coating material, using efficient
Coating pan is coated, wherein the weight of based calcium is the 3% of label weight.
Comparative example 1: lacosamide crystal form II tablet (wet granulation)
Preparation process:
(1) hydroxypropyl cellulose is prepared into the binder aqueous solution of 5wt%, it is spare.
(2) by lacosamide crystal form II, microcrystalline cellulose, crospovidone, low substitution hydroxyls more than 80 mesh of recipe quantity
Propyl cellulose is placed in high shear mixing granulator and is uniformly mixed, and the 5wt% hydroxy propyl cellulose prepared in step (1) is added
Plain aqueous solution is pelletized；Wet granular is placed in fluidized bed dry (60 DEG C, control material moisture 2~5%), crosses 20 after dry
Mesh sieve.
(3) above-mentioned particle is uniformly mixed with silicified microcrystalline cellulose and magnesium stearate in total mix machine.It is pressed using rotation
Piece machine carries out tabletting, and controlling component content difference in label, within ± 5%, tablet hardness is controlled in 5~7kg.
(4) using the Opadry II stomach dissolved film coating pre-mix dose of Shanghai Ka Lekang production as coating material, using efficient
Coating pan is coated, wherein the weight of based calcium is the 3% of label weight.
Comparative example 2: lacosamide crystal form I tablet
Core formulation (1000 amounts)
Preparation process:
(1) hydroxypropyl cellulose is prepared into the binder aqueous solution of 5wt%, it is spare.
(2) by it is more than 80 mesh of recipe quantity lacosamide crystal form I, microcrystalline cellulose, low-substituted hydroxypropyl cellulose and
Crospovidone is put into fluidised bed granulator, is opened fluidised bed granulator and is preheated, and setting inlet air temperature is 60 DEG C, air inlet
Air quantity is in 2000m3/ h makes material maintain preferable fluidized state, when temperature of charge reaches 42 DEG C, opens liquid feeding pump, setting
Binder aqueous solution flow velocity is persistently stirred in 180g/min, pelletization spray adhesive aqueous solution.To be bonded dose of aqueous solution spray
It after complete, maintains intake volume and temperature of charge constant, carries out the drying of material, control material moisture 2%~5%, drying terminates
After discharge.
(3) the above-mentioned particle after 20 meshes excessively is mixed with silicified microcrystalline cellulose and magnesium stearate in total mix machine
It is even.Carry out tabletting using rotary pelleting machine, control in label component content difference within ± 5%, tablet hardness control 5~
7kg。
(4) using the Opadry II stomach dissolved film coating pre-mix dose of Shanghai Ka Lekang production as coating material, using efficient
Coating pan is coated, wherein the weight of based calcium is the 3% of label weight.
Comparative example 3: lacosamide crystal form II tablet
Core formulation (1000 amounts)
Preparation process:
(1) hydroxypropyl cellulose is prepared into the binder aqueous solution of 5wt%, it is spare.
(2) by it is more than 80 mesh of recipe quantity lacosamide crystal form II, microcrystalline cellulose, low-substituted hydroxypropyl cellulose and
Crospovidone is put into fluidised bed granulator, is opened fluidised bed granulator and is preheated, and setting inlet air temperature is 60 DEG C, air inlet
Air quantity is in 2000m3/ h makes material maintain preferable fluidized state, when temperature of charge reaches 42 DEG C, opens liquid feeding pump, setting
Binder aqueous solution flow velocity is persistently stirred in 180g/min, pelletization spray adhesive aqueous solution.To be bonded dose of aqueous solution spray
It after complete, maintains intake volume and temperature of charge constant, carries out the drying of material, control material moisture 2%~5%, drying terminates
After discharge.
(3) the above-mentioned particle after 20 meshes excessively is uniformly mixed with colloidal silicon dioxide and magnesium stearate in total mix machine.
Carry out tabletting using rotary pelleting machine, control in label component content difference within ± 5%, tablet hardness control 5~
7kg。
(4) using the Opadry II stomach dissolved film coating pre-mix dose of Shanghai Ka Lekang production as coating material, using efficient
Coating pan is coated, wherein the weight of based calcium is the 3% of label weight.
4 lacosamide crystal form II tablet of comparative example
Core formulation (1000 amounts)
Preparation process:
(1) hydroxypropyl cellulose is prepared into the binder aqueous solution of 5wt%, it is spare.
(2) by it is more than 80 mesh of recipe quantity lacosamide crystal form II, microcrystalline cellulose, low-substituted hydroxypropyl cellulose and
Crospovidone is put into fluidised bed granulator, is opened fluidised bed granulator and is preheated, and setting inlet air temperature is 60 DEG C, air inlet
Air quantity is in 2000m3/ h when temperature of charge reaches 42 DEG C, opens liquid feeding pump so that material maintains preferable fluidized state, if
Binder aqueous solution flow velocity is set in 180g/min, pelletization spray adhesive aqueous solution persistently stirs.To be bonded dose of aqueous solution
It after having sprayed, maintains intake volume and temperature of charge constant, carries out the drying of material, control material moisture 2%~5%, dry knot
It discharges after beam.
(3) the above-mentioned particle after 20 meshes excessively is mixed with silicified microcrystalline cellulose and magnesium stearate in total mix machine
It is even.Carry out tabletting using rotary pelleting machine, control in label component content difference within ± 5%, tablet hardness control 5~
7kg。
(4) using the Opadry II stomach dissolved film coating pre-mix dose of Shanghai Ka Lekang production as coating material, using efficient
Coating pan is coated, wherein the weight of based calcium is the 3% of label weight.
Effect example 1: study on the stability
Lacosamide piece prepared by comparing embodiment 1~4 and comparative example 1~4 accelerate according to commercial preparation packaging steady
Qualitative investigation, according to " Chinese Pharmacopoeia " four 9001 bulk pharmaceutical chemicals of version in 2015 and drug preparation stability test direction principle into
Row, accelerated test condition are 40 DEG C ± 2 DEG C, and relative humidity is 75% ± 5%, the results are shown in Table 1:
Table 1
By comparative example 1 it is found that the lacosamide prepared using common bulk drug of pretreatment adds with interior granulating process compared with embodiment 1
Crystal form II tablet content and dissolution rate are obviously relatively low.By comparative example 2 it is found that using lacosamide crystal form II compared with embodiment 1
The tablet of preparation significantly improves content compared with the lacosamide crystal form I tablet prepared, improves dissolution rate.By comparative example 3 with
Embodiment 1 compares it is found that the tablet content and dissolution rate that are prepared using silicified microcrystalline cellulose as glidant are substantially better than and are adopted
With the preparation of colloidal silicon dioxide.By embodiment 1 it is found that the recipe quantity of the former triturate of use, micro- by silication compared with comparative example 4
Crystalline cellulose is as filler and adhesive, and using the tablet of fluidized bed granulation preparation, total miscellaneous present invention that is apparently higher than prepares tablet
It is total miscellaneous, and the mobility of particle is poor during tabletting.
Effect example 2: factors influencing
The former triturate of comparing embodiment 1 and list marketing(formulation and technology is purchased from referring to FDA specification
UCB Canada Inc, lot number 78260) factors influencing is carried out, according to four 9001 originals of " Chinese Pharmacopoeia " version in 2015
Expect that medicine and drug preparation stability test direction principle carry out high temperature (60 DEG C), high humidity (25 DEG C, 92.5%RH), illumination (4500
± 500Lx) investigation, the results are shown in Table 2:
Table 2
As shown in Table 2, by high temperature, the content of former triturate is slightly lower compared with the preparation of embodiment 1 after high humidity 10 days, related object
Matter is slightly higher compared with the preparation of embodiment 1, and illumination does not have significant impact to two kinds of preparations.
Effect example 3: dissolution curve is investigated
Lacosamide crystal form II tablet and above-mentioned former triturate prepared by comparing embodiment 1(dissolution is bent
Line, measures lacosamide piece in 0.1N hydrochloric acid solution as follows, pH4.5 hac buffer, water, and pH6.8 phosphate is slow
The dissolution curve in solution is rushed, using Chinese Pharmacopoeia four 0931 dissolution rates of general rule of version in 2015 and the second method of drug release determination method
Paddle method measures obtained lacosamide piece dissolution curve in the embodiment of the present invention, and dissolution medium is respectively 900ml 0.1N salt
Acid, pH4.5 hac buffer, water, pH6.8 phosphate buffer solution, revolving speed was 50 revs/min, at 5 minutes, 10 minutes, 20
Minute, 30 minutes difference leaching solution 2ml supplement the medium of identical volume in sample injection bottle immediately, using efficient liquid phase
Chromatograph calculates the accumulation dissolution rate at each time point, and the results are shown in Table 3:
Table 3
As seen from the above table, former triturate and embodiment 1, lacosamide piece prepared by comparative example 4, in above 4 kinds of media,
When time is 10min, dissolution rate is all larger than 85%, and lacosamide crystal form II tablet dissolution rate prepared by embodiment 1 is more former to be ground
Preparation is fast, and tablet dissolution rate prepared by comparative example 4 is slower.
Effect example 4: the investigation of partial size
Measurement method: each 500g of lacosamide crystal form I and II is respectively adopted and is crushed (crushing air-flow 1.0Mpa, charging speed
Degree is 0.5kg/h) partial size D is measured afterwards90, the results are shown in Table 4:
Table 4
| Project | Lacosamide crystal form I | Lacosamide crystal form II |
| D90/μm | 55.6 | 30.2 |
The result shows that: respectively after crushed, the partial size of crystal form II is significantly less than crystal form I for two kinds of crystal forms.
Effect example 5: the investigation at angle of repose
Measurement method: vibration-free tables device being put into the location hole in instrument center, then puts receiver and angle of repose sample table.
Instrument front door is shut, sample is got out, timer is transferred to 3 minutes or so, opens vibration screen cover, instrument is opened, is existed with small spoon
Feed opening slowly feeds, and material is trickled down on sample table by sieve, discharge port, forms cone.When sample full of sample table simultaneously
After symmetrical cone, stop charging, close instrument, goniometer is placed on the left of sample tray and close to material heap, with circular cone
The inclined-plane of shape material heap is concordant, and measurement is through the crushing latter two crystal form of effect example 1 and through embodiment 1 and 4 step of comparative example (3)
The angle of repose of obtained total mix particle, test result are shown in Table 5:
Table 5
| Sample ID | Angle of repose (°) |
| Smashed lacosamide crystal form I | 65 |
| Smashed lacosamide crystal form II | 40 |
| Total mix particle prepared by embodiment 1 | 33 |
| Total mix particle prepared by comparative example 4 | 60 |
As seen from the above table, angle of repose is significantly less than crystal form I to lacosamide crystal form II after crushed, and embodiment 1 is prepared total
Mixed mobility of particle is substantially better than the total mix particle of the preparation of comparative example 4.
Claims (10)
1. a kind of lacosamide crystal form II tablet comprising label and based calcium, which is characterized in that the label includes such as
The supplementary material of lower mass percentage content: lacosamide crystal form II 10%~60%, microcrystalline cellulose 10%~60%, lactose 0
~40%, crospovidone 3~12%, low-substituted hydroxypropyl cellulose 0~10%, hydroxypropyl cellulose 0.5%~10%, silication
Microcrystalline cellulose 0.1%~5% and magnesium stearate 0.3%~3%.
2. lacosamide crystal form II tablet as described in claim 1, which is characterized in that the label includes following quality percentage
Than the supplementary material of content: lacosamide crystal form II 39%~41%, microcrystalline cellulose 49%~50%, crospovidone 3~
4%, low-substituted hydroxypropyl cellulose 4~5%, hydroxypropyl cellulose 1%~2%, silicified microcrystalline cellulose 0.5%~1% and hard
Fatty acid magnesium 0.3%~1%.
3. lacosamide crystal form II tablet as described in claim 1, which is characterized in that the label includes following quality percentage
Than the supplementary material of content: lacosamide crystal form II 39%~41%, microcrystalline cellulose 12%~13%, lactose 37%~38%,
Crospovidone 3~4%, low-substituted hydroxypropyl cellulose 4~5%, hydroxypropyl cellulose 1%~2%, silicified microcrystalline cellulose
0.5%~1% and magnesium stearate 0.3%~1%.
4. lacosamide crystal form II tablet as described in claim 1, which is characterized in that the label includes following quality percentage
Than the supplementary material of content: lacosamide crystal form II 39%~41%, microcrystalline cellulose 46%~47%, crospovidone 11~
12%, hydroxypropyl cellulose 1%~2%, silicified microcrystalline cellulose 0.5%~1% and magnesium stearate 0.3%~1%.
5. lacosamide crystal form II tablet as described in claim 1, which is characterized in that the label includes following quality percentage
Than the supplementary material of content: lacosamide crystal form II 39%~41%, microcrystalline cellulose 45%~46%, crospovidone 3~
4%, low-substituted hydroxypropyl cellulose 8~9%, hydroxypropyl cellulose 1%~2%, silicified microcrystalline cellulose 0.5%~1% and hard
Fatty acid magnesium 0.3%~1%.
6. a kind of preparation method of lacosamide crystal form II tablet as claimed in any one of claims 1 to 5, which is characterized in that
Include the following steps:
(1) described adhesive is made into binder solution；
(2) the lacosamide crystal form II, the filler and the disintegrating agent are placed in fluidised bed granulator and are preheated, mixed
It closes；
(3) binder solution of step (1) preparation, dry, whole grain are added in fluidised bed granulator；
(4) tabletting after the particle, the glidant and the mix lubricant that obtain step (3), obtains label；
(5) it is coated using the label that the coating material obtains step (4).
7. the preparation method of lacosamide crystal form II tablet as claimed in claim 6, which is characterized in that the lacosamide is brilliant
Type II is through sieving or micronization processes；
And/or the partial size of the lacosamide crystal form II is more than 80 mesh；
And/or in step (1), binder solution is configured to using water and/or ethyl alcohol；
And/or the mass percent concentration of described adhesive solution is 2%~10%.
8. the preparation method of lacosamide crystal form II tablet as claimed in claim 6, which is characterized in that in step (2), setting
The inlet air temperature of fluidised bed granulator is 60~80 DEG C, intake volume 1000m3/ h~3000m3/h；
And/or in step (3), when temperature of charge in fluidised bed granulator reaches 40 DEG C~50 DEG C, liquid feeding pump is opened, is added
The binder solution of step (1) preparation；
And/or in step (3), the flow velocity of described adhesive solution is 50g/min~200g/min, drying temperature is 60 DEG C~
80℃。
9. the preparation method of lacosamide crystal form II tablet as claimed in claim 6, which is characterized in that
In step (4), mixed using total mix machine；
And/or in step (4), tabletting is carried out using rotary pelleting machine；
And/or in step (4), controlling component content difference in label, within ± 5%, tablet hardness is controlled in 5~7kg；
And/or it in step (5), is coated using high-efficiency coating pot.
10. application of the lacosamide crystal form II tablet as claimed in any one of claims 1 to 5 as antiepileptic.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111000812A (en) * | 2020-01-03 | 2020-04-14 | 石药集团中奇制药技术（石家庄）有限公司 | Preparation method of lacosamide tablets |
| CN111494331A (en) * | 2020-04-27 | 2020-08-07 | 浙江华海药业股份有限公司 | Lacosamide medicine oral preparation and preparation method thereof |
| CN113024405A (en) * | 2019-12-25 | 2021-06-25 | 上海奥博生物医药技术有限公司 | Novel lacosamide impurity and preparation method and application thereof |
| CN115581676A (en) * | 2022-09-30 | 2023-01-10 | 澳美制药(苏州)有限公司 | Lacosamide tablet and preparation process thereof |
Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011055385A1 (en) * | 2009-11-03 | 2011-05-12 | Lupin Limited | Modified release formulation of lacosamide |
| CN102596897A (en) * | 2009-08-06 | 2012-07-18 | 麦迪凯姆股份公司 | Solid forms of an N-(phenylmethyl)propanamide derivative and processes of preparation |
| CN102670544A (en) * | 2012-06-05 | 2012-09-19 | 石家庄四药有限公司 | Lacosamide sustained-release tablets and preparation method thereof |
| CN102816083A (en) * | 2012-07-30 | 2012-12-12 | 永光制药有限公司 | Preparation method of lacosamide |
| CN102885796A (en) * | 2012-07-30 | 2013-01-23 | 永光制药有限公司 | Lacosamide tablet for treating epilepsy and preparation method for lacosamide tablet |
| CN103561727A (en) * | 2010-12-02 | 2014-02-05 | 优时比制药有限公司 | Once daily formulation of lacosamide |
| WO2015079010A2 (en) * | 2013-11-29 | 2015-06-04 | Ucb Pharma Gmbh | Pharmaceutical composition comprising lacosamide and levetiracetam |
| CN104784134A (en) * | 2015-04-12 | 2015-07-22 | 石家庄四药有限公司 | Lacosamidesolid preparation and preparation method thereof |
| CN105228608A (en) * | 2013-04-02 | 2016-01-06 | 比奥生物有限公司 | The pharmaceutical compositions of easy adjustment scheme for lacosamide or its pharmaceutically stripping pattern of admissible salt |
-
2018
- 2018-09-05 CN CN201811032814.8A patent/CN109010301B/en active Active
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102596897A (en) * | 2009-08-06 | 2012-07-18 | 麦迪凯姆股份公司 | Solid forms of an N-(phenylmethyl)propanamide derivative and processes of preparation |
| WO2011055385A1 (en) * | 2009-11-03 | 2011-05-12 | Lupin Limited | Modified release formulation of lacosamide |
| CN103561727A (en) * | 2010-12-02 | 2014-02-05 | 优时比制药有限公司 | Once daily formulation of lacosamide |
| CN102670544A (en) * | 2012-06-05 | 2012-09-19 | 石家庄四药有限公司 | Lacosamide sustained-release tablets and preparation method thereof |
| CN102816083A (en) * | 2012-07-30 | 2012-12-12 | 永光制药有限公司 | Preparation method of lacosamide |
| CN102885796A (en) * | 2012-07-30 | 2013-01-23 | 永光制药有限公司 | Lacosamide tablet for treating epilepsy and preparation method for lacosamide tablet |
| CN105228608A (en) * | 2013-04-02 | 2016-01-06 | 比奥生物有限公司 | The pharmaceutical compositions of easy adjustment scheme for lacosamide or its pharmaceutically stripping pattern of admissible salt |
| WO2015079010A2 (en) * | 2013-11-29 | 2015-06-04 | Ucb Pharma Gmbh | Pharmaceutical composition comprising lacosamide and levetiracetam |
| CN104784134A (en) * | 2015-04-12 | 2015-07-22 | 石家庄四药有限公司 | Lacosamidesolid preparation and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| 刘文: "《药用高分子材料学》", 30 July 2017, 中国中医药出版社 * |
| 王影等: "拉科酰胺凝胶骨架片的制备及体外释放评价", 《中国新药杂志》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113024405A (en) * | 2019-12-25 | 2021-06-25 | 上海奥博生物医药技术有限公司 | Novel lacosamide impurity and preparation method and application thereof |
| CN111000812A (en) * | 2020-01-03 | 2020-04-14 | 石药集团中奇制药技术（石家庄）有限公司 | Preparation method of lacosamide tablets |
| CN111494331A (en) * | 2020-04-27 | 2020-08-07 | 浙江华海药业股份有限公司 | Lacosamide medicine oral preparation and preparation method thereof |
| CN115581676A (en) * | 2022-09-30 | 2023-01-10 | 澳美制药(苏州)有限公司 | Lacosamide tablet and preparation process thereof |
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