CN107334740A - For stable rivastigmine-hydrogentartrate piece of fortified phenol and preparation method thereof - Google Patents
For stable rivastigmine-hydrogentartrate piece of fortified phenol and preparation method thereof Download PDFInfo
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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
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- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
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- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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- 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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Abstract
This application discloses one kind for fortified phenol impurity 3 [（1S）‑1‑（Dimethylamino）Ethyl] the stable rivastigmine-hydrogentartrate piece of phenol and preparation method thereof, it is described for impurity 3 [（1S）‑1‑（Dimethylamino）Ethyl] the stable rivastigmine-hydrogentartrate piece of phenol includes the components of following parts by weight：2 10 parts of rivastigmine-hydrogentartrate, microcrystalline cellulose is not less than 55 parts, 0 41 parts of other fillers in addition to microcrystalline cellulose, 1 10 parts of disintegrant, 0.1 2 parts of lubricant.Its preparation method comprises the following steps：The rivastigmine-hydrogentartrate, the filler, the disintegrant, the lubricant is taken to be pre-processed；Pretreated rivastigmine-hydrogentartrate, filler is taken to add wetting agent softwood；The softwood is taken to obtain particle by screen cloth；Disintegrant and lubricant quantity are converted after particle drying, disintegrant is added and mix lubricant is uniform, obtain and always mix material；The always mixed material is taken to carry out tabletting.
Description
Technical field
The application be related to it is a kind of for fortified phenol 3-[（1S）-1-（Dimethylamino）Ethyl] the stable heavy wine of phenol
Stone acid Rivastigmine piece and preparation method thereof, belong to pharmaceutical technology field.
Background technology
Rivastigmine-hydrogentartrate（Rivastigmine Tartrate）, chemical name（S）- N- ethyl-N-methyls -3-
[1-（Dimethylamino）- ethyl] phenyl carbamate -2R, 3R- biatrate]（Structural formula sees below formula）, it is a kind of amino first
Esters of gallic acid brain tissue selectivity anticholinesterase.Yuan Yan companies are Novartis Co., Ltd, and in December, 1997 is with trade name Exelon®
（Exelon®）Listed in Switzerland, and it is granted in FDA in April, 2000, light, moderate alzheimer dementia is treated for treating,
I.e. suspicious Alzheimer disease or Alzheimer disease.In July, 2006, FDA ratify rivastigmine-hydrogentartrate and can be used for controlling again
In treating caused by Parkinson's, mild dementia, turn into first FDA approval and can be used for dull-witted medicine caused by treatment Parkinson's
Thing：
。
The content of the invention
Fortified phenol impurity 3-[（1S）-1-（Dimethylamino）Ethyl] phenol（Structural formula is as follows）It is liquor epinephrinae bitartratis ophthalmicus card
Ba Lating synthesis starting material, under soda acid wet heat condition, rivastigmine-hydrogentartrate can slough tartaric acid, and further drop
Solve for starting material 3-[（1S）-1-（Dimethylamino）Ethyl] phenol, as impurity 3-[（1S）-1-（Dimethylamino
Base）Ethyl] phenol.Due to impurity 3-[（1S）-1-（Dimethylamino）Ethyl] phenol is without pharmacological action, and aldehydes matter can
Cause cytotoxicity, should strictly control its content limit.According to the application one kind for impurity 3-[（1S）-1-（Dimethylamino
Base）Ethyl] the stable rivastigmine-hydrogentartrate piece of phenol and preparation method thereof, it has been found that when microcrystalline cellulose in preparation
Plain weight ratio be not less than 55% when, can stablize impurity 3-[（1S）-1-（Dimethylamino）Ethyl] phenol content, suppress
Rivastigmine-hydrogentartrate be degraded to impurity 3-[（1S）-1-（Dimethylamino）Ethyl] phenol, European Pharmacopoeia standard at present
For impurity 3-[（1S）-1-（Dimethylamino）Ethyl] phenol content must not be higher than 0.1%, structural formula is as follows：
。
On the one hand, the application be related to for impurity 3-[（1S）-1-（Dimethylamino）Ethyl] the stable heavy wine of phenol
Stone acid Rivastigmine piece, it is described for impurity 3-[（1S）-1-（Dimethylamino）Ethyl] the stable liquor epinephrinae bitartratis ophthalmicus card of phenol
Ba Lating pieces include the component of following parts by weight：Rivastigmine-hydrogentartrate 2-10 parts, microcrystalline cellulose are not less than 55 parts, its
His filler 0-41 parts, disintegrant 1-10 parts, lubricant 0.1-2 parts.
For impurity 3-[（1S）-1-（Dimethylamino）Ethyl] the stable rivastigmine-hydrogentartrate piece preparation of phenol
Method comprises the following steps：The rivastigmine-hydrogentartrate, the filler, the disintegrant, the lubricant is taken to carry out
Pretreatment；Take rivastigmine-hydrogentartrate after the pretreatment, filler to add wetting agent and obtain softwood；The softwood is taken to pass through sieve
Net obtains particle；Disintegrant and lubricant quantity are converted after particle drying, disintegrant is added and mix lubricant is uniform, obtain and always mix
Material；The always mixed material is taken to carry out tabletting.
According to the application for impurity 3-[（1S）-1-（Dimethylamino）Ethyl] the stable liquor epinephrinae bitartratis ophthalmicus kappa of phenol
Spit of fland piece and preparation method thereof is drawn, using rivastigmine-hydrogentartrate and auxiliary material by wet granulation technology, is mixed with additional material
After uniformly, tabletting is carried out.
In certain embodiments, it is described for impurity 3-[（1S）-1-（Dimethylamino）Ethyl] phenol stabilization
Rivastigmine-hydrogentartrate piece, include the component of following parts by weight：Rivastigmine-hydrogentartrate 2-10 parts, microcrystalline cellulose is not
Less than 55 parts, other fillers 0-41 parts, disintegrant 1-10 parts, lubricant 0.1-2 parts.
In certain embodiments, it is described for impurity 3-[（1S）-1-（Dimethylamino）Ethyl] phenol stabilization
Rivastigmine-hydrogentartrate piece, filler also include the one or more in mannitol, lactose, starch in addition to microcrystalline cellulose,
Preferably lactose.
In certain embodiments, it is described for impurity 3-[（1S）-1-（Dimethylamino）Ethyl] phenol stabilization
Rivastigmine-hydrogentartrate piece, disintegrant include Ac-Di-Sol, sodium carboxymethyl starch, low substituted hydroxy-propyl fiber
One or more in element and PVPP, preferably Ac-Di-Sol.
In certain embodiments, it is described for impurity 3-[（1S）-1-（Dimethylamino）Ethyl] phenol stabilization
Rivastigmine-hydrogentartrate piece, lubricant include one kind in magnesium stearate, sodium stearyl fumarate, magnesium stearate, silica
Or several, preferably magnesium stearate.
In certain embodiments, it is described for impurity 3-[（1S）-1-（Dimethylamino）Ethyl] phenol stabilization
Rivastigmine-hydrogentartrate piece, microcrystalline cellulose parts by weight are not less than 55 parts, such as 60 parts, such as 65 parts, such as 70 parts, example
Such as 75 parts, such as 80 parts, such as 85 parts, such as 90 parts.
In certain embodiments, it is described for impurity 3-[（1S）-1-（Dimethylamino）Ethyl] phenol stabilization
Rivastigmine-hydrogentartrate piece, microcrystalline cellulose parts by weight are preferably not lower than 60 parts.
In certain embodiments, it is described for impurity 3-[（1S）-1-（Dimethylamino）Ethyl] phenol stabilization
Rivastigmine-hydrogentartrate piece microcrystalline cellulose model can be PH101, PH102, PH105, PH112 and PH301.
In certain embodiments, it is described for impurity 3-[（1S）-1-（Dimethylamino）Ethyl] phenol stabilization
Rivastigmine-hydrogentartrate piece, include the component of following parts by weight：Rivastigmine-hydrogentartrate 2.4-7.2 parts, microcrystalline cellulose
Element is not less than 60 parts, other fillers 0-35 parts, disintegrant 2-10 parts, lubricant 0.5-1.5 parts.
In certain embodiments, described rivastigmine-hydrogentartrate piece, the component of following parts by weight is included：Weight wine
Stone acid Rivastigmine is 2.4-4.8 parts, and microcrystalline cellulose is 58-62 parts, and other fillers are 34-36 parts, disintegrant 2-5
Part, lubricant is 0.5-1 parts.
In certain embodiments, described rivastigmine-hydrogentartrate piece, the component of following parts by weight is included：Weight wine
Stone acid Rivastigmine is preferably 2.4-4.8 parts, and microcrystalline cellulose is preferably 60 parts, and other fillers are preferably 34-35 parts, disintegration
Agent is preferably 2-4 parts, and lubricant is preferably 0.5-0.7 parts.
In certain embodiments, described rivastigmine-hydrogentartrate piece, the component of following parts by weight is included：Weight wine
Stone acid Rivastigmine is 2.4 parts, and microcrystalline cellulose is 60 parts, and other fillers are 34.2 parts, and disintegrant is 2.9 parts, lubricant
For 0.5 part.
On the other hand, the application is related to the preparation method of rivastigmine-hydrogentartrate piece, and it comprises the following steps：
（1）Rivastigmine-hydrogentartrate, filler, disintegrant, lubricant is taken to be pre-processed；
（2）Take after rivastigmine-hydrogentartrate, filler are sufficiently mixed uniformly after pretreatment, wetting agent is added, after stirring
Obtain softwood；
（3）Take softwood that wet granular is made by screen cloth；
（4）Wet granular is taken to be sufficiently mixed uniformly, obtain by obtaining dry particle, whole grain, additional disintegrant and lubricant after drying
Always mixed material；
（5）Material will always be mixed and carry out tabletting.
In certain embodiments, the preparation method of the rivastigmine-hydrogentartrate piece, wherein step（1）
Pass through screen cloth including rivastigmine-hydrogentartrate is crushed, the sieve mesh number is 60-120 mesh；By filler, disintegration
Agent, lubricant sieving processing, the sieve mesh number is 60-100 mesh；Or step（3）It is by particle diameter including the wet granular
The screen cloth of 10-30 mesh is made；Or step（4）It is 1%-3% including the dry particle moisture, the dry particle whole grain
Particle diameter is 16-40 mesh afterwards.
In certain embodiments, the preparation method of the rivastigmine-hydrogentartrate piece, the wetting agent be purified water,
The mixture of ethanol or the two composition.
In certain embodiments, the preparation method of the rivastigmine-hydrogentartrate piece, microcrystalline cellulose is in tablets
Feed postition can be it is interior plus, it is additional, interior additional.It is wherein interior plus refer to add microcrystalline cellulose before wet granulation, crystallite
Cellulose and rivastigmine-hydrogentartrate and lactose together wet granulation；It is additional to refer to after wet granular is dried together with lubricant
Add microcrystalline cellulose；Inside and outside to add as a part of microcrystalline cellulose and added before wet granulation, another part microcrystalline cellulose exists
Added after wet granular drying.
Embodiment
Further illustrate the application with embodiment below, further appreciate that it is a kind of for impurity 3-[（1S）-1-（Two
Methylamino）Ethyl] the stable rivastigmine-hydrogentartrate piece of phenol and preparation method thereof, but the application is not limited except as.
The tablet of following embodiment compacting, if not otherwise indicated, is suppressed, piece weight with the tablet press machine of same model
For 100mg, and by hardness control in the range of 40-60N.Fortified phenol impurity 3-[（1S）-1-（Dimethylamino）Second
Base] phenol refers both to 3-[（1S）-1-（Dimethylamino）Ethyl] phenol, structural formula is as follows：
。
The preparation of the 2mg specification rivastigmine-hydrogentartrate pieces of embodiment 1
Composition：
Preparation technology：
（1）Preprocessing raw material and auxiliary material：Rivastigmine-hydrogentartrate be crushed into 80 mesh sieves, lactose, microcrystalline cellulose, cross-linked carboxymethyl
Sodium cellulosate and magnesium stearate cross 60 mesh sieves respectively, standby；
（2）Softwood processed：Weigh the rivastigmine-hydrogentartrate of pretreated recipe quantity, lactose mixes in wet granulator
It is even；Appropriate purified water is added into wet granulator as wetting agent, stir to obtain softwood；
（3）Wet granulation：Softwood is passed through into 30 mesh sieve series wet granulars；
（4）Particle drying：It is 2.5% or so that the wet granular is dried to pellet moisture in 50-55 DEG C, and whole with 40 eye mesh screens
Grain；
（5）Tabletting：Microcrystalline cellulose, Ac-Di-Sol and magnesium stearate dosage are converted, tabletting after being well mixed.
The preparation of the 2.4mg specification rivastigmine-hydrogentartrate pieces of embodiment 2
Composition：
Preparation technology：
（1）Preprocessing raw material and auxiliary material：Rivastigmine-hydrogentartrate be crushed into 100 mesh sieves, lactose, microcrystalline cellulose and crosslinking carboxylic first
Base sodium cellulosate crosses 80 mesh sieves respectively, and magnesium stearate crosses 60 mesh sieves, standby；
（2）Softwood processed：The rivastigmine-hydrogentartrate, lactose, microcrystalline cellulose of pretreated recipe quantity are weighed in wet method system
It is well mixed in grain machine；Appropriate purified water is added into wet granulator as wetting agent, stir to obtain softwood；
（3）Wet granulation：Softwood is passed through into 16 mesh sieve series wet granulars；
（4）Particle drying：By the wet granular, 45-55 DEG C of drying to pellet moisture is 2% or so in heat-circulation oven, is used in combination
24 eye mesh screen whole grains；
（5）Tabletting：Ac-Di-Sol and magnesium stearate dosage are converted, tabletting after being well mixed.
The preparation of the 4.8mg specification rivastigmine-hydrogentartrate pieces of embodiment 3
Composition：
Preparation technology：
（1）Preprocessing raw material and auxiliary material：Rivastigmine-hydrogentartrate be crushed into 60 mesh sieves, microcrystalline cellulose and cross-linked carboxymethyl fiber
Plain sodium crosses 100 mesh sieves respectively, and sodium stearyl fumarate crosses 80 mesh sieves, standby；
（2）Softwood processed：The rivastigmine-hydrogentartrate of pretreated recipe quantity, interior plus microcrystalline cellulose are weighed in wet granulation
It is well mixed in machine；Appropriate 30% is added into wet granulator（Ethanol/water）As wetting agent, stir to obtain softwood；
（3）Wet granulation：Softwood is passed through into 10 mesh sieve series wet granulars；
（4）Particle drying：By the wet granular, 45-55 DEG C of drying to pellet moisture is 1.5% or so in fluid bed, and with 16
Eye mesh screen whole grain；
（5）Tabletting：Additional microcrystalline cellulose, Ac-Di-Sol and sodium stearyl fumarate dosage are converted, mixing is equal
Tabletting after even.
The preparation of the 4.8mg specification rivastigmine-hydrogentartrate pieces of embodiment 4
Composition：
Preparation technology：
（1）Preprocessing raw material and auxiliary material：Rivastigmine-hydrogentartrate be crushed into 60 mesh sieves, starch, microcrystalline cellulose and the poly- dimension of crosslinking
Ketone crosses 80 mesh sieves respectively, and magnesium stearate crosses 60 mesh sieves, standby；
（2）Softwood processed：The rivastigmine-hydrogentartrate, starch, microcrystalline cellulose of pretreated recipe quantity are weighed in wet method system
It is well mixed in grain machine；Ethanol in proper amount is added into wet granulator as wetting agent, stir to obtain softwood；
（3）Wet granulation：Softwood is passed through into 24 mesh sieve series wet granulars；
（4）Particle drying：By the wet granular, 45-55 DEG C of drying to pellet moisture is 1.5% or so in fluid bed, and with 24
Eye mesh screen whole grain；
（5）Tabletting：PVPP and magnesium stearate dosage are converted, tabletting after being well mixed.
The preparation of the 6mg specification rivastigmine-hydrogentartrate pieces of embodiment 5
Composition：
Preparation technology：
（1）Preprocessing raw material and auxiliary material：Rivastigmine-hydrogentartrate be crushed into 60 mesh sieves, mannitol, microcrystalline cellulose and crosslinking are poly-
Tie up ketone and cross 80 mesh sieves respectively, magnesium stearate crosses 60 mesh sieves, standby；
（2）Softwood processed：The rivastigmine-hydrogentartrate, mannitol, microcrystalline cellulose of pretreated recipe quantity are weighed in wet method
It is well mixed in granulator；Ethanol in proper amount is added into wet granulator as wetting agent, stir to obtain softwood；
（3）Wet granulation：Softwood is passed through into 24 mesh sieve series wet granulars；
（4）Particle drying：By the wet granular, 45-55 DEG C of drying to pellet moisture is 1.5% or so in fluid bed, and with 24
Eye mesh screen whole grain；
（5）Tabletting：PVPP and magnesium stearate dosage are converted, tabletting after being well mixed.
The preparation of the 8mg specification rivastigmine-hydrogentartrate pieces of embodiment 6
Composition：
Preparation technology：
（1）Preprocessing raw material and auxiliary material：Rivastigmine-hydrogentartrate be crushed into 120 mesh sieves, lactose, microcrystalline cellulose and crosslinking carboxylic first
Base sodium cellulosate crosses 100 mesh sieves respectively, and silica crosses 60 mesh sieves, standby；
（2）Softwood processed：The rivastigmine-hydrogentartrate, lactose, microcrystalline cellulose of pretreated recipe quantity are weighed in wet method system
It is well mixed in grain machine；50% is added into wet granulator（Ethanol/water）As wetting agent, stir to obtain softwood；
（3）Wet granulation：Softwood is passed through into 16 mesh sieve series wet granulars；
（4）Particle drying：By the wet granular, 45-55 DEG C of drying to pellet moisture is 1.5% or so in baking oven, and with 30 mesh
Screen cloth whole grain；
（5）Tabletting：Ac-Di-Sol and silica content are converted, tabletting after being well mixed.
The preparation of the 7.2mg specification rivastigmine-hydrogentartrate pieces of embodiment 7
Composition：
Preparation technology：
（1）Preprocessing raw material and auxiliary material：Rivastigmine-hydrogentartrate be crushed into 120 mesh sieves, starch, microcrystalline cellulose and low substitution hydroxyl
Propyl cellulose crosses 100 mesh sieves respectively, and magnesium stearate crosses 80 mesh sieves, standby；
（2）Softwood processed：The rivastigmine-hydrogentartrate, starch, microcrystalline cellulose of pretreated recipe quantity are weighed in wet method system
It is well mixed in grain machine；50% is added into wet granulator（Ethanol/water）As wetting agent, stir to obtain softwood；
（3）Wet granulation：Softwood is passed through into 30 mesh sieve series wet granulars；
（4）Particle drying：By the wet granular, 50-60 DEG C of drying to pellet moisture is 1.5% or so in fluid bed, and with 40
Eye mesh screen whole grain；
（5）Tabletting：Low-substituted hydroxypropyl cellulose and magnesium stearate dosage are converted, tabletting after being well mixed.
The preparation of the 3mg specification rivastigmine-hydrogentartrate pieces of embodiment 8
Composition：
Preparation technology：
（1）Preprocessing raw material and auxiliary material：Rivastigmine-hydrogentartrate be crushed into 100 mesh sieves, lactose, microcrystalline cellulose and carboxymethyl form sediment
Powder sodium crosses 60 mesh sieves respectively, and sodium stearyl fumarate crosses 60 mesh sieves, standby；
（2）Softwood processed：Weigh the rivastigmine-hydrogentartrate of pretreated recipe quantity, lactose mixes in wet granulator
It is even；Purified water is added into wet granulator as wetting agent, stir to obtain softwood；
（3）Wet granulation：Softwood is passed through into 30 mesh sieve series wet granulars；
（4）Particle drying：By the wet granular, 50-60 DEG C of drying to pellet moisture is 1.5% or so in fluid bed, and with 40
Eye mesh screen whole grain；
（5）Tabletting：Additional microcrystalline cellulose, sodium carboxymethyl starch and sodium stearyl fumarate dosage are converted, is pressed after well mixed
Piece.
The preparation of the 10mg specification rivastigmine-hydrogentartrate pieces of embodiment 9
Composition：
Preparation technology：
（1）Preprocessing raw material and auxiliary material：Rivastigmine-hydrogentartrate be crushed into 100 mesh sieves, lactose, microcrystalline cellulose PH301, carboxylic first
Base sodium starch and magnesium stearate cross 100 mesh sieves respectively, standby；
（2）Softwood processed：The rivastigmine-hydrogentartrate, lactose, microcrystalline cellulose PH301 of pretreated recipe quantity are weighed in wet
It is well mixed in method granulator；Purified water is added into wet granulator as wetting agent, stir to obtain softwood；
（3）Wet granulation：Softwood is passed through into 30 mesh sieve series wet granulars；
（4）Particle drying：By the wet granular, 50-60 DEG C of drying to pellet moisture is 3% or so in fluid bed, and with 30 mesh
Screen cloth whole grain；
（5）Tabletting：Sodium carboxymethyl starch and magnesium stearate dosage are converted, tabletting after being well mixed.
The preparation of the 7.2mg specification rivastigmine-hydrogentartrate pieces of embodiment 10
Composition：
Preparation technology：
（1）Preprocessing raw material and auxiliary material：Rivastigmine-hydrogentartrate be crushed into 100 mesh sieves, lactose, microcrystalline cellulose PH102, carboxylic first
Base sodium starch and magnesium stearate cross 80 mesh sieves respectively, standby；
（2）Softwood processed：The rivastigmine-hydrogentartrate, lactose, microcrystalline cellulose PH102 of pretreated recipe quantity are weighed in wet
It is well mixed in method granulator；Ethanol is added into wet granulator as wetting agent, stir to obtain softwood；
（3）Wet granulation：Softwood is passed through into 16 mesh sieve series wet granulars；
（4）Particle drying：By the wet granular, 50-60 DEG C of drying to pellet moisture is 2.5% or so in fluid bed, and with 24
Eye mesh screen whole grain；
（5）Tabletting：Sodium carboxymethyl starch and magnesium stearate dosage are converted, tabletting after being well mixed.
The preparation of the 2.4mg specification rivastigmine-hydrogentartrate pieces of embodiment 11
Composition：
Preparation technology：
（1）Preprocessing raw material and auxiliary material：Rivastigmine-hydrogentartrate be crushed into 100 mesh sieves, lactose, microcrystalline cellulose PH101 and friendship
Join sodium carboxymethylcellulose and cross 80 mesh sieves respectively, magnesium stearate crosses 60 mesh sieves, standby；
（2）Softwood processed：Weigh the rivastigmine-hydrogentartrate, lactose, interior plus microcrystalline cellulose PH101 of pretreated recipe quantity
It is well mixed in wet granulator；Appropriate purified water is added into wet granulator as wetting agent, stir to obtain softwood；
（3）Wet granulation：Softwood is passed through into 16 mesh sieve series wet granulars；
（4）Particle drying：By the wet granular, 45-55 DEG C of drying to pellet moisture is 2% or so in heat-circulation oven, is used in combination
24 eye mesh screen whole grains；
（5）Tabletting：Additional microcrystalline cellulose PH101, Ac-Di-Sol and magnesium stearate dosage are converted, is well mixed
Tabletting afterwards.
The preparation of the 2.4mg specification rivastigmine-hydrogentartrate pieces of comparative example 1
Composition：
Preparation technology：
（1）Preprocessing raw material and auxiliary material：Rivastigmine-hydrogentartrate be crushed into 100 mesh sieves, lactose, microcrystalline cellulose PH101 and friendship
Join sodium carboxymethylcellulose and cross 80 mesh sieves respectively, magnesium stearate crosses 60 mesh sieves, standby；
（2）Softwood processed：Weigh the rivastigmine-hydrogentartrate of pretreated recipe quantity, lactose mixes in wet granulator
It is even；Appropriate purified water is added into wet granulator as wetting agent, stir to obtain softwood；
（3）Wet granulation：Softwood is passed through into 16 mesh sieve series wet granulars；
（4）Particle drying：By the wet granular, 45-55 DEG C of drying to pellet moisture is 2% or so in heat-circulation oven, is used in combination
24 eye mesh screen whole grains；
（5）Tabletting：Additional microcrystalline cellulose PH101, Ac-Di-Sol and magnesium stearate dosage are converted, is well mixed
Tabletting afterwards.
The preparation of the 4.8mg specification rivastigmine-hydrogentartrate pieces of comparative example 2
Composition：
Preparation technology：
（1）Preprocessing raw material and auxiliary material：Rivastigmine-hydrogentartrate be crushed into 80 mesh sieves, lactose, microcrystalline cellulose, cross-linked carboxymethyl
Sodium cellulosate and magnesium stearate cross 60 mesh sieves respectively, standby；
（2）Softwood processed：The rivastigmine-hydrogentartrate, lactose, microcrystalline cellulose of pretreated recipe quantity are weighed in wet method system
It is well mixed in grain machine；Appropriate purified water is added into wet granulator as wetting agent, stir to obtain softwood；
（3）Wet granulation：Softwood is passed through into 30 mesh sieve series wet granulars；
（4）Particle drying：It is 2.5% or so that the wet granular is dried to pellet moisture in 50-55 DEG C, and whole with 40 eye mesh screens
Grain；
（5）Tabletting：Disintegrant and lubricant quantity are converted, tabletting after being well mixed.
Experimental result：Unless otherwise specified, impurity A is European Pharmacopoeia impurity A, refer both to fortified phenol impurity 3-[（1S）-
1-（Dimethylamino）Ethyl] phenol, structural formula is as follows：
。
1st, the sample is taken in intensity of illumination 5000lx ± 500lx, high temperature（40℃、60℃）, high humidity（RH92.5%,
RH75%）Under the conditions of place respectively 10 days, investigate the growth pattern of impurity A, it is as a result as follows：
。
From above-mentioned experimental result, rivastigmine-hydrogentartrate bulk drug and comparative example 1,2 are under illumination condition
Impurity A amplification is smaller, mainly in high temperature（40℃、60℃）, high humidity（RH92.5%, RH75%）Under the conditions of amplification it is larger, contain
Amount is more than 0.1%, and after being prepared into rivastigmine-hydrogentartrate piece according to the embodiment of the present application 1-11, the amplification of impurity A substantially drops
It is low, illustrate that the composition of the application and preparation method can suppress the generation of impurity A very well.
2nd, take the sample to be placed under the conditions of 25 ± 2 DEG C of temperature, relative humidity RH60 ± 5% to 12 months, investigate impurity
A growth pattern is as a result as follows：
。
From above-mentioned experimental result, rivastigmine-hydrogentartrate bulk drug and comparative example 1,2 are in 25 ± 2 DEG C of temperature, phase
The long-term conditions of humidity RH60 ± 5% are placed 12 months, impurity A amplification is larger, and content is more than 0.1%, according to the embodiment of the present application
After 1-11 is prepared into rivastigmine-hydrogentartrate piece, the amplification of impurity A substantially reduces, and illustrates composition and the preparation of the application
Method can suppress the generation of impurity A very well.
3rd, take the sample to be placed under the conditions of 40 ± 2 DEG C of temperature, relative humidity RH75 ± 5% to 6 months, investigate the increasing of impurity A
Long situation is as a result as follows：
。
From above-mentioned experimental result, rivastigmine-hydrogentartrate bulk drug and comparative example 1,2 are in temperature 40 ± 2
DEG C, the conditions of relative humidity RH75 ± 5% place 12 months after, impurity A amplification is larger, and content is implemented more than 0.1% according to the application
After example 1-11 is prepared into rivastigmine-hydrogentartrate piece, the amplification of impurity A substantially reduces, and illustrates the composition and system of the application
Preparation Method can suppress the generation of impurity A very well.
To sum up, after being prepared into rivastigmine-hydrogentartrate piece according to the embodiment of the present application 1-11, the amplification of impurity A substantially drops
It is low, and content is less than 0.1%, within the acceptable range, the composition and preparation method for illustrating the application can suppress very well
The generation of impurity A, improve the stability of rivastigmine-hydrogentartrate piece.
Although embodiments of the invention have been shown and described above, it is to be understood that above-described embodiment is example
Property, it is impossible to limitation of the present invention is interpreted as, one of ordinary skill in the art within the scope of the invention can be to above-mentioned
Embodiment is changed, changed, replacing and modification.
Claims (10)
1. for fortified phenol impurity 3-[（1S）-1-（Dimethylamino）Ethyl] the stable rivastigmine-hydrogentartrate of phenol
Piece, include the component of following parts by weight：
Rivastigmine-hydrogentartrate 2-10 parts, microcrystalline cellulose are not less than 55 parts, other fillers in addition to microcrystalline cellulose
0-41 parts, disintegrant 1-10 parts, lubricant 0.1-2 parts, wherein impurity 3-[（1S）-1-（Dimethylamino）Ethyl] phenol
Content is not higher than 0.1% (weight ratio), and impurity 3-[（1S）-1-（Dimethylamino）Ethyl] phenol structural formula it is as follows：
。
2. it is according to claim 1 for impurity 3-[（1S）-1-（Dimethylamino）Ethyl] the stable heavy wine of phenol
Stone acid Rivastigmine piece, described other fillers in addition to microcrystalline cellulose include mannitol, lactose, one kind in starch or
It is several, preferred lactose.
3. according to any claim in claim 1-2 for impurity 3-[（1S）-1-（Dimethylamino）Second
Base] the stable rivastigmine-hydrogentartrate piece of phenol, the disintegrant includes Ac-Di-Sol, CMS
One or more in sodium, low-substituted hydroxypropyl cellulose and PVPP, preferably Ac-Di-Sol.
4. according to any claim in claim 1-3 for impurity 3-[（1S）-1-（Dimethylamino）Second
Base] the stable rivastigmine-hydrogentartrate piece of phenol, the lubricant include magnesium stearate, sodium stearyl fumarate, magnesium stearate,
One or more in silica, preferably magnesium stearate.
5. according to any claim in claim 1-4 for impurity 3-[（1S）-1-（Dimethylamino）Second
Base] the stable rivastigmine-hydrogentartrate piece of phenol, the microcrystalline cellulose parts by weight are not less than 55 parts, such as 60 parts, example
Such as 65 parts, such as 70 parts, such as 75 parts, such as 80 parts, such as 85 parts, such as 90 parts.
6. according to any claim in claim 1-5 for impurity 3-[（1S）-1-（Dimethylamino）Second
Base] the stable rivastigmine-hydrogentartrate piece of phenol, the microcrystalline cellulose parts by weight are preferably not lower than 60 parts.
7. according to any claim in claim 1-6 for impurity 3-[（1S）-1-（Dimethylamino）Second
Base] the stable rivastigmine-hydrogentartrate piece of phenol, include the components of following parts by weight：Rivastigmine-hydrogentartrate 2.4-
7.2 parts, microcrystalline cellulose is not less than 60 parts, other fillers 0-35 parts in addition to microcrystalline cellulose, disintegrant 2-10 parts, moistens
Lubrication prescription 0.5-1.5 parts.
8. in claim 1-7 described in any claim for impurity 3-[（1S）-1-（Dimethylamino）Ethyl] benzene
The preparation method of the stable rivastigmine-hydrogentartrate piece of phenol, comprises the following steps：
（1）Rivastigmine-hydrogentartrate, filler, disintegrant, lubricant is taken to be pre-processed；
（2）Take after rivastigmine-hydrogentartrate, filler are sufficiently mixed uniformly after pretreatment, wetting agent is added, after stirring
Obtain softwood；
（3）Take softwood that wet granular is made by screen cloth；
（4）Wet granular is taken to be sufficiently mixed uniformly, obtain by obtaining dry particle, whole grain, additional disintegrant and lubricant after drying
Always mixed material；
（5）Material will always be mixed and carry out tabletting.
9. it is according to claim 8 for impurity 3-[（1S）-1-（Dimethylamino）Ethyl] the stable heavy wine of phenol
The preparation method of stone acid Rivastigmine piece, wherein step（1）
Pass through screen cloth including rivastigmine-hydrogentartrate is crushed, the sieve mesh number is 60-120 mesh；By filler, disintegration
Agent, lubricant sieving processing, the sieve mesh number is 60-100 mesh；Or step（3）It is by particle diameter including the wet granular
The screen cloth of 10-30 mesh is made；Or step（4）It is 1%-3% including the dry particle moisture, the dry particle whole grain
Particle diameter is 16-40 mesh afterwards.
10. according to any claim in claim 8-9 for impurity 3-[（1S）-1-（Dimethylamino）Second
Base] the stable rivastigmine-hydrogentartrate piece of phenol preparation method, the feed postition of the microcrystalline cellulose in tablets can
Be it is interior plus, it is additional, interior additional.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101204389A (en) * | 2006-12-19 | 2008-06-25 | 北京德众万全药物技术开发有限公司 | Iatric composite containing Rivastigmine and preparation method thereof |
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2017
- 2017-05-18 CN CN201710351303.1A patent/CN107334740A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101204389A (en) * | 2006-12-19 | 2008-06-25 | 北京德众万全药物技术开发有限公司 | Iatric composite containing Rivastigmine and preparation method thereof |
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