CN103211770B - A kind of Ailamode slow release multicomponent composition and preparation method thereof - Google Patents
A kind of Ailamode slow release multicomponent composition and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to pharmaceutical fields, are related to a kind of slow release multicomponent composition and preparation method thereof of Ailamode.More particularly to one kind using Ailamode as active constituent, using the medicament slow release multicomponent composite that matrix carrier material and release regulator are prepared as carrier, plasticizer is added when necessary, to achieve the purpose that reduce extrusion temperature, easyization extrusion process.The preparation method is that hot-melt extruded method, this method preparation process is simple, is easy to industrialized production, is not related to organic solvent.The slow release multicomponent composition is made of several or tens uniform particle sizes slow-releasing granules, highly-safe.
Description
Technical field
The invention belongs to pharmaceutical field, it is related to a kind of Ailamode slow release multicomponent composition and preparation method thereof.
Background technique
Rheumatoid arthritis (Rheumatoid arthritis, RA) is a kind of characterized by chronic erosive arthritis
Systemic autoimmune diseases, it is considered that the factors such as itself and heredity, environment, infection are closely related, and how above-mentioned pathogenic factors beats
The process of broken immune tolerance starting autoimmunity, it is still not fully aware of at present.The joint manifestations of rheumatoid arthritis have swollen joint
Bitterly, morning stiffness, lesion characteristic are synovitis and articular cartilage resulting from and destruction of bone, eventually lead to joint deformity；It closes
Section is outer to show as rheumatoid nodules, involves internal organ, nervous system and hemopoietic system etc..It is each that rheumatoid arthritis is distributed in the world
Ground, the illness rate in different crowd are 0.18%~1.07%, and morbidity has certain racial difference, total illness in China
Number is more than 5,000,000.Rheumatoid arthritis can all fall ill in each age, the peak age at 30~50 years old or so, general women
Morbidity is more than male.
Ailamode (Iguratimod, T-614) is the small-molecule drug for treating rheumatoid, and alternative inhibits COX-2
It generates, immunoglobulin, inflammatory cytokine is inhibited to generate to play anti-inflammatory and immunoregulation effect.Not with traditional NSAIDs
Together, T-614 will not inhibit cell Proliferation, and gastrointestinal side effect is small.Its chemical name is N- [3- (formamido) -4- oxygen -6-
Phenoxy group -4H-1- chromene -7- base]-Methanesulfonamide, the entitled N- [7- [(methanesulfonyl) amino]-of English
4-oxo-6-phenoxy-4H-1-benzopyran-3-yl]-formamide.Structural formula is as follows:
Ailamode
Ailamode molecular weight is 374.37, molecular formula C17H14N2O6S.Ailamode is weakly acidic, it is not soluble in water, sour and
Methanol, ethyl alcohol etc. are slightly soluble in acetonitrile and acetone there are commonly solvent, and about 241 DEG C of fusing point.Ailamode commercial preparation is equal at present
For ordinary preparation, need to take twice within one day.Existing clinical data shows that clinical efficacy, adverse reaction and the clinic of Ailamode make
Stability with dosage, usage and blood concentration is related, and the medicine is for needing the rheumatoid arthritis of Long-term taking medicine to suffer from
Person, therefore Ailamode is designed to have more longlasting release time, more stable blood concentration and be taken more easily slow
Release formulation can be improved curative effect of medication, reduces adverse reaction, improves the compliance of patient.
However, insoluble drug prepares sustained release preparation there is certain difficulty, drug solubility is low to be not meant to it
With slow release characteristic.On the contrary, being limited by solubility, this kind of drug cannot sufficiently dissolve in skeleton and depot carrier system
With diffuse out, ability and stable burst size without sustained release.
The patent for being related to Ailamode oral slow-releasing preparation at present has:
200610014448.4 " Iguratimod oral double-layer sustained-release preparation " on January 2nd, 2008 is open.The invention is related to
A kind of oral double-layer controlled release preparation, preparation are made of release layer and slow release layer, the drug quick release in release layer, are played rapidly
Effect；Ailamode in slow release layer gradually discharges, and maintains effective blood drug concentration.
200910028066.0 " Iguratimod osmotic pump controlled slow-release preparation " on October 28th, 2009 is open.The invention relates to
And with it is a kind of with osmotic pumps osmotic pressure be main drug release power osmotic pump type double-layer tablets.Said preparation is by double-deck core, semi-permeable membrane
It is formed with small delivery aperture, there is more longlasting Release Performance and more stable blood concentration compared with ordinary tablet, take one within one day
It is secondary.
Certain deficiency is individually present in the above method, and double-layer tablets preparation process is complex, and the factor for influencing release is more；It seeps
Pump is unstable in vivo thoroughly, and release hole is easy blocking in vivo, and has the shortcomings that time lag.
Summary of the invention
The object of the present invention is to provide a kind of slow release multicomponent composition containing Ailamode, in the slow release multicomponent composition
Ailamode, which can reach 12~24 hours, to be sustained, conducive to the clinical application of Ailamode, including the treatment effectively measured
Object is closed, there are ideal drug release characteristics.
It is a further object of the present invention to provide a kind of preparation method of slow release multicomponent composition, the preparation method can gram
The deficiencies in the prior art are taken, it is a kind of to be simplified without tabletting and coating steps, preparation process, matrix type sustained release can be prepared
The method of multicomponent composite.
To achieve the above object, the present invention takes following technical scheme:
A kind of slow release multicomponent composition contains the Ailamode and matrix type carrier material as active constituent.
In slow release multicomponent composition of the invention, the matrix carrier material is ethylene/vinyl acetate copolymer, gathers
Vinyl acetate esters, povidone, polylactic acid, lactic acid/co-glycolic acid, ethyl cellulose type, cellulose acetate class, hydroxypropyl
Base cellulose family, hydroxypropyl methylcellulose class, polycaprolactone, polyacrylic acid resin class, microcrystalline wax, calcium stearate or palm wax
One of or it is a variety of, preferably be selected from ethylene/vinyl acetate copolymer, lactic acid/co-glycolic acid, ethyl cellulose type,
One of hydroxypropyl methylcellulose class, polyacrylic acid resin class or calcium stearate are a variety of.
In slow release multicomponent composition of the invention, plasticizer can also be contained, the plasticizer be selected from polyethylene glycols,
Dibutyl sebacate, diethyl phthalate, dibutyl phthalate, triethyl citrate, tributyl citrate, three second
One of acid glyceride, propylene glycol, glycerine or methyl p-hydroxybenzoate are a variety of, preferably are selected from polyethylene glycols, the last of the ten Heavenly stems two
Dibutyl phthalate, one of triethyl citrate, glyceryl triacetate or methyl p-hydroxybenzoate or a variety of.
In slow release multicomponent composition of the invention, release regulator can also be contained, the release regulator is polyoxy
Vinyl, polyethylene glycols, poloxamer class, polyvinylpyrrolidone, polyvinylpyrrolidone/acetate ethylene copolymer, card
Wave nurse class, xanthan gum, chitosan, PEG6000/ caprolactam/vinyl acetate co-polymer or laurel acid polyethylene glycol
One of glyceride type is a variety of.
In slow release multicomponent composition of the invention, Ailamode and matrix carrier material, plasticizer and/or release are adjusted
Dosage form at mixed carrier weight ratio be 1:0.5~1:20, preferably 1:0.5,1:1,1:1.5,1:3.2,1:4,1:9 or 1:
19。
In slow release multicomponent composition of the invention, the mixed carrier middle skeleton carrier material, plasticizer, release are adjusted
The weight ratio of agent is 20~90:0~36:0~70.
It is a further object of the present invention to provide a kind of hot-melt extrusion process for preparing slow release multicomponent composition, by the Rameau that ends
Moral, carrier material, plasticizer and/or release regulator are uniformly mixed, at a high temperature of obtained mixture is in hot-melt extruded instrument
Softening or fusing, and the insoluble drug is scattered in high molecular material in hot procedure and is squeezed out.It will
Extrudate is cooling and reduces granularity, prepares slow release multicomponent composition.
Hot-melt extrusion process in the present invention, specifically:
(1) matrix type carrier material is uniformly mixed first with plasticizer, release regulator is then added and is uniformly mixed, shape
At mixed carrier.Mixed carrier is taken, is mixed with Ailamode, obtained mixture is known as physical mixture；According to release profiles
Adjust composition and each component ratio.
In above-mentioned mixed carrier, matrix carrier material parts by weight are 20~90 parts, and plasticizer parts by weight are 0~36
Part, release regulator parts by weight are 0~70 part of release regulator.In above-mentioned physical mixture, Ailamode and mixed carrier
Weight ratio is 1:0.5~1:20, preferably 1:0.5,1:1,1:1.5,1:3.2,1:4,1:9 or 1:19.
(2) temperature of each section of hot-melt extruded machine to head is set between 50 DEG C~180 DEG C, by physics after equalized temperature
Hot-melt extruded machine is added in mixture, and material is squeezed out by head die hole；
(3) after being cooled to room temperature extrudate, it is crushed to suitable particle size.
The particle of hot-melt extruded preparation can be directly prepared into granule, capsule etc. without being further processed or adding auxiliary material
Pharmaceutical preparation.
It the suitable example of multiple definition mentioned in description explained in detail below in this specification context and says
It is bright.
' slow release multicomponent composition ' it is necessary to be defined?
Term ' therapeutically effective amount ' or ' effective quantity ', which refer to, is enough to show it for the dosage of institute's subject benefit.Application
Actual amount, and application velocity and time process can depend on institute curer own situation or severity.
Term ' polyacrylic acid resin ' includes for example ....Preferably include Eudragit RS PO and Eudragit
RD100。
Term ' hydroxypropyl methylcellulose ' includes for example ....Preferably include HPMC K100M.
Term ' polyethylene glycol ' includes for example ....Preferably include PEG400 and PEG6000.
Term ' polyoxyethylene ' includes for example ....Preferably include PEO1000000 and PEO7000000.
Term ' carbomer ' includes for example ....Preferably include 974P.
Term ' poloxamer ' includes for example ....Preferably include 407.
Term ' Gelucire 44/14 ' includes for example ....Preferably include Gelucire44/14).
Term ' polyvinylpyrrolidone/acetate ethylene copolymer ' includes for example ....Preferably include PVP/VA64.
Detailed description of the invention
The tablets in vitro curve of Fig. 1 Examples 1 to 4
The tablets in vitro curve of Fig. 2 embodiment 5~8
The In-vitro release curves of Fig. 3 the Comparative Examples 1 to 5
Beneficial effects of the present invention
(1) Ailamode slow release multicomponent composition prepared by the present invention was sustained up to 12~24 hours, and release profiles are adjustable；
Process is applied widely, and especially suitable conventional method is cumbersome or the insoluble drug of releasing effect is not achieved.Difference between batch
It is different small, favorable reproducibility.
(2) the slow release multicomponent composition of Ailamode prepared by the present invention is by several or tens uniform particle sizes sustained releases
Grain composition, oral rear particle spread out, and local drug concentration is lower than sustained release tablets, eliminates local stimulation of the drug to gastrointestinal tract；
And individual particles fault during the preparation process or defect, which will not generate the drug release behavior of entire preparation, seriously affect, therefore
It is more safer than sustained release tablets.The composition releases the active pharmaceutical ingredient being embedded in high molecular material in a controlled fashion, can be
Internal slow release keeps relatively stable blood concentration.
(3) present invention prepare using hot-melt extruded method the sustained release preparation of Ailamode, and preparation process is opposite to permeate
Pump-type double-layer tablets are more simple to operation, short the time required to operating process, can continuous production, it is convenient and do not use organic solvent,
It is suitable for facile hydrolysis drug.Have the characteristics that improve producers' compliance, protection environment, is conducive to industrialization promotion.
Specific embodiment
The present invention is described further with reference to embodiments, it is noted that these embodiments are merely to illustrate this
It invents and does not have to limit the scope of the invention.In addition, under the premise of not departing from the present invention for those skilled in the art, being done
Some improvements and modifications also belong to protection scope of the present invention.
Embodiment 1
Use (spray-on process) (whether for common process, if not, it is necessary to be described in detail.) by the 4.75g plasticizer last of the ten Heavenly stems
Adipate is sprayed onto 10 top grade of 9.5g matrix carrier material ethyl cellulose, is plasticized to ethyl cellulose, then plus
Enter release regulator polyoxyethylene (PEO1000000) 33.25g mixing, mixed carrier is made.By Ailamode (source) 2.5g
It is uniformly mixed with mixed carrier and prepares physical mixture.Hot-melt extruded machine (model, producer) temperature is set at 50 DEG C, to temperature liter
Hot-melt extruded machine is added to setting value and after balancing by physical mixture in height, and material is squeezed out by head die hole；Extrudate is cooling
It is crushed after to room temperature and carries out extracorporeal releasing experiment.
Embodiment 2
By matrix carrier material ethylene/vinyl acetate copolymer 40.5g and release regulator xanthan gum 2.25g and Ka Bo
Nurse 974P2.25g is mixed, and mixed carrier is made.Ailamode 5g is uniformly mixed with mixed carrier and prepares physical mixture.If
Hot-melt extruded machine temperature is determined at 70 DEG C, and hot-melt extruded machine is added in physical mixture after temperature is increased to setting value and balances,
Material is squeezed out by head die hole；It is crushed after extrudate is cooled to room temperature and carries out extracorporeal releasing experiment.
Embodiment 3
By 10 top grade 21.6g of matrix carrier material ethyl cellulose and plasticizer polyethylene glycol (PEG400) 14.4g, release
Regulator CARBOPOL 974P 4g is mixed, and mixed carrier is made.Ailamode 10g is uniformly mixed with mixed carrier and prepares physics and mixes
Close object.Hot-melt extruded machine temperature is set at 90 DEG C, physical mixture is added after temperature is increased to setting value and balances and is heated
Extruder, material are squeezed out by head die hole；It is crushed after extrudate is cooled to room temperature and carries out extracorporeal releasing experiment.
Embodiment 4
By matrix carrier material polyacrylic acid resin (Eudragit RS PO) 19g and plasticizer methyl p-hydroxybenzoate
9.5g, release regulator poloxamer188 4.75g and xanthan gum 4.75g are mixed, and mixed carrier is made.By Ailamode 12g with
Mixed carrier is uniformly mixed and prepares physical mixture.Set hot-melt extruded machine temperature at 120 DEG C, to temperature be increased to setting value and
Hot-melt extruded machine is added in physical mixture after balance, material is squeezed out by head die hole；It is crushed after extrudate is cooled to room temperature
And carry out extracorporeal releasing experiment.
Embodiment 5
6g plasticizer triethyl citrate is sprayed by 18g matrix carrier material polyacrylic acid resin using spray-on process
In (Eudragit RD100), Eudragit RD100 is plasticized, release regulator PEG6000/ vinyl is then added
Caprolactam/vinyl acetate co-polymer (Soluplus) 3g and chitosan 3g are mixed, and mixed carrier is made.By Ailamode
20g is uniformly mixed with mixed carrier and prepares physical mixture.Hot-melt extruded machine temperature is set at 120 DEG C, is increased to and sets to temperature
Hot-melt extruded machine is added in physical mixture after definite value and balance, material is squeezed out by head die hole；Extrudate is cooled to room temperature
After crush and carry out extracorporeal releasing experiment.
Embodiment 6
3g plasticizer glyceryl triacetate is sprayed onto 12g matrix carrier material calcium stearate using spray-on process, to tristearin
Sour calcium is plasticized, and it is mixed that release regulator polyvinylpyrrolidone/acetate ethylene copolymer (PVP/VA64) 15g is then added
It is even, mixed carrier is made.Ailamode 20g and mixed carrier are uniformly mixed and prepare physical mixture.Set hot-melt extruded machine
At 150 DEG C hot-melt extruded machine is added after temperature is increased to setting value and balances, material is by head die in physical mixture by temperature
Hole squeezes out；It is crushed after extrudate is cooled to room temperature and carries out extracorporeal releasing experiment.
Embodiment 7
By matrix carrier material lactic acid/co-glycolic acid (PLGA) 20g and release regulator laurel acid polyethylene glycol
Glyceride (Gelucire44/14) 2.5g and polyoxyethylene (PEO7000000) 2.5g is mixed, and mixed carrier is made.To end Rameau
Moral 25g and mixed carrier, which are uniformly mixed, prepares physical mixture.Hot-melt extruded machine temperature is set at 160 DEG C, is increased to temperature
Hot-melt extruded machine is added in physical mixture after setting value and balance, material is squeezed out by head die hole；Extrudate is cooled to room
It is crushed after temperature and carries out extracorporeal releasing experiment.
Embodiment 8
By matrix carrier material hydroxypropyl methylcellulose (HPMC K100M) 12.25g and plasticizer polyethylene glycol (PEG6000)
5.25g is mixed, and mixed carrier is made.Ailamode 32.5g and mixed carrier are uniformly mixed and prepare physical mixture.Setting heat
Extruder temperature is melted at 180 DEG C, and hot-melt extruded machine, material is added in physical mixture after temperature is increased to setting value and balances
It is squeezed out by head die hole；It is crushed after extrudate is cooled to room temperature and carries out extracorporeal releasing experiment.
Comparative example 1: bulk pharmaceutical chemicals
Extracorporeal releasing experiment is directly carried out using Ailamode bulk pharmaceutical chemicals 50mg.
Comparative example 2: physical mixture
Physical mixture is prepared according to embodiment 1, the physical mixture for being equivalent to bulk pharmaceutical chemicals 50mg is taken directly to carry out in vitro
Release experiment.
Comparative example 3: hydrogel matrix tablet (K4M containing 20%HPMC)
Composition
Technique: Ailamode is weighed respectively, Chinese name is preferred in MCC(, mark concrete model) and lactose, it is added viscous
Mixture softwood crosses the granulation of 30 meshes, and dry 2h at 60 DEG C makes moisture < 3%, whole grain, and the HPMC K4M that corresponding amount is added is blended,
Tabletting after addition magnesium stearate and superfine silica gel powder mix.
Comparative example 4: hydrogel matrix tablet (K4M containing 16%HPMC)
Composition
Technique: weighing Ailamode, MCC and lactose respectively, and adhesive softwood is added, and crosses 30 meshes and pelletizes, at 60 DEG C
Dry 2h makes moisture < 3%, whole grain, and the HPMC K4M that corresponding amount is added is blended, and presses after magnesium stearate and superfine silica gel powder mixing is added
Piece.
Comparative example 5: insoluble matrix (top grade containing 40%EC10)
Composition
Technique: Ailamode, lactose, carbomer and EC(ethyl cellulose are weighed respectively?), it is mixed using equivalent gradually-increased
It is even, dehydrated alcohol softwood is added, crosses the granulation of 30 meshes, the magnesium stearate of corresponding amount and micro- is added in dry 2h, whole grain at 60 DEG C
Tabletting after powder silica gel mixes.
The measurement of release
Example and each oral dose (content of dispersion 50mg) of comparative example are used as sample respectively, according to Chinese Pharmacopoeia
2010 editions two the second methods of annex XC, using pH7.8 phosphate buffer 1 000ml as dissolution medium, revolving speed 75rpm divides
Solution 6ml was not taken at 1,2,4,6,8,12,24 hour and supplemented mutually synthermal, same volume dissolution medium, release liquid simultaneously
It is centrifuged, takes supernatant according to spectrophotometry, absorbance is measured at 345nm wavelength, calculate drug Cumulative release amount.
Invention effect one: the slow releasing function of slow release multicomponent composition
Fig. 1 and 2's the result shows that: the rate of release of the slow release multicomponent composition of each embodiment preparation is significantly slower than raw material
Medicine, up to 12~24 hours sustained releases.
Invention effect two: the preparation method and its simple, it is few to be related to processing step, reduces pollution, saves energy consumption, behaviour
Make, control and use simplicity, it is easy to accomplish industrialized production.
Claims (2)
1. a kind of Ailamode slow release multicomponent composition, which is characterized in that the slow release multicomponent composition contains as active constituent
Ailamode, matrix type carrier material, plasticizer and release regulator, the matrix type carrier material be selected from ethylene/acetic acid
Vinyl ester copolymers, lactic acid/co-glycolic acid, ethyl cellulose, hydroxypropyl methylcellulose, polyacrylic acid resin or stearic acid
One of calcium is a variety of；The plasticizer is selected from Macrogol 6000, polyethylene glycol 400, dibutyl sebacate, citric acid three
One of ethyl ester, glyceryl triacetate or methyl p-hydroxybenzoate are a variety of；The release regulator is selected from polyoxyethylene
PE01000000, polyoxyethylene PE07000000, poloxamer188, CARBOPOL 974P, xanthan gum, chitosan, PEG6000/ second
Alkenyl caprolactam/one of vinyl acetate co-polymer or Gelucire 44/14 or a variety of；Ailamode with
The weight ratio for the mixed carrier that matrix carrier material, plasticizer and release regulator are formed is 1:0.5,1:1,1:1.5,1:3.2,
1:4,1:9 or 1:19；The weight ratio of the mixed carrier middle skeleton carrier material, plasticizer and release regulator is 20~90:0
~36:0~70；
The slow release multicomponent composition is prepared using torching mark, comprising the following steps:
(1) matrix type carrier material, plasticizer and release regulator are uniformly mixed, are prepared into mixed carrier, then draw Chinese mugwort
Mo De is uniformly mixed with mixed carrier, obtains physical mixture；
(2) temperature for setting hot-melt extruded machine, is added hot-melt extruded machine for physical mixture after balance, and material is squeezed by head die hole
Out；
(3) extrudate is cooled to room temperature, is crushed to get the Ailamode slow release multicomponent composition.
2. composition as described in claim 1, which is characterized in that the temperature of hot-melt extruded machine described in step (2) is 50 DEG C
~180 DEG C.
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| CN106806353B (en) * | 2015-12-02 | 2021-04-27 | 江苏先声药业有限公司 | Iguratimod sustained-release capsule and preparation method thereof |
| CN106619531A (en) * | 2016-10-02 | 2017-05-10 | 上海奥科达生物医药科技有限公司 | Preparation method of stable oral slow-release suspension |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101375834A (en) * | 2007-09-02 | 2009-03-04 | 杨喜鸿 | Solid dispersion of Ailamode and preparation method thereof and medicament application |
| CN101885717A (en) * | 2005-10-09 | 2010-11-17 | 天津药物研究院 | Iguratimod crystal habit and composition thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101885717A (en) * | 2005-10-09 | 2010-11-17 | 天津药物研究院 | Iguratimod crystal habit and composition thereof |
| CN101375834A (en) * | 2007-09-02 | 2009-03-04 | 杨喜鸿 | Solid dispersion of Ailamode and preparation method thereof and medicament application |
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| GR01 | Patent grant |