CN103211770A - Igutimod slow release multielement composition and preparation method thereof - Google Patents
Igutimod slow release multielement composition and preparation method thereof Download PDFInfo
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- CN103211770A CN103211770A CN201310124889XA CN201310124889A CN103211770A CN 103211770 A CN103211770 A CN 103211770A CN 201310124889X A CN201310124889X A CN 201310124889XA CN 201310124889 A CN201310124889 A CN 201310124889A CN 103211770 A CN103211770 A CN 103211770A
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Abstract
The invention belongs to the pharmaceutical field, relates to an igutimod slow release multielement composition and a preparation method thereof, and in particular relates to a medical slow release multielement composition prepared by using igutimod as the active component and a framework carrier material and a release adjustor as a carrier. A plasticizer is added if necessary to reduce the extruding temperature and simplify the extruding process. The preparation method is a thermal melting extruding method which is simple in process and easy for industrial production, and is not involved in organic solvents. The slow release multielement composition consists of severe of dozens of slow release particles which are uniform in grain size, so that the composition is high in safety.
Description
Technical field
The invention belongs to pharmaceutical field, relate to a kind of Ailamode slow release multicomponent composition and method of making the same.
Background technology
Rheumatoid arthritis (Rheumatoid arthritis, RA) be a kind of general autoimmune disease that is feature with chronic aggressivity arthritis, it is generally acknowledged that it is closely related with factors such as heredity, environment, infection, how above-mentioned pathogenic factors is broken immunologic tolerance and is started autoimmune process, still not fully aware of at present.The performance of the joint of rheumatoid arthritis has arthralgia, morning deadlock, and lesion characteristic is synovitis and articular cartilage that causes thus and bone destruction, finally causes joint deformity; Show as rheumatoid nodules outside the joint, involve internal organs, nervous system and hemopoietic system etc.Rheumatoid arthritis is distributed in all over the world, and the prevalence in different crowd is 0.18%～1.07%, and its morbidity has certain race difference, surpasses 5,000,000 at total number of patients of China.Rheumatoid arthritis all can be fallen ill in each age, and the peak age, general women's morbidity was more than the male about 30～50 years old.
(Iguratimod is to treat rheumatoid small-molecule drug T-614) to Ailamode, and the alternative COX-2 of inhibition generates, thereby suppresses immunoglobulin, inflammatory cytokine generation performance antiinflammatory and immunoregulation effect.Different with traditional NSAIDs, T-614 can not suppress cell proliferation, and gastrointestinal side effect is little.Its chemical name is N-[3-(formamido)-4-oxygen-6-phenoxy group-4H-1-.alpha.-5:6-benzopyran-7-yl]-amsacrine, English N-[7-[(methanesulfonyl by name) amino]-4-oxo-6-phenoxy-4H-1-benzopyran-3-yl]-formamide.Structural formula is as follows:
The Ailamode molecular weight is 374.37, molecular formula C
17H
14N
2O
6S.Ailamode is faintly acid, and the organic solvent that water insoluble, acid and methanol, ethanol etc. are commonly used is slightly soluble in acetonitrile and acetone, about 241 ℃ of fusing point.The Ailamode commercial preparation is ordinary preparation at present, need take twice in one day.Existing clinical data shows that the clinical efficacy of Ailamode, untoward reaction are relevant with the stability of clinical using dosage, usage and blood drug level, and this medicine is used for the patient with rheumatoid arthritis that need take medicine for a long time, therefore Ailamode is designed to have more persistent release time, more stable blood drug level and take slow releasing preparation more easily, can improve curative effect of medication, reduce untoward reaction, improve patient's compliance.
Yet insoluble drug prepares slow releasing preparation and exists certain difficulty, and drug solubility is low and do not mean that it has slow release characteristic.On the contrary, be subjected to the restriction of dissolubility, this class medicine can not fully dissolve in skeleton and depot carrier system and diffuse out, and does not have lasting ability that discharges and stable burst size.
The patent that relates to the Ailamode oral slow-releasing preparation at present has:
200610014448.4 " Iguratimod oral double-layer sustained-release preparation " on January 2nd, 2008 is open.This invention relates to a kind of oral double-layer controlled release preparation, and preparation is made up of release layer and slow release layer, and the medicine rapid release in the release layer plays a role rapidly; Ailamode in the slow release layer discharges gradually, keeps effective blood drug concentration.
200910028066.0 " Iguratimod osmotic pump controlled slow-release preparation " on October 28th, 2009 is open.This invention relate to a kind of be the osmotic pump type double-layer tablet of main release power with the osmotic pumps osmotic pressure.Said preparation is made up of double-deck label, semipermeable membrane and small delivery aperture, compares with ordinary tablet to have more durable release performance and more stable blood drug level, takes once in one day.
There is certain deficiency separately in said method, and double-layer tablet preparation technology is comparatively complicated, and the factor that influence discharges is many; Osmotic pumps is unstable in vivo, and drug release hole is stopped up in vivo easily, and the shortcoming of time lag is arranged.
Summary of the invention
The purpose of this invention is to provide a kind of slow release multicomponent compositions that contains Ailamode, Ailamode can reach 12～24 hours slow release in this slow release multicomponent compositions, be beneficial to the clinical practice of Ailamode, the treatment chemical compound comprising effective dose has ideal drug release characteristics.
Another object of the present invention provides a kind of this slow release multicomponent preparation of compositions method, this preparation method can overcome the deficiencies in the prior art, be that a kind of tabletting and coating steps, preparation technology of not containing simplified, can prepare matrix type slow release multicomponent method for compositions.
For achieving the above object, the present invention takes following technical scheme:
A kind of slow release multicomponent compositions contains Ailamode and matrix type carrier material as active component.
In slow release multicomponent compositions of the present invention, described skeleton carrier material is an ethylene/vinyl acetate copolymer, the polyvinyl acetate esters, polyvidone, polylactic acid, lactic acid/co-glycolic acid, the ethyl cellulose class, the cellulose acetate class, the hydroxypropyl cellulose class, the hypromellose class, polycaprolactone, polyacrylic acid resin class, microcrystalline wax, in calcium stearate or the palm wax one or more are preferably from ethylene/vinyl acetate copolymer, lactic acid/co-glycolic acid, the ethyl cellulose class, the hypromellose class, in polyacrylic acid resin class or the calcium stearate one or more.
In slow release multicomponent compositions of the present invention, can also contain plasticizer, described plasticizer is selected from one or more in polyethylene glycols, dibutyl sebacate, diethyl phthalate, dibutyl phthalate, triethyl citrate, tributyl citrate, glyceryl triacetate, propylene glycol, glycerol or the methyl parahydroxybenzoate, preferably from polyethylene glycols, dibutyl sebacate,, in triethyl citrate, glyceryl triacetate or the methyl parahydroxybenzoate one or more.
In slow release multicomponent compositions of the present invention, can also contain release regulator, described release regulator is one or more of polyoxyethylene, polyethylene glycols, poloxamer class, polyvinylpyrrolidone, polyvinylpyrrolidone/acetate ethylene copolymer, carbomer class, xanthan gum, chitosan, PEG6000/ caprolactam/vinyl acetate co-polymer or lauric acid polyethyleneglycol glyceride apoplexy due to endogenous wind.
In slow release multicomponent compositions of the present invention, the weight ratio of the mixed carrier that Ailamode and skeleton carrier material, plasticizer and/or release regulator form is 1:0.5～1:20, is preferably 1:0.5,1:1,1:1.5,1:3.2,1:4,1:9 or 1:19.
In slow release multicomponent compositions of the present invention, the weight ratio of skeleton carrier material, plasticizer, release regulator is 20～90:0～36:0～70 in the described mixed carrier.
Another object of the present invention provides a kind of hot melt expressing technique for preparing the slow release multicomponent compositions, with Ailamode, carrier material, plasticizer and/or release regulator mix homogeneously, the mixture that obtains is extruded softening or fusing under the high temperature in the instrument at hot melt, and makes described insoluble drug be scattered in the macromolecular material in hot procedure and extrude.With extrudate cooling and reduce granularity, preparation slow release multicomponent compositions.
Hot melt expressing technique among the present invention is specially:
(1) at first with matrix type carrier material and plasticizer mix homogeneously, adds the release regulator mix homogeneously then, form mixed carrier.Get mixed carrier, with the Ailamode mixing, the mixture that obtains is called physical mixture; Form and each component ratio according to release profiles adjustment prescription.
In the above-mentioned mixed carrier, skeleton carrier material weight umber is 20～90 parts, and the plasticizer parts by weight are 0～36 part, and the release regulator parts by weight are 0～70 part of release regulator.In the above-mentioned physical mixture, Ailamode and mixed carrier weight ratio are 1:0.5～1:20, are preferably 1:0.5,1:1,1:1.5,1:3.2,1:4,1:9 or 1:19.
(2) set each section of hot melt extruder to the temperature of head between 50 ℃～180 ℃, after the hygral equilibrium physical mixture is added the hot melt extruder, material is extruded by the head nib;
(3) extrudate is cooled to room temperature after, be crushed to suitable particle size.
The granule that hot melt is extruded preparation need not further to handle or add adjuvant, can directly make pharmaceutical preparatioies such as granule, capsule.
Below will explain the suitable example and the explanation of a plurality of definition mentioned in the description of this context in detail.
Be ' slow release multicomponent compositions ' necessary to define?
Term ' treatment effective dose ' or ' effective dose ' are meant and are enough to show its dosage for institute's subject benefit.The actual amount of using, and the speed of using and time course can depend on the s own situation or the order of severity of institute's therapist.
Term ' polyacrylic acid resin ' for example comprises ...Preferably include Eudragit RS PO and Eudragit RD100.
Term ' hypromellose ' for example comprises ...Preferably include HPMC K100M.
Term ' Polyethylene Glycol ' for example comprises ...Preferably include PEG400 and PEG6000.
Term ' polyoxyethylene ' for example comprises ...Preferably include PEO1000000 and PEO7000000.
Term ' carbomer ' for example comprises ...Preferably include 974P.
Term ' poloxamer ' for example comprises ...Preferably include 407.
Term ' lauric acid polyethyleneglycol glyceride ' for example comprises ...Preferably include Gelucire44/14).
Term ' polyvinylpyrrolidone/acetate ethylene copolymer ' for example comprises ...Preferably include PVP/VA64.
Description of drawings
The external release curve of Fig. 1 embodiment 1～4
The external release curve of Fig. 2 embodiment 5～8
The release in vitro curve of Fig. 3 comparative example 1～5
Beneficial effect of the present invention
(1) the Ailamode slow release multicomponent compositions of the present invention's preparation can reach 12～24 hours slow release, and release profiles is adjustable; Process is applied widely, especially is fit to loaded down with trivial details or do not reach the insoluble drug of releasing effect with conventional method.Differences between batches are little, favorable reproducibility.
(2) the slow release multicomponent compositions of the Ailamode of the present invention's preparation is made up of several or tens uniform slow-releasing granules of particle diameter, and oral back Dispersion of Particles comes, and local drug concentration is lower than slow releasing tablet, eliminates medicine to the gastrointestinal local excitation; And error or the defective of individual particles in preparation process can not have a strong impact on the drug release behavior generation of whole preparation, and be therefore safer than slow releasing tablet.Said composition is disengaged the active constituents of medicine that is embedded in the macromolecular material in the mode of control, can slowly discharge in vivo, keeps relative stable blood concentration.
(3) the present invention adopts the hot melt extrusion method to be prepared the slow releasing preparation of Ailamode, preparation technology is relative, and the osmotic pump type double-layer tablet is more simple to operation, and the operating process required time is short, but continuous production, convenient and not with an organic solvent, be suitable for the facile hydrolysis medicine.Have the advantages that to improve producers' compliance, protection environment, be beneficial to industrialization promotion.
The specific embodiment
The present invention is described further below in conjunction with embodiment, should be pointed out that these embodiment only are used to the present invention is described and need not limit the scope of the invention.In addition, for those skilled in the art under the premise of not departing from the present invention, the some improvement done and modification also belong to protection scope of the present invention.
Embodiment 1
Employing (nebulization) (whether be common process, if not, be necessary to describe in detail.) the 4.75g Dibutyl Sebacate is sprayed onto in 9.5g skeleton carrier material ethyl cellulose 10 top grades, ethyl cellulose is plastified, add release regulator polyoxyethylene (PEO1000000) 33.25g mixing then, make mixed carrier.Ailamode (source) 2.5g and mixed carrier mix homogeneously are prepared physical mixture.Set hot melt extruder (model, producer) temperature at 50 ℃, treat after temperature is elevated to setting value and balance physical mixture to be added the hot melt extruder, material is extruded by the head nib; Extrudate is cooled to pulverizes after the room temperature and carry out extracorporeal releasing experiment.
Embodiment 2
With skeleton carrier material ethylene/vinyl acetate copolymer 40.5g and release regulator xanthan gum 2.25g and carbomer 974P2.25g mixing, make mixed carrier.Ailamode 5g and mixed carrier mix homogeneously are prepared physical mixture.Set the hot melt extruder temperature at 70 ℃, treat after temperature is elevated to setting value and balance physical mixture to be added the hot melt extruder, material is extruded by the head nib; Extrudate is cooled to pulverizes after the room temperature and carry out extracorporeal releasing experiment.
Embodiment 3
With skeleton carrier material ethyl cellulose 10 top grade 21.6g and plasticizer Polyethylene Glycol (PEG400) 14.4g, release regulator carbomer 974P4g mixing, make mixed carrier.Ailamode 10g and mixed carrier mix homogeneously are prepared physical mixture.Set the hot melt extruder temperature at 90 ℃, treat after temperature is elevated to setting value and balance physical mixture to be added the hot melt extruder, material is extruded by the head nib; Extrudate is cooled to pulverizes after the room temperature and carry out extracorporeal releasing experiment.
With skeleton carrier material polyacrylic acid resin (Eudragit RS PO) 19g and plasticizer methyl parahydroxybenzoate 9.5g, release regulator poloxamer 4074.75g and xanthan gum 4.75g mixing, make mixed carrier.Ailamode 12g and mixed carrier mix homogeneously are prepared physical mixture.Set the hot melt extruder temperature at 120 ℃, treat after temperature is elevated to setting value and balance physical mixture to be added the hot melt extruder, material is extruded by the head nib; Extrudate is cooled to pulverizes after the room temperature and carry out extracorporeal releasing experiment.
Embodiment 5
Adopt nebulization that 6g plasticizer triethyl citrate is sprayed onto in the 18g skeleton carrier material polyacrylic acid resin (Eudragit RD100), Eudragit RD100 is plastified, add release regulator PEG6000/ caprolactam/vinyl acetate co-polymer (Soluplus) 3g and chitosan 3g mixing then, make mixed carrier.Ailamode 20g and mixed carrier mix homogeneously are prepared physical mixture.Set the hot melt extruder temperature at 120 ℃, treat after temperature is elevated to setting value and balance physical mixture to be added the hot melt extruder, material is extruded by the head nib; Extrudate is cooled to pulverizes after the room temperature and carry out extracorporeal releasing experiment.
Embodiment 6
Adopt nebulization that 3g plasticizer glyceryl triacetate is sprayed onto in the 12g skeleton carrier material calcium stearate, calcium stearate is plastified, add release regulator polyvinylpyrrolidone/acetate ethylene copolymer (PVP/VA64) 15g mixing then, make mixed carrier.Ailamode 20g and mixed carrier mix homogeneously are prepared physical mixture.Set the hot melt extruder temperature at 150 ℃, treat after temperature is elevated to setting value and balance physical mixture to be added the hot melt extruder, material is extruded by the head nib; Extrudate is cooled to pulverizes after the room temperature and carry out extracorporeal releasing experiment.
Embodiment 7
With skeleton carrier material lactic acid/co-glycolic acid (PLGA) 20g and release regulator lauric acid polyethyleneglycol glyceride (Gelucire44/14) 2.5g and polyoxyethylene (PEO7000000) 2.5g mixing, make mixed carrier.Ailamode 25g and mixed carrier mix homogeneously are prepared physical mixture.Set the hot melt extruder temperature at 160 ℃, treat after temperature is elevated to setting value and balance physical mixture to be added the hot melt extruder, material is extruded by the head nib; Extrudate is cooled to pulverizes after the room temperature and carry out extracorporeal releasing experiment.
With skeleton carrier material hypromellose (HPMC K100M) 12.25g and plasticizer Polyethylene Glycol (PEG6000) 5.25g mixing, make mixed carrier.Ailamode 32.5g and mixed carrier mix homogeneously are prepared physical mixture.Set the hot melt extruder temperature at 180 ℃, treat after temperature is elevated to setting value and balance physical mixture to be added the hot melt extruder, material is extruded by the head nib; Extrudate is cooled to pulverizes after the room temperature and carry out extracorporeal releasing experiment.
Comparative example 1: crude drug
Use Ailamode crude drug 50mg directly to carry out extracorporeal releasing experiment.
Comparative example 2: physical mixture
According to embodiment 1 preparation physical mixture, get the physical mixture that is equivalent to crude drug 50mg and directly carry out extracorporeal releasing experiment.
Comparative example 3: hydrogel matrix tablet (containing 20%HPMC K4M)
Prescription is formed
Technology: take by weighing Ailamode, MCC(respectively and preferably use Chinese full name, mark concrete model) and lactose, add binding agent system soft material, crossing 30 mesh sieves granulates, dry 2h under 60 ℃ makes moisture＜3%, granulate, the HPMC K4M blend that adds respective amount, tabletting behind adding magnesium stearate and the micropowder silica gel mixing.
Comparative example 4: hydrogel matrix tablet (containing 16%HPMC K4M)
Prescription is formed
Technology: take by weighing Ailamode, MCC and lactose respectively, add binding agent system soft material, cross 30 mesh sieves and granulate, 60 ℃ of dry 2h down make moisture＜3%, and granulate adds the HPMC K4M blend of respective amount, tabletting behind adding magnesium stearate and the micropowder silica gel mixing.
Comparative example 5: insoluble matrix tablet (containing the 40%EC10 top grade)
Prescription is formed
Technology: take by weighing Ailamode, lactose, carbomer and EC(ethyl cellulose respectively?), adopt the equivalent method mixing that progressively increases, add dehydrated alcohol system soft material, crossing 30 mesh sieves granulates, dry 2h under 60 ℃, granulate, tabletting behind the magnesium stearate of adding respective amount and the micropowder silica gel mixing.
The mensuration of release
Get each oral dose (content of dispersion is 50mg) of embodiment and comparative example respectively as sample, according to 2010 editions two appendix XC second methods of Chinese Pharmacopoeia, adopt pH7.8 phosphate buffer 1 000ml as release medium, rotating speed is 75rpm, get solution 6ml respectively at 1,2,4,6,8,12,24 hour and replenish the dissolution medium of uniform temp, equal volume simultaneously, discharge liquid through centrifugal, get supernatant according to spectrophotography, measure absorbance at 345nm wavelength place, calculate medicine accumulative total burst size.
Invention effect one: the slow releasing function of slow release multicomponent compositions
The result of Fig. 1 and 2 shows: the rate of release of the slow release multicomponent compositions of each embodiment preparation all significantly is slower than crude drug, can reach 12～24 hours and continue to discharge.
Invention effect two: this preparation method and simple, it is few to relate to processing step, has reduced pollution, has saved energy consumption, and operation, control and easy to use are easy to realize industrialized great production.
Claims (9)
1. an Ailamode slow release multicomponent compositions is characterized in that, this slow release multicomponent compositions contains as the Ailamode of active component and matrix type carrier material.
2. slow release multicomponent compositions as claimed in claim 1, it is characterized in that, described matrix type carrier material is selected from ethylene/vinyl acetate copolymer, the polyvinyl acetate esters, polyvidone, polylactic acid, lactic acid/co-glycolic acid, the ethyl cellulose class, the cellulose acetate class, the hydroxypropyl cellulose class, the hypromellose class, polycaprolactone, polyacrylic acid resin class, microcrystalline wax, in calcium stearate or the palm wax one or more are preferably from ethylene/vinyl acetate copolymer, lactic acid/co-glycolic acid, the ethyl cellulose class, the hypromellose class, in polyacrylic acid resin class or the calcium stearate one or more.
3. slow release multicomponent compositions as claimed in claim 1, it is characterized in that, this slow release multicomponent compositions also contains plasticizer, described plasticizer is selected from one or more in polyethylene glycols, dibutyl sebacate, diethyl phthalate, dibutyl phthalate, triethyl citrate, tributyl citrate, glyceryl triacetate, propylene glycol, glycerol, the methyl parahydroxybenzoate, preferably from polyethylene glycols, dibutyl sebacate,, in triethyl citrate, glyceryl triacetate or the methyl parahydroxybenzoate one or more.
4. slow release multicomponent compositions as claimed in claim 1, it is characterized in that, this slow release multicomponent compositions also contains release regulator, and described release regulator is selected from one or more of polyoxyethylene, polyethylene glycols, poloxamer class, polyvinylpyrrolidone/acetate ethylene copolymer, carbomer class, xanthan gum, chitosan, PEG6000/ caprolactam/vinyl acetate co-polymer or lauric acid polyethyleneglycol glyceride apoplexy due to endogenous wind.
5. as each described slow release multicomponent compositions among the claim 1-4, it is characterized in that the weight ratio of the mixed carrier that Ailamode and skeleton carrier material, plasticizer and/or release regulator form in this slow release multicomponent compositions is 1:0.5～1:20.
6. as each described slow release multicomponent compositions among the claim 1-4, it is characterized in that the weight ratio of the mixed carrier that Ailamode and skeleton carrier material, plasticizer and/or release regulator form in this slow release multicomponent compositions is 1:0.5,1:1,1:1.5,1:3.2,1:4,1:9 or 1:19.
7. as each described slow release multicomponent compositions among the claim 1-4, it is characterized in that the weight ratio of skeleton carrier material, plasticizer and release regulator is 20～90:0～36:0～70 in the described mixed carrier.
8. a slow release multicomponent preparation of compositions method is characterized in that, this slow release multicomponent compositions adopts the preparation of hot melt extruding technology, may further comprise the steps:
(1) with matrix type carrier material, plasticizer and/or release regulator mix homogeneously, is prepared into mixed carrier, with Ailamode and mixed carrier mix homogeneously, obtains physical mixture then;
(2) temperature of setting hot melt extruder adds the hot melt extruder with physical mixture after the balance, and material is extruded by the head nib;
(3) extrudate is cooled to room temperature, pulverizes, promptly get described Ailamode slow release multicomponent compositions.
9. preparation method as claimed in claim 8 is characterized in that, the temperature of hot melt extruder described in the step (2) is 50 ℃～180 ℃.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
| CN106806353A (en) * | 2015-12-02 | 2017-06-09 | 江苏先声药业有限公司 | Ailamode spansule and preparation method thereof |
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| 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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| 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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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106806353A (en) * | 2015-12-02 | 2017-06-09 | 江苏先声药业有限公司 | Ailamode spansule 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 |
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Effective date of registration: 20170119 Address after: Tong Xiang, Gulou District of Nanjing city in Jiangsu province 210009 No. 24 (near Hunan Road) Applicant after: Chinese Medicinal Univ. Applicant after: Jiangsu Simcere Pharmaceutical Co., Ltd. Address before: Tong Xiang, Gulou District of Nanjing city in Jiangsu province 210009 No. 24 (near Hunan Road) Applicant before: Chinese Medicinal Univ. Applicant before: Xiansheng Medicines Research Co., Ltd., Jiangsu Prov. Applicant before: Jiangsu Simcere Pharmaceutical Co., Ltd. |
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