CN101095671B - Iguratimod oral double-layer sustained-release preparation - Google Patents

Iguratimod oral double-layer sustained-release preparation Download PDF

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Publication number
CN101095671B
CN101095671B CN2006100144484A CN200610014448A CN101095671B CN 101095671 B CN101095671 B CN 101095671B CN 2006100144484 A CN2006100144484 A CN 2006100144484A CN 200610014448 A CN200610014448 A CN 200610014448A CN 101095671 B CN101095671 B CN 101095671B
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Prior art keywords
release layer
ailamode
layer
release
iguratimod
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CN101095671A (en
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王杏林
高晶
梅林雨
刘昌孝
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Tianjin Institute of Pharmaceutical Research Co Ltd
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Tianjin Institute of Pharmaceutical Research Co Ltd
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Abstract

The invention relates to oral double iguratimod controlled release formulation, which comprises fast release layer and slow release layer that are composed of 8-30% micronizing iguratimod crystal powder and medical findings, and the granule size of iguratimod crystal powder is 1-10 um. The effective component in fast release layer is released in short time and reaches to effective blood chemical concentration for effective action; the iguratimod in sloe release layer is released gradually and maintains effective blood medical concentration for continuous effective action. The invention overcomes shortcomings of short effective action time and a little high toxic effect.

Description

Iguratimod oral double-layer sustained-release preparation
Technical field
The present invention relates to insoluble drug Ailamode crystallinity micropowder, micropowder preparing process, particularly a kind of Iguratimod oral double-layer sustained-release preparation and preparation method.
Background technology
The Iguratimod general by name of Ailamode, chemistry N-[3-(formamido) by name-4-oxygen-6-phenoxy group-4H-1-.alpha.-5:6-benzopyran-7-yl]-amsacrine, English name is: N-[3-(formylamino)-4-oxo-6-phenoxy-4H-1-benzopyran-7-yl]-methanesulfonamide, its chemical constitution, manufacture method, purposes is recorded in that the special permission communique of TOHKEMY 2001-240540 is existing, show flat 6-623714 number more altogether with Japan Japanese kokai publication hei 2-49778 number and published the Ailamode antipyretic-antalgic, the arthritis effect, immunoregulation effect is to the prevention of autoimmune disease, therapeutical effect.
Ailamode is the improved-type arthritis medicine of the state of an illness (DMARD), but the inflammation-inhibiting cytokine comprises il-1,6,8 (IL-1, IL-6, IL-8) and the generation of tumor necrosis factor (TNF), clinical trial shows, its bone that can effectively slow down damages, no matter whether the existence of recombined human bone morphogenetic protein-2 (rhBMP-2) is arranged, but all osteoblastic differentiation in effective stimulus substrate (stromal) and osteoblast precursor (preosteoblastic) cell line of this chemical compound.Except having the heavy absorbing activity of good inhibition bone, it is also influential for the anabolism of bone.
At present clinical report mainly is two dosage, promptly every day oral Ailamode 50mg, 70mg.With placebo during with the double-blind treatment arthritis in 209 16 weeks of case, clinical symptoms is significantly improved, and is respectively 73.5%, 59.6% and 11.9%, and optimal dose is 25mg, twice of every day.
The Ailamode raw material and the conventional sheet of inventor's development have obtained the clinical official written reply of National Drug Administration, are carrying out clinical research.Find in the research, the purified Ailamode of different solvents, its powder x-ray diffraction figure difference illustrates that there is polymorphic in Ailamode.Because the Ailamode poorly water-soluble, bioavailability is low, therefore in conventional sheet preparation process, adopts band water polishing to overcome raw material static and to reduce the material powder particle diameter, and the tablet bioavailability is improved.
The Ailamode sheet is the 25mg/ sheet, every day twice, each a slice.The gastrointestinal irritation symptom that causes in order to reduce conventional tablet to discharge in a large number at short notice, reduce blood concentration fluctuation, reduce the medication number of times, make things convenient for the patient to take medicine, the inventor has developed two-layer release-controlled preparation once a day, do sth. in advance the onset time of medicine, and keep effective treatment concentration longer time, make blood drug level steady, drug effect is lasting, reduce the toxic and side effects of medicine, improve drug safety.The Ailamode two-layer release-controlled tablet of inventor's development has not yet to see the report of pertinent literature.
Summary of the invention
The purpose of this invention is to provide a kind of in patient's body rapidly onset and the Ailamode two-layer release-controlled tablet and the preparation method that prolong its efficacy effect time.The two-layer release-controlled tablet of Ailamode provided by the invention, only need take once every day, owing to reduced medicining times, can improve the compliance that patient takes medicine.
For realizing purpose of the present invention, adopt following technical scheme:
The invention provides the two-layer release-controlled tablet of a kind of Ailamode, form release layer and slow release layer, and Ailamode crystallinity grain size of micropowder scope is 1～10 μ m by 8%～30% micronization Ailamode crystalline powder and pharmaceutic adjuvant.
Micronized Ailamode crystalline powder of the present invention transforms by dimethyl formamide and aqueous solvent and separates out fine crystal manufacturing.Promptly with diformazan Methanamide dissolving Ailamode raw material, water is medicine crystallize solvent, and preparation has the Ailamode micropowder of novel crystal forms.Powder diameter below 50 μ m, preferred 1～10 μ m, more preferably 2～5 μ m.Measure with D/max-2500 Japan X-ray polycrystalline powder diffractometer of science, adopt graphite monochromator, emission types is Cuka, and Guan Tongwei 100mA, pipe press and be 40KV.Have following x-ray diffraction pattern:
2θ(°) Interplanar distance d (A) Relative abundance (%) 2θ(°) Interplanar distance d (A) Relative abundance (%)
5.940 14.8665 48 24.300 3.6598 63
8.140 10.8528 10 25.160 3.5366 61
10.480 8.4342 100 25.620 3.4741 61
11.960 7.3937 14 27.200 3.2758 61
12.440 7.1094 16 28.280 3.1531 13
14.820 5.9726 15 29.020 3.0744 28
15.920 5.5623 14 29.720 3.0035 15
17.400 5.0924 88 31.780 2.8134 18
18.320 4.8387 57 33.180 2.6978 11
18.740 4.7312 37 34.480 2.5990 12
20.060 4.4227 37 36.860 2.4365 9
20.620 4.3039 36 38.220 2.3528 10
21.120 4.2031 37 40.100 2.2468 16
21.800 4.0735 40 41.900 2.1543 10
22.980 3.8669 68 44.380 2.0395 9
24.000 3.7048 74 47.180 1.9248 9
Two-layer release-controlled tablet of the present invention, release layer wherein is made up of following components in weight percentage: Ailamode crystallinity micropowder 5%～30%, disintegrating agent 5%～20%, surfactant 0～5%, diluent 40%～80%.Ailamode crystallinity micropowder wherein, dosage can be 5～30mg, preferred 5～15mg.
Wherein said disintegrating agent comprises: carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose or polyvinylpolypyrrolidone, and preferred cross-linking sodium carboxymethyl cellulose, the percentage by weight of disintegrating agent consumption in release layer is 7%～15%.
Surfactant wherein comprises: sodium lauryl sulphate, sodium lauryl sulfate or polysorbate acid esters-80, and preferably sodium dodecyl sulfate, dosage of surfactant is advisable 0～5%, and preferred 1%～5%.
Diluent wherein comprises: lactose, microcrystalline Cellulose, sorbitol, starch or sucrose etc., and preferred lactose and microcrystalline Cellulose, its percentage by weight in release layer is 40%～80%, preferred 50%～80%.
The preferred oral administration solid release layer of the present invention, each preparation unit is made up of following compositions:
Active component Ailamode crystallinity micropowder 5％～30％
Disintegrating agent The interlinkage sodium carboxymethyl cellulose 7％～15％
Surfactant Sodium lauryl sulphate 1％～5％
Diluent Lactose and microcrystalline Cellulose 50％～80％
Binding agent 30 POVIDONE K 30 BP/USP 30 1％～8％
Lubricant Magnesium stearate 1％～2％
Each preparation unit of the present invention is meant the percentage by weight that contains mentioned component in the release layer.
Ailamode release layer compacting of the present invention is compared with conventional sheet in flakes, and under the same dose, external stripping is obviously accelerated, and release feature is: stripping quantity＞80% when stripping quantity is 50%～90%, 5 minutes in the time of 0～2 minute.The animal body giving drugs into nose shows for test, compares with conventional sheet, and Ailamode release layer preparation peak reaching time of blood concentration is accelerated, and adds near 2.55 hours by original 3.61 hours; Bioavailability significantly improves, and relative bioavailability is 152.9%.
Two-layer release-controlled tablet of the present invention, slow release layer wherein is made up of following components in weight percentage substantially: Ailamode crystallinity micropowder 5%～30%, framework material 8%～22%, diluent 40%～80%, binding agent 2%～8%.Ailamode crystallinity micropowder wherein, dosage can be 15～50mg, preferred 15～30mg.
Wherein framework material can be hydrophilic gel matrix material and comprises hydroxypropyl emthylcellulose, card pool nurse, sodium carboxymethyl cellulose, preferred hydroxypropyl emthylcellulose, and the framework material consumption is advisable 8%～22%; Be preferably 10%～18%.
Wherein diluent can be lactose, microcrystalline Cellulose, sorbitol, starch, sucrose etc., preferred lactose and microcrystalline Cellulose, and the consumption of diluent is advisable preferred 55%～75% 40%～80%.
Binding agent wherein comprises: polyvidone, ethyl cellulose or hydroxypropyl emthylcellulose, preferred polyvidone, binder dosage be 2%～8%, and preferred 3%～6%.
The preferred oral administration solid slow release layer of the present invention, each preparation unit is made up of following compositions:
Active component Ailamode crystallinity micropowder 5％～30％
Framework material Hydroxypropyl emthylcellulose 10％～18％
Diluent Lactose and microcrystalline Cellulose 55％～75％
Binding agent 30 POVIDONE K 30 BP/USP 30 3％～6％
Lubricant Magnesium stearate 1％～2％
Each preparation unit of the present invention is meant the percentage by weight that contains mentioned component in the slow release layer.
Ailamode slow release layer compacting of the present invention is compared with conventional sheet in flakes, external stripping is obviously slowed down, and release feature is: burst size 20%～40% in 2 hours, and burst size 30%～70% in 4 hours, burst size 60%～90% in 8 hours, and burst size was more than 80% in 12 hours.The Ailamode two-layer release-controlled tablet shows for test at Beagle Canis familiaris L. body giving drugs into nose, takes Isodose 50mg, compares with conventional sheet, and Ailamode slow release layer preparation peak reaching time of blood concentration obviously prolongs, and extends to 6 hours by original 3 hours; Bioavailability significantly improves, and relative bioavailability is 184.5%.
Further explanation, Ailamode double-layer tablet of the present invention, dosage can be 20mg～70mg, preferred 25mg～40mg, active component is the Ailamode micropowder, grain size of micropowder is made up of release layer and slow release layer at 1～10 μ m.
Release layer preferably is made up of following components in weight percentage: Ailamode crystallinity micropowder 5%～30%, interlinkage sodium carboxymethyl cellulose 7%～15%, sodium lauryl sulphate 1%～5%, lactose and microcrystalline Cellulose 50%～80%.
Slow release layer preferably is made up of following components in weight percentage: Ailamode crystallinity micropowder 5%～30%, hydroxypropyl emthylcellulose 10%～18%, lactose and microcrystalline Cellulose 55%～75%, polyvidone 3%～6%, magnesium stearate 1%～2%.
The preparation technology of above-mentioned Ailamode two-layer release-controlled tablet is as follows:
(1) preparation release layer granule: take by weighing Ailamode micropowder and other adjuvant by the release layer prescription, comprise lactose, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, the sodium lauryl sulphate equivalent mix homogeneously that progressively increases, with 10% 30 POVIDONE K 30 BP/USP 3050% alcoholic solution is as binding agent, and wet granulation is crossed 30 mesh sieve system soft materials, and after 60 ℃ of dryings, 20 mesh sieve granulate add magnesium stearate, and mixing gets the release layer granule.
(2) preparation slow release layer granule: take by weighing Ailamode micropowder and other adjuvant by the slow release layer prescription, comprise hydroxypropyl emthylcellulose, lactose, microcrystalline Cellulose, the 30 POVIDONE K 30 BP/USP 30 equivalent mix homogeneously that progressively increases, with 50% ethanol mist projection granulating, after the drying, cross 30 mesh sieve granulate, the magnesium stearate mixing that adds recipe quantity gets the slow release layer granule.
(3) tabletting: after release layer granule and slow release layer granule adjusted weight in proportion, be pressed into double-layer tablet through bi-layer tablet press.
Wherein said bi-layer tablet press refers to two kinds of granules and enters punch die through hopper separately and be pressed into bilayer tablet.
Above-mentioned sample release in vitro is characterized as: discharged 20%～50%, 2 hour and discharge release in 50%～65%, 4 hour release in 60%～80%, 8 hour release in 70%～90%, 12 hour more than 80% in 5～15 minutes.
Two-layer release-controlled preparation of the present invention its characteristics of comparing with existing Ailamode sheet are:
1, according to the Ailamode product characteristics, used rapid release to add the double-layer tablet dosage form of slow release first to this kind, behind oral these product of patient, the functional component rapid release in the release layer reaches effective blood drug concentration, plays a role rapidly; Then, Ailamode discharges gradually in the slow release layer, keeps effective blood drug level, continues the performance curative effect, thereby it is rapid to make this product have an analgesic activity, effectively the effect that prolongs of analgesia time.Can remedy the slow shortcoming of conventional sheet short onset action time, reduce toxic and side effects.
2, in order to make the Ailamode quick acting and to improve bioavailability, adopt solvent crystallization,, reduce diameter of aspirin particle, increase the medicine specific surface area, thereby improved the water solublity and the water dispersible of medicine superfine Iguratimod powder.Therefore improve the bioavailability of Ailamode, accelerated onset time, reduced drug dose.
3, in the release layer of double-layer tablet, active component is micronized Ailamode, can improve bioavailability; Add sodium carboxymethyl cellulose and make disintegrating agent, sodium lauryl sulphate is made surfactant, and lactose, microcrystalline Cellulose are made filler, makes this product can reach quick disintegrate and dissolving.
4, to the slow release layer of double-layer tablet, active component is micronized Ailamode, can improve bioavailability; Adopting the hydrogel matrix technology, is framework material with the hydroxypropyl emthylcellulose, and lactose, microcrystalline Cellulose are filler and release regulator, adopts spray-drying process, and Ailamode is slowly evenly discharged, and reaches the effect long purpose of holding time.
Term
The HPMC hydroxypropyl emthylcellulose
Description of drawings:
The powder x-ray diffraction figure of Fig. 1 Ailamode micropowder;
Fig. 2 write out a prescription 1,2 and the external dissolution of conventional sheet relatively;
The different HPMC consumption of Fig. 3 Ailamode slow release layer release in vitro degree relatively;
The different lactose consumption of Fig. 4 Ailamode slow release layer release in vitro degree relatively;
The different binder dosage Ailamode of Fig. 5 slow release layer release in vitro degree relatively;
Fig. 6 Ailamode double-layer tablet release in vitro line of writing music;
The specific embodiment
The preparation of embodiment 1 Ailamode crystallinity micropowder
Get Ailamode raw material 1.0g and add the dissolving of 17.5ml dimethyl formamide, slowly (or dropping) enters in the 500ml water, and the limit drips, and stir on the limit, and mixing speed is 800r/min, and Ailamode is separated out immediately and is dispersed in the water.Filter, stir with distilled water and give a baby a bath on the third day after its birth time, filter, 60 ℃ of dryings 2 hours.Get above-mentioned powder, carry out powder x-ray diffraction and measure and the powder diameter inspection, above-mentioned powder mean diameter is about 4 μ m.Yield is 97.5%.The powder x-ray diffraction collection of illustrative plates is seen accompanying drawing 1.
Embodiment 2 Ailamode release layer technologies are investigated (1000):
Prescription is formed Prescription 1 Prescription 2 Prescription 3
The Ailamode micropowder 25g 25g 25g
Lactose 50g 25g 50g
Microcrystalline Cellulose 50g 50g 25g
Mannitol / 37.5g /
Cross-linking sodium carboxymethyl cellulose 20g 20g 24g
Sodium lauryl sulphate 4.5g 5g /
30 POVIDONE K 30 BP/USP 30 In right amount In right amount In right amount
Magnesium stearate 3g 3g 2.3g
Preparation process:
(1) former, adjuvant were pulverized respectively 200 mesh sieves, standby.
(2) except that 30 POVIDONE K 30 BP/USP 30, magnesium stearate, take by weighing recipe quantity by prescription, 60 mesh sieve mix homogeneously add 10% 30 POVIDONE K 30 BP/USP, 30 solution system soft materials, and 30 mesh sieves are granulated, 60 ℃ of dryings 2 hours.
(3) get above-mentioned granule, add the magnesium stearate of recipe quantity, 20 mesh sieve granulate.Tabletting, 3～4 kilograms of controlled pressures.
Dissolution determination:
According to Chinese Pharmacopoeia version requirement in 2000, be dissolution medium with phosphate buffer (pH is 7.8), the slurry method, rotating speed is 100 rev/mins, determined by ultraviolet spectrophotometry, prescription 1, prescription 2 and conventional sheet dissolution determination result are as follows:
Figure G2006114448420060711D000071
The stripping curve of prescription 1, prescription 2 and conventional sheet is seen accompanying drawing 2.
The influence (1000) that embodiment 3 different HPMC consumptions discharge the Ailamode slow release layer
Prescription is formed Prescription 4 Prescription 5 Prescription 6
The Ailamode micropowder 50g 50g 50g
HPMC(K4M) 50g 35g 24g
Lactose 80g 80g 80g
Microcrystalline Cellulose 20g 20g 20g
30 POVIDONE K 30 BP/USP 30 In right amount In right amount In right amount
Magnesium stearate
2％ 2％ 2％
HPMC (K4M), lactose, microcrystalline Cellulose are crossed 80 mesh sieves, fully mix with the micronization Ailamode, adding concentration is that 50% alcoholic solution of 10% 30 POVIDONE K 30 BP/USP 30 is made soft material in right amount, 30 mesh sieves are granulated, wet granular adds the magnesium stearate mixing, tabletting in 2 hours 20 mesh sieve granulate of 60 ℃ of dryings.
Release in vitro degree measurement result shows that the HPMC consumption is few more, and rate of release is fast more, and consumption increases rate of release and slows down.The release curve is seen accompanying drawing 3.
The influence (1000) that embodiment 4 different lactose consumptions discharge the Ailamode slow release layer
Prescription is formed Prescription 6 Prescription 7 Prescription 8
The Ailamode micropowder 50g 50g 50g
HPMC(K4M) 24g 30g 35g
Lactose 80g 120g 160g
Microcrystalline Cellulose 20g 20g 20g
30 POVIDONE K 30 BP/USP 30 In right amount In right amount In right amount
Magnesium stearate
2％ 2％ 2％
The sample preparation mode is identical with embodiment 3.
Drug release determination is the result show, the lactose consumption increases, and rate of release is accelerated.The release curve is seen accompanying drawing 4.
The influence (1000) that embodiment 5 different binder dosages discharge the Ailamode slow release layer
Prescription is formed Prescription 7 Prescription 9 Prescription 10
The Ailamode micropowder 50g 50g 50g
HPMC(K4M) 30g 30g 30g
Lactose 120g 120g 120g
Microcrystalline Cellulose 20g 20g 20g
30 POVIDONE K 30 BP/USP 30 8g 9.5g 13.5g
Magnesium stearate
2％ 2％ 2％
The sample preparation mode is identical with embodiment 3.
Drug release determination is the result show, reduces along with binder dosage increases release.The release curve is seen accompanying drawing 5.
Embodiment 6 binding agents add mode discharges the uniformity to the Ailamode slow release layer influence (1000)
Prescription is formed Prescription 7 Prescription 11 Prescription 12
The Ailamode micropowder 50g 50g 50g
HPMC(K4M) 30g 30g 30g
Lactose 120g 120g 120g
Microcrystalline Cellulose 20g 20g 20g
30 POVIDONE K 30 BP/USP 30 8g 8g 12g
Magnesium stearate
2％ 2％ 2％
Prescription 11～12 preparation methoies: HPMC (K4M), lactose, microcrystalline Cellulose and 30 POVIDONE K 30 BP/USP 30 are crossed 80 mesh sieves, fully mix with the micronization Ailamode, with 50% alcoholic solution spray granulation, wet granular was in 60 ℃ of dryings 2 hours, 30 mesh sieve granulate add the magnesium stearate mixing, tabletting.
It is influential to discharging the uniformity and rate of release that binding agent adds mode, in add binding agent, it is better to discharge the uniformity with 50% alcoholic solution spray granulation, discharges soon slightly, measurement result sees the following form.
Figure G2006114448420060711D000091
The preparation (1000) of embodiment 7 Ailamode sustained release double-layer tablet
Figure G2006114448420060711D000092
Preparation technology
With release layer write out a prescription Central Plains, adjuvant is crossed 50 mesh sieve mix homogeneously by the equivalent method of progressively increasing, and is binding agent with 10%PVPK30 solution, make soft material and cross 30 mesh sieves and granulate, dry under 60 ℃ condition, use 20 mesh sieve granulate then, add the magnesium stearate mixing of recipe quantity, stand-by.
After slow release layer adjuvant and principal agent equivalent incremental method crossed 80 mesh sieve mix homogeneously, carry out spray granulation, after the drying, cross 30 mesh sieve granulate, add the magnesium stearate mixing of recipe quantity with 50% ethanol, stand-by.
After release layer granule and slow release layer granule adjusted weight in proportion, be pressed into double-layer tablet through bi-layer tablet press.
Above-mentioned sample release in vitro curve is seen accompanying drawing 6.

Claims (1)

1. Ailamode two-layer release-controlled tablet is characterized in that its composition is composed as follows:
Release layer:
Figure FSB00000545697200011
Slow release layer:
Its preparation technology:
With release layer write out a prescription Central Plains, adjuvant is crossed 50 mesh sieve mix homogeneously by the equivalent method of progressively increasing, and is binding agent with 10%PVPK30 solution, make soft material and cross 30 mesh sieves and granulate, dry under 60 ℃ condition, use 20 mesh sieve granulate then, add the magnesium stearate mixing of recipe quantity, stand-by; After slow release layer adjuvant and principal agent equivalent incremental method crossed 80 mesh sieve mix homogeneously, carry out spray granulation, after the drying, cross 30 mesh sieve granulate, add the magnesium stearate mixing of recipe quantity with 50% ethanol, stand-by; After release layer granule and slow release layer granule adjusted weight in proportion, be pressed into double-layer tablet through bi-layer tablet press.
CN2006100144484A 2006-06-26 2006-06-26 Iguratimod oral double-layer sustained-release preparation Expired - Fee Related CN101095671B (en)

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CN103610658B (en) * 2013-11-15 2017-04-12 广州帝奇医药技术有限公司 Immunomodulator slow-release preparation and preparation method thereof
CN112057429B (en) * 2019-06-11 2023-04-07 上海京新生物医药有限公司 Lei Xina Deg controlled release pharmaceutical composition
JP7426832B2 (en) * 2020-01-10 2024-02-02 株式会社トクヤマ Iguratimod with a novel crystal structure and its production method

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CN1531925A (en) * 2003-03-24 2004-09-29 天津药物研究院 Process for preparing colatemo solid preparation and its solid preparation

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Publication number Priority date Publication date Assignee Title
CN1531925A (en) * 2003-03-24 2004-09-29 天津药物研究院 Process for preparing colatemo solid preparation and its solid preparation

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