CN102846573B - Silibinin double-layer slow-release tablets and preparation method thereof - Google Patents
Silibinin double-layer slow-release tablets and preparation method thereof Download PDFInfo
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- CN102846573B CN102846573B CN201210326074.5A CN201210326074A CN102846573B CN 102846573 B CN102846573 B CN 102846573B CN 201210326074 A CN201210326074 A CN 201210326074A CN 102846573 B CN102846573 B CN 102846573B
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Abstract
The present invention discloses silibinin double-layer slow-release tablets, which comprise an immediate release layer and a slow-release layer, wherein the immediate release layer mainly comprise a silibinin solid dispersion, a filler, a disintegrating agent and a lubricant, the slow-release layer mainly comprises silibinin, a slow-release material, a filler, a lubricant and a binder, a weight ratio of the silibinin content in the immediate release layer to the silibinin content in the slow-release layer is 2:8-3:7, and a weight ratio of the immediate release layer to the slow-release layer is (1.5-2.4):1. A purpose of the present invention is to provide the silibinin double-layer slow-release tablets with characteristics of good patient compliance, low side effect, rapid effect, and lasting maintenance of stable effective blood drug level. The present invention further discloses a preparation method for the silibinin double-layer slow-release tablets. The method of the present invention has characteristics of good reproducibility and high production efficiency, and is suitable for industrial mass production. In addition, the prepared double-layer slow-release tablets have good release uniformity.
Description
Technical field
The present invention relates to a kind of silibinin double-layer sustained release tablets and preparation method thereof, particularly, relate to a kind of silibinin rapid release and add sustained-release double-layer slow releasing tablet and preparation method thereof, belong to formulation art.
Background technology
Silibinin (silybin, SLB) is the effective ingredient extracting in catananche's Herba Silybi mariani.Having obvious protection and stable hepatocyte effect, various hepatic disease are had to therapeutical effect in various degree, is the hepatic injury repair medicine of current generally acknowledged determined curative effect.Preparation taking it as principal agent has been widely used in treatment acute, chronic hepatitis and liver cirrhosis etc.Be mainly used in clinically treating [the Kaur M such as acute, chronic hepatitis, various hepatic injury, hepatic fibrosis and early stage liver cirrhosis, Agarwal R.Silymarin and epithelial cancer chemoprevention:How to close we are to bedside? [J] .Toxicol and Appl Pharmacol, 2007,224:350].Listing preparation has Silybin Capsules, silybin meglumine tablets and capsule at present.
Because silibinin Half-life in vivo is short, for maintaining effective blood drug concentration, clinical oral administration Silybin Capsules needs medication repeatedly, and need take multi-disc at every turn, make troubles not only to patient clinical medication, and because blood concentration fluctuation causes greatly adverse reaction rate high.
In addition silibinin or a kind of insoluble drug, water insoluble and common organic solvents.Therefore, silibinin is made to common slow releasing tablet and carry out oral administration, because medicine release in gastric juice is very low, after taking, blood drug level reaches rapidly treatment concentration certain difficulty, play a role slow, prove effective slow.Can not reach desirable therapeutic effect.
At present, domestic existing (1) milk thistle silybum marianum long effect and preparation method thereof (CN 1623539A), actual water miscible silybin-N-methylglucamine, the not silibinin of slightly water-soluble of only limiting to of medicine described in this invention; (2) high-efficient oral silibinin sustained-release preparation and preparation method thereof (CN 101164537 B), its technique is the technology that taking a kind of PVPK30 as carrier, silibinin is prepared into solid dispersion and makes slow releasing preparation.Although its inventor recognizes " two release " principle that solid dispersion technology and slow release hydrophilic gel old friend technology is combined to reach slow release after first rapid release.But do not have relevant embodiment and supports its prepared slow releasing tablet of explanation and reached the object of slow release after first rapid release.The cumulative release of made solid dispersion in the time of 2h is 69.3%, and silibinin dissolubility increases, but in said preparation using silibinin solid dispersion as principal agent, thereby because of the excessive content of dispersion that causes of adjuvant ratio low; And in the vitro release test of slow releasing preparation, only show that the cumulative release amount of 12h is more than 80%, its technical scheme there is no slow releasing preparation embodiment and supports, and should not select 3 points must ask for characterizing external slow releasing preparation drug release rate according to Chinese Pharmacopoeia about slow releasing preparation; Stability test does not have embodiment and relevant data supporting to play conclusion yet.
Summary of the invention
The object of the present invention is to provide the silibinin double-layer sustained release tablets that a kind of good patient compliance, side effect are little, can quick acting can maintain lastingly again steady effective blood drug concentration.Adopt solid dispersion technology, silibinin is prepared into solid dispersion, then itself and proper auxiliary materials are prepared into immediate release section.Rapid-action, curative effect feature rapidly that immediate release section has; Silibinin and suitable specification HPMC framework material are prepared into slow-released part, and slow-released part has that onset is slow, release is steady, the feature that curative effect is lasting.Immediate release section and slow-released part are pressed into double-layer tablet, just can reach not only quick-acting but also long-acting object, thereby reach desirable release and therapeutic effect.Both avoided ordinary preparation medication frequent, blood concentration fluctuation is large, easily produces the shortcoming of untoward reaction, has reached again quick acting, maintains lastingly blood drug level stably, has improved patient's compliance and therapeutic effect.
Another object of the present invention is to provide a kind of preparation method of silibinin double-layer sustained release tablets, the method preparation technology's favorable reproducibility, and production efficiency is high, is applicable to industrialized mass, and it is good that the double-layer sustained release tablets making discharges homogeneity.
The silibinin double-layer sustained release tablets the present invention relates to, it comprises release layer and slow release layer, it is characterized in that, described release layer is mainly made up of silibinin solid dispersion, disintegrating agent and filler, and solid dispersion makes the silibinin of slightly solubility have quick-acting functions.Described slow release layer is mainly made up of silibinin crude drug, slow-release material, filler and binding agent, lubricant.Wherein in release layer and slow release layer, the weight ratio of silibinin content is 2:8～3:7.
The contained disintegrating agent of described release layer is a kind of or its combination in any in L-HPC, CCNa, PVPP, CMS-Na and dried starch;
The contained slow-release material of described slow release layer is a kind of or its combination in any in HPMC, PVA, sodium alginate, carbomer, EC; Described binding agent is a kind of or its combination in any in water, 5%EC alcoholic solution, 5%PVPk30 alcoholic solution, 95% alcoholic solution;
The contained filler of described release layer and slow release layer is lactose, calcium hydrogen phosphate, MCC, amylum pregelatinisatum, mannitol, CaSO
4in a kind of or its combination in any; Described lubricant is a kind of or its combination in any in micropowder silica gel, Pulvis Talci, magnesium stearate, sodium stearate; Wherein in release layer and slow release layer, the weight ratio of silibinin content is 2:8～3:7.
The part by weight of described release layer and slow release layer is (1.5～2.3): 1.
In described release layer, silibinin solid dispersion carrier material is selected from a kind of or its combination in any in PEG, PVP, poloxamer, carbamide, citric acid, be preferably the combination of joint vector PEG6000 and poloxamer, the PEG6000 that more preferably mass ratio is 1:1 and the combination of poloxamer; Surfactant is selected from tween 80, SDS, is preferably SDS; Disintegrating agent is preferably the combination of PVPP and the L-HPC of 3:2 mass ratio; Filler is preferably microcrystalline Cellulose; Lubricant is preferably micropowder silica gel;
In described release layer, the weight ratio of silibinin and adjuvant is 1:(6.5～10).
Described slow release layer slow-release material is preferably HPMC k4M; Filler is preferably lactose; Lubricant is preferably magnesium stearate; Binding agent is preferably 5% PVPk30 alcoholic solution;
In described slow release layer, the weight ratio of silibinin and adjuvant is 1:(0.8～1.5).
Silibinin solid dispersion carrier in release layer of the present invention is the mixture of PEG6000, poloxamer and sodium lauryl sulphate.
Also comprise the preparation method of solid dispersion according to the present invention: solvent method, fusion method, solvent-fusion method, spray drying method.
The prescription of silibinin double-layer sustained release tablets of the present invention is:
Count by weight percentage, described release layer and slow release layer consist of:
The prescription of silibinin double-layer sustained release tablets provided by the invention can be:
Count by weight percentage, described release layer and slow release layer consist of:
The present invention also provides a kind of preparation method of silibinin double-layer sustained release tablets, it is characterized in that the method comprises the following steps:
(a) material is prepared: silibinin crude drug and silibinin solid dispersion are pulverized, crossed 80 mesh sieves, each adjuvant is crossed 80 mesh sieves, for subsequent use.
(b) release layer preparation: silibinin solid dispersion is mixed homogeneously with required adjuvant, obtain release layer mixture, for subsequent use.
(c) slow release layer preparation: silibinin is mixed homogeneously with required adjuvant, obtain slow release layer mixture, for subsequent use.
(d) granulate: respectively described release layer mixture and slow release layer mixture are carried out to direct powder compression or dry granulation or wet granulation, cross 20～60 mesh sieves, add lubricant to mix in right amount, obtain release layer granule and slow release layer granule.
(e) tabletting: first the light slow release layer granule of pressing becomes loose, then adds the extrusion forming of release layer granule, tablet hardness 60～80N; Or (d) gained release layer granule and slow release layer granule are carried out to tabletting in bi-layer tablet press, obtain silibinin double-layer sustained release tablets.
The release profiles of described silibinin double-layer sustained release tablets is: making half an hour cumulative release degree is that 15～35%, 6h cumulative release degree is 50～70%, 12h cumulative release degree >=80%, shows to have obvious rapid release and slow release effect.
beneficial effect of the present invention
A. in the In Vitro Dissolution curve of the silibinin solid dispersion of preparation, the release of 30 minutes is that release in 78.37%, 90 minute is 99.01%, and basic release is complete.Show silibinin and water-solubility carrier material and surfactant to be prepared into solid dispersion by solvent-fusion method, increased significantly the dissolubility of silibinin, and then improve bioavailability in its body.
B. this preparation has release layer and slow release layer double-decker, simultaneously, effective ingredient silibinin in the allocation proportion of release layer and slow release layer by repeated multiple times test, on the basis of comparing, analyzed test data, determined, make quickly medicine reach effective blood drug concentration by release layer release, the slow release of slow release layer maintains steadily, uniform effective blood drug concentration, and reduces medicining times, improves patient's compliance.Wherein in release layer in the In Vitro Dissolution curve of silibinin, the release of 30 minutes is 92.89%, and release is substantially complete, can meet the requirement in release half an hour 20%; In slow release layer, in the release in vitro curve of silibinin, the release that the release that the release that the release of 0.5h is 10.95%, 2h is 27.20%, 6h is 46.56%, 10h is 65.36.Known release is excessively slow, can not reach very soon blood drug level, and release is incomplete.In the silibinin double-layer sustained release tablets release in vitro curve of preparation, 0.5h release approximately 20%, 2h release approximately 35%, 6h release approximately 55%, 10h release is greater than 80%.Release profiles is carried out to zero level, one-level and Higuchi equation model, and result shows that release profiles meets Higuchi equation, and 12h cumulative release degree is greater than 80%, shows to have slow release effect after obvious first rapid release.Meet the prescription of slow releasing preparation.
C. stability test shows: in accelerated test 6 months time the content of silibinin be 0 month 95.6%, in long term test 12 months time the content of silibinin be 0 month 96.8%, other indices all conform with the regulations, and prove that this silibinin double-layer sustained release tablets is stable.
D. preparation technology's favorable reproducibility of silibinin double-layer sustained release tablets, and production efficiency is high, is applicable to industrialized mass.
Brief Description Of Drawings:
Fig. 1 is preparation technology's schematic flow sheet of silibinin double-layer sustained release tablets of the present invention;
Fig. 2 is the In Vitro Dissolution curve chart of silibinin solid dispersion in the present invention;
Fig. 3 be in the present invention silibinin release layer and slow release layer release in vitro curve chart;
Fig. 4 is silibinin double-layer sustained release tablets 1 in the present invention (embodiment 1), silibinin double-layer sustained release tablets 2(embodiment 2), silibinin double-layer sustained release tablets 3(embodiment 3) release in vitro curve chart.
Fig. 5 is the stability test result figure of the embodiment of the present invention 8.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is described in further detail, should be appreciated that these embodiment illustrate of the present invention, instead of limit the scope of the invention.
1. embodiment
embodiment 1
| Formula | Consumption |
| SLB crude drug | 10g |
| PEG6000 | 25g |
| Poloxamer | 25g |
| SDS | 5g |
Preparation technology: adopt the preparation of solvent-fusion method.Take silibinin 10g, add a small amount of 80% ethanol (1:10, w/v), sonic oscillation makes its dissolving; Separately take the each 25g of PEG6000 and poloxamer in evaporating dish, 70 DEG C of heating in water bath, treat that its complete melting is fallen back to fly Ji guest solution, add 5gSDS, stir, fling to solvent, gained mixture is placed in to-38 DEG C of refrigerator-freezers, stir it is solidified rapidly, place 24h, taking-up is placed in vacuum drying oven and places 24h, pulverizes, cross 80 mesh sieves, obtain solid dispersion.
embodiment 2
Preparation technology: silibinin solid dispersion, MCC, PVPP, L-HPC are crossed to 80 mesh sieve mix homogeneously, add 6g micropowder silica gel mix homogeneously, obtain release layer granule; By slow-released part adjuvant mix homogeneously, silibinin crude drug part replaces with the lactose of equivalent, adds 5%PVPk30 alcoholic solution 20ml soft material processed, cross 26 mesh sieves and granulate, under 45 DEG C of conditions, dry 24 mesh sieve granulate, add 1% magnesium stearate mix homogeneously, obtain blank slow release layer granule.Slow-releasing granules and immediate-release granules are made to double-layer sustained release tablets with 8 ㎜ scrobicula punching presses.
embodiment 3
Preparation technology: by immediate release section adjuvant sieve method mix homogeneously, SLB solid dispersion part MCC equivalent replacement, obtains release layer granule; Silibinin crude drug is mixed homogeneously with polishing with HPMCk4M, lactose, add 5%PVPk30 alcoholic solution 20ml soft material processed, cross 26 mesh sieves and granulate, under 45 DEG C of conditions, dry, 24 mesh sieve granulate, add 1% magnesium stearate mix homogeneously, obtain slow release layer granule.Slow-releasing granules and immediate-release granules are made to double-layer sustained release tablets with 8 ㎜ scrobicula punching presses.
embodiment 4
Preparation technology: first main and all adjuvants are crossed respectively to 80 mesh sieves.Other adjuvants in silibinin solid dispersion in release layer and release layer, to cross sieve method mix homogeneously, then are added to the abundant mix homogeneously of micropowder silica gel, obtain immediate-release granules; The silibinin of getting in slow release layer is mixed homogeneously with HPMCk4M, lactose polishing, and 5%PVPk30 alcoholic solution 10ml soft material processed is crossed 26 mesh sieves and granulated, and under 45 DEG C of conditions, dries, and 24 mesh sieve granulate, add magnesium stearate mix homogeneously, obtain slow-releasing granules.Slow-releasing granules and immediate-release granules are made to double-layer sustained release tablets with 8 ㎜ scrobicula punching presses.
embodiment 5
Preparation technology: first main and all adjuvants are crossed respectively to 80 mesh sieves.Other adjuvants in silibinin solid dispersion in release layer and release layer, to cross sieve method mix homogeneously, then are added to the abundant mix homogeneously of micropowder silica gel, obtain immediate-release granules; The silibinin of getting in slow release layer is mixed homogeneously with HPMCk4M, lactose polishing, and 5%PVPk30 alcoholic solution 10ml soft material processed is crossed 26 mesh sieves and granulated, and under 45 DEG C of conditions, dries, and 24 mesh sieve granulate, add magnesium stearate mix homogeneously, obtain slow-releasing granules.Slow-releasing granules and immediate-release granules are made to double-layer sustained release tablets with 8 ㎜ scrobicula punching presses.
embodiment 6
Preparation technology: first principal agent and all adjuvants are crossed respectively to 80 mesh sieves.Other adjuvants in silibinin solid dispersion in release layer and release layer, to cross sieve method mix homogeneously, then are added to the abundant mix homogeneously of micropowder silica gel, obtain immediate-release granules; The silibinin of getting in slow release layer is mixed homogeneously with HPMCk4M, lactose polishing, and 5%PVPk30 alcoholic solution 10ml soft material processed is crossed 26 mesh sieves and granulated, and under 45 DEG C of conditions, dries, and 24 mesh sieve granulate, add magnesium stearate mix homogeneously, obtain slow-releasing granules.Slow-releasing granules and immediate-release granules are made to double-layer sustained release tablets with 8 ㎜ scrobicula punching presses.
embodiment 7
The silibinin double-layer sustained release tablets prepared to embodiment 1-7 carries out dissolution test.
Assay method: press 2010 editions annex drug release determination method first method pertinent regulations of Chinese Pharmacopoeia.37 ± 0.5 DEG C of temperature, rotating speed is 100 rmin
-1, release medium is 0.5%SDS aqueous solution 1000ml, measures release in vitro curve.Result is shown in respectively Fig. 2, Fig. 3, Fig. 4.In the release in vitro curve of Fig. 3, cumulative release degree when silibinin double-layer sustained release tablets 0.5h is that 15～35%, 6 cumulative release degree are 50～70%, 12h cumulative release degree >=80%.
embodiment 8
The silibinin double-layer sustained release tablets prepared with embodiment 2 carries out stability test, result shows: in accelerated test 6 months time the content of silibinin be 0 month 95.6%, in long term test 12 months time the content of silibinin be 0 month 96.8%, other indices all conform with the regulations, and prove that this silibinin double-layer sustained release tablets is stable.The results are shown in Figure 5.
embodiment 9
The cumulative release curve of silibinin double-layer sustained release tablets prepared embodiment 2 is carried out to zero level equation, First-order equation, Higuchi equation and Rigter-Peppas equation and carry out matching, the results are shown in Table 1.
| Fit equation | Correlation coefficient | |
| Zero level equation | Q=5.1856t+25.532 | R 2=0.9771 |
| First-order equation | ln(100-Q)=-0.1308t+4.420 | R 2=0.9889 |
| Higuchi equation | Q=22.051t 1/2+6.8042 | R 2=0.9972 |
| Rigter-Peppas equation | Q=0.4105t+3.3785 | R 2=0.9963 |
As shown in Table 1, Higuchi equation can represent dispose procedure and the release dynamics feature of silibinin double-layer sustained release tablets.
Claims (4)
1. a silibinin double-layer sustained release tablets, is characterized in that, described silibinin double-layer sustained release tablets is made up of release layer and slow release layer, counts by weight percentage, and described release layer and slow release layer consist of:
2. silibinin double-layer sustained release tablets as claimed in claim 1, counts by weight percentage, and preferred described release layer and slow release layer consist of:
3. silibinin double-layer sustained release tablets as claimed in claim 1, is characterized in that, the preparation method of this silibinin double-layer sustained release tablets comprises:
(a) material is prepared: silibinin crude drug and silibinin solid dispersion are pulverized, crossed 80 mesh sieves, each adjuvant is crossed 80 mesh sieves, for subsequent use;
(b) release layer preparation: silibinin solid dispersion is mixed homogeneously with required adjuvant, obtain release layer mixture, for subsequent use;
(c) slow release layer preparation: silibinin is mixed homogeneously with required adjuvant, obtain slow release layer mixture, for subsequent use;
(d) granulate: respectively described release layer mixture and slow release layer mixture are carried out to direct powder compression or dry granulation or wet granulation, cross 20～60 mesh sieves, add lubricant to mix in right amount, obtain release layer granule and slow release layer granule;
(e) tabletting: first the light slow release layer granule of pressing becomes loose, then adds the extrusion forming of release layer granule, tablet hardness 60～80N; Or (d) gained release layer granule and slow release layer granule are carried out to tabletting in bi-layer tablet press, obtain silibinin double-layer sustained release tablets.
4. silibinin double-layer sustained release tablets as claimed in claim 1, it is characterized in that, the release profiles of described silibinin double-layer sustained release tablets is: 0.5h cumulative release degree 15%～30%, 6h cumulative release degree 50%～70%, 12h cumulative release degree >=80%, discharge first hour in mainly by release layer release, after first hour by slow release layer release.
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| CN108187058A (en) * | 2018-01-29 | 2018-06-22 | 中国药科大学 | The preparation and its application in sustained-release preparation of a kind of auxiliary material of processing altogether |
| CN109223721A (en) * | 2018-09-28 | 2019-01-18 | 江苏天美健大自然生物工程有限公司 | Phosphatide milk thistle vitamin E composition and its preparation method and application |
| CN111297814A (en) * | 2019-12-18 | 2020-06-19 | 湖南千金协力药业有限公司 | Compound preparation for reducing liver toxicity of tripterygium glycosides tablets and preparation method thereof |
| CN112791057B (en) * | 2021-02-07 | 2022-03-18 | 齐飞 | Slow release preparation containing edoxaban and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101164537A (en) * | 2006-10-16 | 2008-04-23 | 江苏大学 | High-efficient oral silibinin sustained-release preparation and preparation method thereof |
| CN101444503A (en) * | 2008-12-31 | 2009-06-03 | 江苏大学 | Efficient long-acting silibinin preparation and preparation method thereof |
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| CN101164537A (en) * | 2006-10-16 | 2008-04-23 | 江苏大学 | High-efficient oral silibinin sustained-release preparation and preparation method thereof |
| CN101444503A (en) * | 2008-12-31 | 2009-06-03 | 江苏大学 | Efficient long-acting silibinin preparation and preparation method thereof |
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