CN102846573A - 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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- CN102846573A CN102846573A CN2012103260745A CN201210326074A CN102846573A CN 102846573 A CN102846573 A CN 102846573A CN 2012103260745 A CN2012103260745 A CN 2012103260745A CN 201210326074 A CN201210326074 A CN 201210326074A CN 102846573 A CN102846573 A CN 102846573A
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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 that extracts in catananche's Herba Silybi mariani.Having obvious protection and stable hepatocyte effect, various hepatic disease are had in various degree therapeutical effect, is the hepatic injury repair medicine of the determined curative effect of generally acknowledging at present.Preparation take 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].The listing preparation has Silybin Capsules, silybin meglumine tablets and capsule at present.
Because the silibinin Half-life in vivo is short, for keeping effective blood drug concentration, the clinical oral administration Silybin Capsules needs repeatedly medication, and need take multi-disc at every turn, make troubles not only for the patient clinical medication, and because blood concentration fluctuation cause greatly adverse reaction rate high.
In addition, silibinin or a kind of insoluble drug, water insoluble and common organic solvents.Therefore, silibinin is made common slow releasing tablet carry out oral administration, because medicine release in gastric juice is very low, blood drug level reaches rapidly treatment concentration after taking 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), this is invented, and described medicine is actual to only limit to water miscible silybin-N-methylglucamine, is not the silibinin of slightly water-soluble; (2) high-efficient oral silibinin sustained-release preparation and preparation method thereof (CN 101164537 B), its technique are the technology that solid dispersion is made slow releasing preparation again that silibinin is prepared into take a kind of PVPK30 as carrier.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 behind the first rapid release.But relevant embodiment does not support the purpose that its prepared slow releasing tablet of explanation has reached slow release behind the first rapid release.The cumulative release of made solid dispersion when 2h is 69.3%, and the silibinin dissolubility increases, but in the said preparation with the 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 to be used for characterizing external slow releasing preparation drug release rate according to Chinese Pharmacopoeia about slow releasing preparation and must ask; Stability test does not have embodiment to play conclusion with relevant data supporting 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 keep lastingly again steady effective blood drug concentration.Adopt solid dispersion technology, silibinin is prepared into solid dispersion, again itself and proper auxiliary materials are prepared into immediate release section.That immediate release section has is rapid-action, curative effect characteristics rapidly; 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 characteristics 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 purpose, thereby reach desirable release and therapeutic effect.Both avoided the ordinary preparation medication frequent, blood concentration fluctuation is large, easily produces the shortcoming of untoward reaction, has reached again quick acting, keeps lastingly stably blood drug level, 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 fit to industrialized mass, and it is good that the double-layer sustained release tablets that makes discharges homogeneity.
The silibinin double-layer sustained release tablets that the present invention relates to, it comprises release layer and slow release layer, it is characterized in that described release layer mainly is made of silibinin solid dispersion, disintegrating agent and filler, solid dispersion is so that the silibinin of slightly solubility has quick-acting functions.Described slow release layer mainly is comprised of silibinin crude drug, slow-release material, filler and binding agent, lubricant.Wherein the weight ratio of silibinin content is 2:8～3:7 in release layer and the slow release layer.
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 the dried starch;
The contained slow-release material of described slow release layer is a kind of or its combination in any among HPMC, PVA, sodium alginate, carbomer, the 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, the sodium stearate; Wherein the weight ratio of silibinin content is 2:8～3:7 in release layer and the slow release layer.
The part by weight of described release layer and slow release layer is (1.5～2.3): 1.
Silibinin solid dispersion carrier material is selected from a kind of or its combination in any in PEG, PVP, poloxamer, carbamide, the citric acid in the described release layer, be preferably the combination of joint vector PEG6000 and poloxamer, more preferably mass ratio is the combination of PEG6000 and the poloxamer of 1:1; 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;
The weight ratio of silibinin and adjuvant is 1:(6.5～10 in the described release layer).
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;
The weight ratio of silibinin and adjuvant is 1:(0.8～1.5 in the described slow release layer).
Silibinin solid dispersion carrier in the release layer of the present invention is the mixture of PEG6000, poloxamer and sodium lauryl sulphate.
The preparation method that also comprises 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 may further comprise the 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, and is for subsequent use.
(b) release layer preparation: with silibinin solid dispersion and required adjuvant mix homogeneously, obtain the release layer mixture, for subsequent use.
(c) slow release layer preparation: with silibinin and required adjuvant mix homogeneously, obtain the slow release layer mixture, for subsequent use.
(d) granulate: respectively described release layer mixture and slow release layer mixture are carried out direct powder compression or dry granulation or wet granulation, cross 20～60 mesh sieves, add an amount of mixing of lubricant, obtain release layer granule and slow release layer granule.
(e) tabletting: the light slow release layer granule of pressing becomes loose first, adds the extrusion forming of release layer granule, tablet hardness 60～80N again; Or (d) gained release layer granule and slow release layer granule carried out tabletting on bi-layer tablet press, namely get the silibinin double-layer sustained release tablets.
The release profiles of described silibinin double-layer sustained release tablets is: so that half an hour, the cumulative release degree was that 15～35%, 6h cumulative release degree is 50～70%, 12h cumulative release degree 〉=80%, show 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, 30 minutes release 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 are 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, the 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 the release layer release, the slow release of slow release layer is kept steadily, uniformly effective blood drug concentration, and minimizing medicining times, improves patient's compliance.Wherein in the release layer in the In Vitro Dissolution curve of silibinin, 30 minutes release is 92.89%, and release is substantially complete, can satisfy the requirement in release half an hour 20%; In the slow release layer in the release in vitro curve of silibinin, the release of 0.5h is that the release of 10.95%, 2h is that the release of 27.20%, 6h is that the release of 46.56%, 10h is 65.36.Release is excessively slow as can be known, 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, the 0.5h release is about 20%, and the 2h release is about 35%, and the 6h release is about 55%, and the 10h release is greater than 80%.Release profiles is carried out zero level, one-level and Higuchi equation model, and the result shows that release profiles meets the Higuchi equation, and 12h cumulative release degree is greater than 80%, shows to have slow release effect behind the obvious first rapid release.The prescription that meets slow releasing preparation.
C. stability test shows: in the accelerated test 6 months the time content of silibinin be 0 month 95.6%, in the long term test 12 months the time content of silibinin be 0 month 96.8%, other indices are all up to specification, 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 fit 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 among the present invention;
Fig. 3 be among the present invention silibinin release layer and slow release layer the release in vitro curve chart;
Fig. 4 is silibinin double-layer sustained release tablets 1 among the present invention (embodiment 1), silibinin double-layer sustained release tablets 2(embodiment 2), silibinin double-layer sustained release tablets 3(embodiment 3) the release in vitro curve chart.
Fig. 5 is the stability test figure as a result of the embodiment of the invention 8.
The specific embodiment
The present invention is described in further detail below in conjunction with embodiment, should be appreciated that these embodiment specify of the present invention, rather than limit the scope of the invention.
1. embodiment
Embodiment 1
| Prescription | Consumption |
| The SLB crude drug | 10g |
| PEG6000 | 25g |
| Poloxamer | 25g |
| SDS | 5g |
Preparation technology: adopt solvent-fusion method preparation.Take by weighing silibinin 10g, add a small amount of 80% ethanol (1:10, w/v), sonic oscillation makes its dissolving; Other takes by weighing PEG6000 and each 25g of poloxamer in evaporating dish, and 70 ℃ of heating in water bath are treated that its complete melting is fallen back to fly Ji guest solution, add 5gSDS, stir, fling to solvent, the gained mixture is placed-38 ℃ of refrigerator-freezers, stirring rapidly solidifies it, place 24h, taking-up places vacuum drying oven to place 24h, pulverizes, cross 80 mesh sieves, get solid dispersion.
Preparation technology: silibinin solid dispersion, MCC, PVPP, L-HPC are crossed 80 mesh sieve mix homogeneously, add 6g micropowder silica gel mix homogeneously, get the release layer granule; With slow-released part adjuvant mix homogeneously, the silibinin crude drug partly replaces with the lactose of equivalent, adds 5%PVPk30 alcoholic solution 20ml soft material processed, cross 26 mesh sieves and granulate, dry 24 mesh sieve granulate under 45 ℃ of conditions, the magnesium stearate mix homogeneously of adding 1% gets blank slow release layer granule.Slow-releasing granules and immediate-release granules are made double-layer sustained release tablets with 8 ㎜ scrobicula punching presses.
Embodiment 3
Preparation technology: with immediate release section adjuvant sieve method mix homogeneously, the SLB solid dispersion is partly used the MCC equivalent replacement, gets the release layer granule; With silibinin crude drug and HPMCk4M, lactose polishing mix homogeneously, add 5%PVPk30 alcoholic solution 20ml soft material processed, cross 26 mesh sieves and granulate, dry under 45 ℃ of conditions, 24 mesh sieve granulate, the magnesium stearate mix homogeneously of adding 1% gets the slow release layer granule.Slow-releasing granules and immediate-release granules are made double-layer sustained release tablets with 8 ㎜ scrobicula punching presses.
Preparation technology: first main and all adjuvants are crossed respectively 80 mesh sieves.Silibinin solid dispersion in the release layer and other adjuvants in the release layer to cross the sieve method mix homogeneously, are added the abundant mix homogeneously of micropowder silica gel again, namely get immediate-release granules; Get silibinin and HPMCk4M, lactose polishing mix homogeneously in the slow release layer, 5%PVPk30 alcoholic solution 10ml soft material processed is crossed 26 mesh sieves and is granulated, and dries under 45 ℃ of conditions, and 24 mesh sieve granulate add the magnesium stearate mix homogeneously, namely get slow-releasing granules.Slow-releasing granules and immediate-release granules are made double-layer sustained release tablets with 8 ㎜ scrobicula punching presses.
Embodiment 5
Preparation technology: first main and all adjuvants are crossed respectively 80 mesh sieves.Silibinin solid dispersion in the release layer and other adjuvants in the release layer to cross the sieve method mix homogeneously, are added the abundant mix homogeneously of micropowder silica gel again, namely get immediate-release granules; Get silibinin and HPMCk4M, lactose polishing mix homogeneously in the slow release layer, 5%PVPk30 alcoholic solution 10ml soft material processed is crossed 26 mesh sieves and is granulated, and dries under 45 ℃ of conditions, and 24 mesh sieve granulate add the magnesium stearate mix homogeneously, namely get slow-releasing granules.Slow-releasing granules and immediate-release granules are made double-layer sustained release tablets with 8 ㎜ scrobicula punching presses.
Preparation technology: first principal agent and all adjuvants are crossed respectively 80 mesh sieves.Silibinin solid dispersion in the release layer and other adjuvants in the release layer to cross the sieve method mix homogeneously, are added the abundant mix homogeneously of micropowder silica gel again, get immediate-release granules; Get silibinin and HPMCk4M, lactose polishing mix homogeneously in the slow release layer, 5%PVPk30 alcoholic solution 10ml soft material processed is crossed 26 mesh sieves and is granulated, and dries under 45 ℃ of conditions, and 24 mesh sieve granulate add the magnesium stearate mix homogeneously, get slow-releasing granules.Slow-releasing granules and immediate-release granules are made 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 appendix drug release determinations of Chinese Pharmacopoeia method first method pertinent regulations.37 ± 0.5 ℃ of temperature, rotating speed are 100 rmin
-1, release medium is 0.5%SDS aqueous solution 1000ml, measures the release in vitro curve.The result sees respectively Fig. 2, Fig. 3, Fig. 4.In the release in vitro curve of Fig. 3, the cumulative release degree during silibinin double-layer sustained release tablets 0.5h is that 15～35%, 6 cumulative release degree are 50～70%, 12h cumulative release degree 〉=80%.
Carry out stability test with embodiment 2 prepared silibinin double-layer sustained release tablets, the result shows: in the accelerated test 6 months the time content of silibinin be 0 month 95.6%, in the long term test 12 months the time content of silibinin be 0 month 96.8%, other indices are all up to specification, 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 the silibinin double-layer sustained release tablets that embodiment 2 is prepared carries out zero level equation, First-order equation, Higuchi equation and Rigter-Peppas equation and carries out match, the results are shown in Table 1.
| Fit equation | Correlation coefficient | |
| The 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 |
| The Higuchi equation | Q=22.051t 1/2+6.8042 | R 2=0.9972 |
| The Rigter-Peppas equation | Q=0.4105t+3.3785 | R 2=0.9963 |
As shown in Table 1, the Higuchi equation can represent dispose procedure and the release dynamics feature of silibinin double-layer sustained release tablets.
Claims (10)
1. a silibinin (SLB) double-layer sustained release tablets is characterized in that, described silibinin double-layer sustained release tablets is comprised of release layer and slow release layer, and wherein release layer mainly is comprised of silibinin solid dispersion, filler, disintegrating agent, lubricant; Slow release layer mainly is comprised of silibinin crude drug, slow-release material, filler, lubricant and binding agent;
The contained disintegrating agent of described release layer is a kind of or its combination in any in L-HPC, CC-Na, PVPP, CMS-Na and the dried starch;
The contained slow-release material of described slow release layer is a kind of or its combination in any among HPMC, PVA, sodium alginate, carbomer, the 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, the sodium stearate; Wherein the weight ratio of silibinin content is 2:8～3:7 in release layer and the slow release layer.
2. silibinin double-layer sustained release tablets as claimed in claim 1 is characterized in that, the part by weight of described release layer and slow release layer is (1.5～2.3): 1.
3. such as claim 1 and 2 described silibinin double-layer sustained release tablets, it is characterized in that, silibinin solid dispersion carrier material is selected from a kind of or its combination in any in PEG, PVP, poloxamer, carbamide, the citric acid in the release layer, be preferably the combination of joint vector PEG6000 and poloxamer, more preferably mass ratio is the combination of PEG6000 and the poloxamer of 1:1; 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 MCC; Lubricant is preferably micropowder silica gel.
4. such as right 1～3 described silibinin double-layer sustained release tablets, it is characterized in that the weight ratio of silibinin and adjuvant is 1:(6.5～10 in the release layer).
5. such as the double-layer sustained release tablets of claim 1 and 2 described silibinin, it is characterized in that the 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.
6. such as the described silibinin double-layer sustained release tablets of claim 1,2 and 5, it is characterized in that the weight ratio of silibinin and adjuvant is 1:(0.8～1.5 in the slow release layer).
7. such as the double-layer sustained release tablets of the described silibinin of claim 1～6, it is characterized in that, count by weight percentage that described release layer and slow release layer consist of:
。
8. the double-layer sustained release tablets of silibinin as claimed in claim 7 is characterized in that, counts by weight percentage, and described release layer and slow release layer consist of:
。
9. preparation method such as the described silibinin double-layer sustained release tablets of claim 1～8 is characterized in that the method 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, and is for subsequent use;
(b) release layer preparation: with silibinin solid dispersion and required adjuvant mix homogeneously, obtain the release layer mixture, for subsequent use;
(c) slow release layer preparation: with silibinin and required adjuvant mix homogeneously, obtain the slow release layer mixture, for subsequent use;
(d) granulate: respectively described release layer mixture and slow release layer mixture are carried out direct powder compression or dry granulation or wet granulation, cross 20～60 mesh sieves, add an amount of mixing of lubricant, obtain release layer granule and slow release layer granule;
(e) tabletting: the light slow release layer granule of pressing becomes loose first, adds the extrusion forming of release layer granule, tablet hardness 60～80N again; Or (d) gained release layer granule and slow release layer granule carried out tabletting on bi-layer tablet press, namely get the silibinin double-layer sustained release tablets.
10. such as each described silibinin double-layer sustained release tablet of claim 1～8, 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%, in discharge first hour mainly by the release layer release, after first hour by the slow release layer release.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN112791057A (en) * | 2021-02-07 | 2021-05-14 | 齐飞 | Slow release preparation containing edoxaban and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
-
2012
- 2012-09-06 CN CN201210326074.5A patent/CN102846573B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN112791057A (en) * | 2021-02-07 | 2021-05-14 | 齐飞 | Slow release preparation containing edoxaban 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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| CN102846573B (en) | 2014-09-03 |
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