CN101961319A - Silybin meglumine enteric agent with high bioavailability and preparation method thereof - Google Patents
Silybin meglumine enteric agent with high bioavailability and preparation method thereof Download PDFInfo
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- CN101961319A CN101961319A CN 201010286575 CN201010286575A CN101961319A CN 101961319 A CN101961319 A CN 101961319A CN 201010286575 CN201010286575 CN 201010286575 CN 201010286575 A CN201010286575 A CN 201010286575A CN 101961319 A CN101961319 A CN 101961319A
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Abstract
The invention relates to the field of medical agent, in particular to a silybin meglumine enteric agent with high bioavailability and a preparation method thereof. The preparation method is characterized by comprising the following steps of: preparing the silybin meglumine into solid dispersoid; adding the medical auxiliary materials to prepare to be the grain, the tablet or the pellet; and packing the grain, the tablet or the pellet into an enteric coat. With the unique shape, the silybin meglumine can not be released in the stomach but can be fast dissolved and absorbed in the intestinal canal; and by being prepared to be the solid dispersoid, the silybin meglumine increases the solubility in the water. Therefore, the invention increases the absorbed dose of the silybin meglumine, has higher bioavailability compared with the common tablet or capsule, is good for curing the hepatopathy, and is simple in preparation technology.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, be specifically related to silybin meglumine enteric coated preparation of a kind of high bioavailability and preparation method thereof.
Background technology
Silibinin (silybin or silibinin) is a kind of flavone compound that extraction separation obtains from feverfew Herba Silybi mariani (Silybum marianum Gaertn) fruit, the good curing hyperlipidemia is arranged, eliminate free radical, anti-liver lipid peroxidation effect is that medicine is repaired in the hepatic injury of determined curative effect.But because its poor solubility in water, fat-soluble also very poor, oral administration biaavailability is very low.In order to improve the water solublity of silibinin, existing people is combined into silybin meglumine with silibinin and meglumine (1-methylamino-1-deoxidation sorbitol).
Silybin meglumine, English name: Silybin Meglumine, chemical name is: 2-[2,3-dihydro-2-(4-hydroxy 3-methoxybenzene base)-3-(hydroxymethyl)-1,4-benzo dioxin-6-yl]-2,3-dihydro-3,5,7-trihydroxy-4H-1-.alpha.-5:6-benzopyran-4-ketone, this product is yellow amorphous powder, almost odorless, the mildly bitter flavor band is puckery, have draw moist.In water, dissolve, molten at methanol or ethanol part omitted, slightly soluble in acetone, soluble,very slightly in chloroform.The molecular formula of this product is C
32H
39O
15N, molecular weight are 677.66.
When discovering 37 ℃, the saturation solubility of silibinin in water is 32.46 μ g/ml, and the saturation solubility of silybin meglumine in water is 4.56mg/ml.
Clinical practice at present silybin meglumine tablets agent and capsule arranged, in order to improve its bioavailability, present existing patent is as follows: silybin meglumine dispersible tablet of treatment hepatitis and preparation method thereof (CN 100348199C), silybin meglumine oral cavity disintegration tablet and preparation technology thereof (CN 1254240C), the prescription of silibinin-n-methylglucamine drop pills and preparation technology thereof (CN1875962A).Though these silybin meglumine dispersible tablets, oral cavity disintegration tablet and drop pill have improved the oral administration biaavailability of silibinin to a certain extent, its raising is limited.
Summary of the invention
The invention discloses a kind of silybin meglumine preparation of high bioavailability, the invention discloses a kind of silybin meglumine enteric coated preparation, because its dosage form is relatively unique, institute is not so that silybin meglumine discharges under one's belt, but can dissolve rapidly at intestinal, absorb, in addition, by silybin meglumine is made solid dispersion, increased the dissolubility of silybin meglumine in water, thereby increased the absorbtivity of silybin meglumine, this product help the treatment of hepatopathy, and preparation technology is simple than conventional tablet or capsular bioavailability height.
In order further to improve the bioavailability of silybin meglumine, by more various route of administration, the bioavailability of finding to pass through silybin meglumine behind the duodenal administration is apparently higher than other oral routes.
We compare for respectively rat oral gavage administration and the AUC after the direct administration of duodenum by the dosage of 9.1mg/kg (in silibinin) in the research.The blood medicine through the time concentration curve the results are shown in Figure 1, data obtain AUC by 3P97 software The Fitting Calculation, find AUC
Duodenal administration/ AUC
Gastric infusion=2.38.From the data of AUC ratio as can be seen, silybin meglumine is made the bioavailability that enteric coated preparation can obviously improve silybin meglumine.
After having determined that silybin meglumine is made enteric coated preparation, we design according to a conventional method and silybin meglumine is added pharmaceutic adjuvant are prepared into behind granule, tablet or the micropill enteric coated again.In preparation during micropill, we have at first attempted preparing silybin meglumine and containing pill core by extruding round as a ball method, wrap one deck enteric coating film then on this basis again.Found that because silybin meglumine has the character of Chinese medical concrete, water or a certain proportion of alcoholic solution are done binding agent and be difficult to prepare the qualified pill core that contains, and have abandoned this kind technology at last.Secondly, we attempt adopting celphere medicine-feeding legal system to be equipped with the silybin meglumine enteric coated micropill.Compare with silibinin though found that silybin meglumine, improved its water solublity, for ball core medicine-feeding method, dissolubility is still not enough, has only 4.56mg/ml.If directly go preparation to contain pill core with such dissolubility, must cause production efficiency low excessively, the production time of a collection of preparation is long.We have attempted also that in addition silybin meglumine is made into suspension and have directly added medicine to, but the crude drug particle diameter is blocked nozzle than Da Yi.
We consider to adopt the method that increases medicine dissolubility in water based on above research, for its preparation that contains pill core lays the foundation.We adopt silybin meglumine are made refabrication micropill behind the solid dispersion, and the result has overcome the various shortcoming in the above-mentioned preparation process.
Silybin meglumine and solid dispersion thereof the dissolubility in 37 ℃ of water sees Table 1.The result as can be seen, the saturation solubility of prepared silybin meglumine solid dispersion in water reaches as high as 500mg/ml, compares with the saturation solubility of silybin meglumine in water and improved nearly 100 times.
Table 1 silybin meglumine and solid dispersion thereof the dissolubility in 37 ℃ of water
| Dissolubility (mg/ml) | Water |
| Silybin meglumine | 4.56 |
| The silybin meglumine solid dispersion | 500 |
We give the rat oral gavage administration by the dosage of 9.1mg/kg (in silibinin) respectively with silybin meglumine and silybin meglumine solid dispersion in the research, the blood medicine through the time concentration curve the results are shown in Figure 2, data obtain AUC by 3P97 software The Fitting Calculation.Find AUC
The silybin meglumine solid dispersion/ AUC
Silybin meglumine=1.28.From the data of AUC ratio as can be seen, silybin meglumine is made the bioavailability that the solid dispersion physical ability obviously improves silybin meglumine.
Formed the application's technical scheme based on above-mentioned invention.
Silybin meglumine oral formulations of the present invention is that silybin meglumine is prepared into solid dispersion earlier, adds pharmaceutic adjuvant again and makes granule, tablet or micropill, and granule, tablet or micropill is promptly enteric coated.
It is routine techniques that silybin meglumine is prepared into solid dispersion, is about to silybin meglumine and makes with the solid dispersion carrier of using always.Can be methods such as solvent method, fusion method or polishing.
The solid dispersion carrier is preferably from Macrogol 4000, polyethylene glycol 6000,30 POVIDONE K 30 BP/USP 15,30 POVIDONE K 30 BP/USP 30,30 POVIDONE K 30 BP/USP 90, poloxamer 188, microcrystalline Cellulose, polyoxyethylene, carbopol, mannitol, sorbitol, xylitol, sucrose, chitosan, galactose, polyacrylic resin base polymer, cellulose acetate-phthalate, phthalic acid hypromellose, carboxylic first and second celluloses one or more.
The solid dispersion carrier more preferably is selected from: Macrogol 4000, polyethylene glycol 6000,30 POVIDONE K 30 BP/USP 15,30 POVIDONE K 30 BP/USP 30, one or more in the 30 POVIDONE K 30 BP/USP 90.
The weight ratio of silybin meglumine and solid dispersion carrier is preferred: 1: 0.1～1: 1.
After finishing the preparation of solid dispersion, add pharmaceutic adjuvant and be prepared into granule, micropill or tablet, enteric coated again getting final product.Described pharmaceutic adjuvant is selected from disintegrating agent and binding agent.Also can add diluent, lubricant etc.
Described disintegrating agent is selected from: one or more in low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, the carboxymethyl starch sodium.
Described binding agent is selected from: ethanol/water mixed solution, water, 30 POVIDONE K 30 BP/USP 15,30 POVIDONE K 30 BP/USP 30, one or more in 30 POVIDONE K 30 BP/USP 90, the hydroxypropyl emthylcellulose.
The weight ratio of solid dispersion and pharmaceutic adjuvant is preferred: 1: 2～1: 6.
Enteric-coating material preferred acrylic resins of the present invention.
Enteric-coating material increases weight preferred 5～25%.
The present invention has not only overcome all difficulty of silybin meglumine in preparation, and bioavailability height, the enteric coated preparation of silybin meglumine solid dispersion and silybin meglumine ordinary preparation compare, and its bioavailability is 4.27 times of ordinary preparation.See Fig. 3.
Description of drawings
Fig. 1 be administration of silybin meglumine rat oral gavage and duodenal administration blood concentration through the time curve
Fig. 2 be silybin meglumine and the administration of silybin meglumine solid dispersion rat oral gavage blood concentration through the time curve
Blood concentration when Fig. 3 is the beasle dog oral administration of silybin meglumine solid dispersion enteric coated capsule of the present invention and commercially available silybin meglumine ordinary tablet through the time curve (n=3)
The specific embodiment
Embodiment 1
Micropill:
Consumption
Silybin meglumine 50mg
30 POVIDONE K 30 BP/USP 30 (PVP K30) 50mg
Sucrose 180mg
Microcrystalline Cellulose 20mg
Suitable (acrylic resin L30D-55) 60mg of refined gram
All on sale on the above-mentioned raw materials market, easily purchase.
Above weight is every weight that capsule is contained.
Its preparation method is: feed intake by 1000 capsular amounts.Step 1, silybin meglumine is placed eggplant-shape bottle, adding dehydrated alcohol dissolves medicine in 60 ℃ fully, after adding 30 POVIDONE K 30 BP/USP 30 dissolvings then eggplant-shape bottle is placed 60 ℃ of evacuation, remove dehydrated alcohol, crushing screening is dissolved in the distilled water, the dissolving back is as the pastille solution for standby, the mixed accessories that other takes by weighing sucrose, microcrystalline Cellulose places fluid bed, will contain drug solns then and be sprayed onto on the mixed accessories, obtains containing pill core; Step 2 takes by weighing refined gram and should (acrylic resin) be made into certain solid content with deionized water, stirs evenly, and as enteric coating liquid, then coating solution is sprayed onto in the step 1 on the gained micropill, promptly.
Micropill
Consumption
Silybin meglumine 50mg
Macrogol 4000 (PEG4000) 10mg
Starch 200mg
Hydroxypropyl emthylcellulose 10mg
You Teqi (acrylic resin L100-55) 40mg
All on sale on the above-mentioned raw materials market, easily purchase.
Above weight is the contained weight of each dosage.
Its preparation method is: feed intake by 1000 capsular amounts.Step 1, silybin meglumine and Macrogol 4000 mixing are placed in the beaker, 60 ℃ make the complete fusion of this mixture, then the fused mass cryogenic quenching is solidified, crushing screening is dissolved in the distilled water that contains hydroxypropyl emthylcellulose E3, the dissolving back is as the pastille solution for standby, other takes by weighing a certain amount of blank starch ball core and places fluid bed, will contain drug solns then and be sprayed onto on the celphere, obtains containing pill core; Step 2 takes by weighing You Teqi (acrylic resin L30D-55) and is diluted to certain solid content with deionized water, stirs evenly, and as enteric coating liquid, then coating solution is sprayed onto in the step 1 on the gained micropill, promptly.
Embodiment 3
Tablet
Consumption
Silybin meglumine 50mg
30 POVIDONE K 30 BP/USP 90 (PVP K90) 15mg
Microcrystalline Cellulose 100mg
Carboxymethyl starch sodium 5mg
Pulvis Talci 3mg
You Teqi (acrylic resin L30D-55) 20mg
Above weight is every contained weight.
Its preparation method is: the amount by 1000 feeds intake.Step 1, silybin meglumine and 30 POVIDONE K 30 BP/USP 90 (PVP K90) mixing are placed in the ball mill, speed is 500 rev/mins, time is 60 minutes, takes out then and pulverizes 80 mesh sieves, with remaining microcrystalline cellulose excipients, carboxymethyl starch sodium, the Pulvis Talci mixing by tabletting behind the dry granulation, gets the pastille label; Step 2 takes by weighing You Teqi (acrylic resin L30D-55) and is diluted to certain solid content with deionized water, stirs evenly, and as enteric coating liquid, then coating solution is sprayed onto in the step 1 on the gained label, promptly.
Capsule
Consumption
Silybin meglumine 50mg
30 POVIDONE K 30 BP/USP 90 (PVP K90) 5mg
Microcrystalline Cellulose 50mg
Pulvis Talci 3mg
You Teqi (acrylic resin L30D-55) 30mg
Above weight is every weight that capsule is contained.
Its preparation method is: feed intake by 1000 capsular amounts.Step 1 is placed on silybin meglumine and 30 POVIDONE K 30 BP/USP 90 (PVPK90) mixing in the ball mill, and speed is 600 rev/mins, time is 30 minutes, takes out then and pulverizes 80 mesh sieves, with remaining microcrystalline cellulose excipients, Pulvis Talci mixing, directly fill hard capsule; Step 2 takes by weighing You Teqi (acrylic resin L30D-55) and is diluted to certain solid content with deionized water, stirs evenly, and as enteric coating liquid, then coating solution is sprayed onto in the step 1 on the gained hard capsule, promptly.
Embodiment 5
Capsule
Consumption
Silybin meglumine 50mg
30 POVIDONE K 30 BP/USP 90 (PVP K90) 10mg
Microcrystalline Cellulose 50mg
Pulvis Talci 3mg
You Teqi (acrylic resin L30D-55) 50mg
Above weight is every weight that capsule is contained.
Its preparation method is: feed intake by 1000 capsular amounts.Step 1, silybin meglumine and 30 POVIDONE K 30 BP/USP 90 (PVPK90) mixing are placed in the ball mill, speed is 600 rev/mins, time is 90 minutes, take out then and pulverized 80 mesh sieves, with remaining microcrystalline cellulose excipients, the Pulvis Talci mixing, do adhesive system granule with 60% ethanol, 60 ℃ of oven dry; Step 2 takes by weighing You Teqi (acrylic resin L30D-55) and is diluted to certain solid content with deionized water, stirs evenly, and as enteric coating liquid, then coating solution is sprayed onto in the step 1 on the gained granule, last directly fill hard capsule, promptly.
Claims (8)
1. silybin meglumine oral formulations is characterized in that: silybin meglumine is prepared into solid dispersion earlier, adds pharmaceutic adjuvant again and make granule, tablet or micropill, and granule, tablet or micropill is promptly enteric coated.
2. the silybin meglumine oral formulations of claim 1, wherein the weight ratio of silybin meglumine and solid dispersion carrier is: 1: 0.1～1: 1.
3. the silybin meglumine oral formulations of claim 1, wherein the solid dispersion carrier is selected from: one or more in Macrogol 4000, polyethylene glycol 6000,30 POVIDONE K 30 BP/USP 15,30 POVIDONE K 30 BP/USP 30,30 POVIDONE K 30 BP/USP 90, poloxamer 188, microcrystalline Cellulose, polyoxyethylene, carbopol, mannitol, sorbitol, xylitol, sucrose, chitosan, galactose, polyacrylic resin base polymer, cellulose acetate-phthalate, phthalic acid hypromellose, carboxylic first and second celluloses.
4. the silybin meglumine oral formulations of claim 3, wherein the solid dispersion carrier is selected from one or more in Macrogol 4000, polyethylene glycol 6000,30 POVIDONE K 30 BP/USP 15,30 POVIDONE K 30 BP/USP 30, the 30 POVIDONE K 30 BP/USP 90.
5. the silybin meglumine oral formulations of claim 1, wherein pharmaceutic adjuvant is disintegrating agent and binding agent.
6. the silybin meglumine oral formulations of claim 1, wherein the weight ratio of solid dispersion and pharmaceutic adjuvant is: 1: 2～1: 6.
7. the silybin meglumine oral formulations of claim 1, wherein enteric-coating material is an acrylic resin.
8. the silybin meglumine oral formulations of claim 1, wherein the enteric-coating material weightening finish 5～25%.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104069071A (en) * | 2014-06-25 | 2014-10-01 | 江苏大学 | Silibinin slow release micropill with double layers of coatings and preparation method of silibinin slow release micropill |
| CN108456199A (en) * | 2017-02-20 | 2018-08-28 | 南京宸翔医药研究有限责任公司 | A kind of production technology, pharmaceutical composition and its clinical application of high-purity silymarin meglumine |
| CN112587488A (en) * | 2020-12-16 | 2021-04-02 | 福建瑞泰来医药科技有限公司 | Silybin composition and preparation method thereof |
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| CN1418637A (en) * | 2002-12-19 | 2003-05-21 | 王登之 | Silicibinin-N-methylglucamine disperser for treating hepatitis, and its prepn. method |
| CN1543943A (en) * | 2003-11-26 | 2004-11-10 | 沈阳药科大学 | Oral silybin sustained release agent and preparation thereof |
| CN1660076A (en) * | 2004-12-16 | 2005-08-31 | 中国药科大学 | Preparation of slowly releasing silybum mariamum |
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2010
- 2010-09-16 CN CN2010102865756A patent/CN101961319B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1418637A (en) * | 2002-12-19 | 2003-05-21 | 王登之 | Silicibinin-N-methylglucamine disperser for treating hepatitis, and its prepn. method |
| CN1543943A (en) * | 2003-11-26 | 2004-11-10 | 沈阳药科大学 | Oral silybin sustained release agent and preparation thereof |
| CN1660076A (en) * | 2004-12-16 | 2005-08-31 | 中国药科大学 | Preparation of slowly releasing silybum mariamum |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104069071A (en) * | 2014-06-25 | 2014-10-01 | 江苏大学 | Silibinin slow release micropill with double layers of coatings and preparation method of silibinin slow release micropill |
| CN108456199A (en) * | 2017-02-20 | 2018-08-28 | 南京宸翔医药研究有限责任公司 | A kind of production technology, pharmaceutical composition and its clinical application of high-purity silymarin meglumine |
| CN112587488A (en) * | 2020-12-16 | 2021-04-02 | 福建瑞泰来医药科技有限公司 | Silybin composition and preparation method thereof |
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