CN100335050C - Compsn. of medication of silybum mariamum - Google Patents
Compsn. of medication of silybum mariamum Download PDFInfo
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- CN100335050C CN100335050C CNB2005100133907A CN200510013390A CN100335050C CN 100335050 C CN100335050 C CN 100335050C CN B2005100133907 A CNB2005100133907 A CN B2005100133907A CN 200510013390 A CN200510013390 A CN 200510013390A CN 100335050 C CN100335050 C CN 100335050C
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- silibinin
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Abstract
The present invention relates to the medical composition of silibinin, which comprises silibinin with the effective quantity and a self-micro-emulsion medicine releasing system, wherein the weight ratio of the silibinin and the self-micro-emulsion medicine releasing system is 1: 5 to 100. A surface active agent, an auxiliary surface active agent and an oil phase of the self-micro-emulsion medicine releasing system are formed by that the surface active agent is from 20 to 60 %, the auxiliary surface active agent is from 0.1 to 40 %, and the oil phase is from 20 to 50 %, the surface active agent is a derivate of polyoxyethylene castor oil, the auxiliary surface active agent adopts and selects ethanol or diethylene glycol single aether, and the oil phase selects and adopts medium-chain triglyceride glycerate or edible vegetable oil. The present invention can form stable water drum oil emulsion of which the grain diameter is less than 1 mum, and can be suitable for the preparation of oral agents such as soft capsules, liquid capsules, oral medicinal liquid, etc. The present invention can be quickly distributed in the whole gstrointestinal tract, can reduce stimulation caused by the direct contact of medicine and the gastrointestinal wall, and can greatly improve biological availability.
Description
Technical field
The present invention relates to the pharmaceutical composition of silibinin, the prescription of said composition is applicable to the preparation of peroral dosage forms such as soft capsule, liquid capsule.
Background technology
Silibinin (Silybin) is extraction separation and flavanolignan's class monomer component of obtaining from feverfew Herba Silybi mariani (Silybum marianum) fruit; the effect that has protection and stablize liver plasma membrane; and can promote liver cell regeneration, be mainly used in diseases such as the various acute, chronic hepatitis of treatment, the poisoning of first cirrhosis regulating liver-QI.The molecular formula of silibinin: C
25H
22O
10Chemical name is that 2 α-[2,3-is trans-2,3-dihydro-3-(4-hydroxy 3-methoxybenzene base)-2-methylol-1,4-benzodioxane-6-yl]-2,3-dihydro-3 β, 5,7-trihydroxy-4H-1-.alpha.-5:6-benzopyran-4-ketone monohydrate, be off-white color or pale yellow powder, almost insoluble in water, soluble,very slightly in ethanol, and in acetone slightly soluble.The dosage form of silibinin preparation mainly contains ordinary tablet and capsule formulation at present.Be limited to silibinin and be insoluble in water and common organic solvents, oral absorption is poor, and its bioavailability is lower, thereby has influenced its clinical efficacy.
In order to improve the bioavailability of silibinin, domestic and international many researcheres have been done a large amount of effort.Seeley guest amine sheet is that the water soluble preparation that organic amine salt is an active component is made in silibinin and the reaction of organic amine meglumine; Silibinin-phospholipid acid choline complex shows stronger fat-soluble, and water solublity reduces, and promotes drug molecule combine with cell membrane and promotes absorption, the raising bioavailability of medicament.
Summary of the invention
The pharmaceutical composition that the purpose of this invention is to provide a kind of new silibinin, silibinin and surfactant, cosurfactant, oil phase be combined into the pharmaceutical composition that comprises the active component silibinin, this compositions is under room temperature and gentle agitation, and spontaneous formation particle diameter is less than the oil-in-water Emulsion of 1 μ m in the water.Preparation applicable to peroral dosage forms such as soft capsule, liquid capsule, oral liquids.The present invention can be distributed in the whole gastrointestinal tract fast, has reduced owing to medicine and gastrointestinal wall direct contacts the stimulation that causes, bioavailability improves greatly.
The self-micro-emulsification medicine-releasing system is the solution of the transparent and homogeneous that formed by oil phase, surfactant and cosurfactant, and under ambient temperature and gentle agitation situation, spontaneous emulsification forms particle diameter less than 1 micron Emulsion.Medicine is present in these tiny oil droplets, is distributed in fast in the whole gastrointestinal tract, has reduced owing to medicine and gastrointestinal wall direct contacts the stimulation that causes.Medicine distributes between oil/water is biphase, and the stripping that relies on the huge surface area of tiny oil droplet to improve poorly water soluble drugs has greatly improved bioavailability of medicament.Studies show that the absorption of poorly water soluble drugs, bioavailability and emulsion droplet size are closely related, emulsion droplet is thin more, and it is good more to absorb, and bioavailability is high more.
Pharmaceutical composition of the present invention comprises the silibinin and the self-micro-emulsification medicine-releasing system of effective dose, and wherein, the self-micro-emulsification medicine-releasing system is made up of surfactant, cosurfactant and oil phase.
Weight ratio=1 of silibinin and self-micro-emulsification medicine-releasing system: 5-100 in the pharmaceutical composition of the present invention.Preferred 1: 15-30.
The surfactant of self-micro-emulsification medicine-releasing system, cosurfactant and oil phase percentage ratio are in the pharmaceutical composition:
Surfactant 20～60%
Cosurfactant 0.1～40%
Oil phase 20～50%
Above-mentioned surfactant is meant that selecting the HLB value for use is 10 to 19 hydrophilic surfactant active, and this class surfactant is a castor oil derivatives: Cremophor EL, Cremophor RH40, Cremophor 60 (being German BASF AG produces); Or Tweens: Tween 80, Tween 65, Tween 20 or wheat pool class (Myrj 52) one of or they optional two or more.Preferential is castor oil derivatives.
Above-mentioned cosurfactant is selected ethanol or diethylene glycol monoethyl ether (trade name: Transcutol P for use, one of France Jia Fasai company produces), or Transcutol P and alcohol mixture, wherein ethanol and Transcutol P ratio are 1: 1-10 is preferably 1: 3-7.
Above-mentioned oil phase is selected midchain glycerine triglyceride (trade name: Labrafac CC, French Jia Fasai company produces) or edible vegetable oil for use, or their mixture; Wherein vegetable oil can be selected Semen Maydis oil, Oleum Ricini, Oleum Glycines, and the best is an Oleum Ricini, and Oleum Ricini and Labrafac CC ratio are preferably 1: 0-10, the best is 1: 0.5-2.
The weight of the pharmaceutical composition of silibinin recited above is formed, and is wherein preferred:
Labrafac?CC 25-40％
Cremophor?RH40 25-50％
Transcutol?P 15-30％
Ethanol 2-6%
Labrafac?CC 12-25％
Oleum Ricini 12-20%
Cremophor?EL 25-50％
Transcutol?P 15-30％
Ethanol 2-6%
Labrafac?CC 12-25％
Oleum Ricini 12-25%
Cremophor?RH40 25-35％
Transcutol?P 15-35％
Oleum Ricini 20-40%
Cremophor?EL 25-45％
Transcutol?P 15-30％
Ethanol 2-6%
When compositions of the present invention is made various dosage form, as required, can add needed adjuvant of concrete dosage form or additives, as antioxidant, flavoring agent, antiseptic or the like, be not subjected to the restriction of listed content.The preparation method of different dosage form can require according to the routine of this dosage form to carry out.
Preparation technology of the present invention adds the cosurfactant sonic oscillation in the silibinin of metering to become solution, and under agitation once more oil phase and surfactant is added in the gained solution, and pack into hard capsules and sealing of mixture makes liquid capsule; Or mixture is pressed into soft capsule with the Zhanang machine.
Pharmaceutical composition of the present invention contains the 35mg silibinin in every capsules, 3 times on the one, each 2, amounted to 6 in one day.
The present composition forms the stable oil-in-water Emulsion of particle diameter less than 1 μ m under room temperature and gentle agitation.The present invention is applicable to the preparation of peroral dosage forms such as soft capsule, liquid capsule.The present invention can be distributed in the whole gastrointestinal tract fast, has reduced owing to medicine and gastrointestinal wall direct contacts the stimulation that causes, bioavailability improves greatly.
The following examples will be made a more detailed description to the present invention.But, should be understood that these embodiment be not be used for limiting of the present invention.
The specific embodiment
The capsular preparation of embodiment 1 silibinin
Preparation technology adds the cosurfactant sonic oscillation in the silibinin of metering to become solution, and under agitation once more oil phase and surfactant is added in the gained solution, and pack into hard capsules and sealing of mixture makes liquid capsule; Or mixture is pressed into soft capsule with the Zhanang machine.Following preparation technology is identical.
Amounts of components (gram)
Silibinin 35
Labrafac?CC 200
Cremophor?RH40 260
Transcutol?P 130
Ethanol 30
Make 1000
Embodiment 2
Amounts of components (gram)
Silibinin 35
Labrafac?CC 100
Oleum Ricini 100
Cremophor?EL 400
Transcutol?P 170
Ethanol 30
Make 1000
Embodiment 3
Amounts of components (gram)
Silibinin 35
Labrafac?CC 130
Oleum Ricini 120
Cremophor?RH40 120
Transcutol?P 200
Make 1000
Embodiment 4
Amounts of components (gram)
Silibinin 35
Oleum Ricini 240
Cremophor?EL 360
Transcutol?P 170
Ethanol 30
Make 1000
Embodiment 5
Amounts of components (gram)
Silibinin 35
Labrafac?CC 130
Oleum Ricini 120
Cremophor?RH40 120
Transcutol?P 170
Ethanol 30
Make 1000
Get amount of embodiment 5 pharmaceutical compositions, add 500ml, in 37 ℃ of water, gentle agitation 5min under the 50r/min rotating speed obtains being with the blue light clear solution, measures at BI-90Plus laser particle analyzer (Nicolet Instrument Co.), the results are shown in Figure 1.Wherein abscissa is represented emulsion particle diameter (lgnm), and vertical coordinate is represented little emulsion droplet number (%), and mean diameter is 57.5nm, and polydispersity (claiming dispersion of distribution index again) is 0.270.
Claims (8)
1, a kind of pharmaceutical composition that contains silibinin, it comprises the silibinin and the self-micro-emulsification medicine-releasing system of effective dose, wherein, the self-micro-emulsification medicine-releasing system is made up of surfactant, cosurfactant and oil phase, it is characterized in that weight ratio=1 of silibinin and self-micro-emulsification medicine-releasing system: 5-100; Surfactant, cosurfactant and oil phase percentage ratio are in the described self-micro-emulsification medicine-releasing system:
Surfactant 20～60%
Cosurfactant 0.1～40%
Oil phase 20～50%
Surfactant is a castor oil derivatives: Cremophor EL, Cremophor RH40, Cremophor 60; Or Tweens: Tween 80, Tween 65, Tween 20 or wheat pool class (Myrj 52) one of or they optional two or more;
Above-mentioned cosurfactant is selected ethanol or diethylene glycol monoethyl ether for use, or diethylene glycol monoethyl ether and alcohol mixture, and wherein ethanol and Transcutol P ratio are 1: 1-10;
Above-mentioned oil phase is selected midchain glycerine triglyceride or edible vegetable oil for use, or their mixture, and wherein vegetable oil can be selected Semen Maydis oil, Oleum Ricini, Oleum Glycines; Oleum Ricini and Labrafac CC ratio are 1: 0-10.
3, pharmaceutical composition according to claim 1, the weight ratio that it is characterized in that described silibinin and self-micro-emulsification medicine-releasing system is 1: 15-30.
4, pharmaceutical composition according to claim 1 is characterized in that described surfactant is a castor oil derivatives.
5, pharmaceutical composition according to claim 1 is characterized in that described oil phase is an Oleum Ricini.
6, pharmaceutical composition according to claim 1 is characterized in that the weight of described self-micro-emulsification medicine-releasing system is formed:
Labrafac?CC 25-40％
Cremophor?RH40 25-50％
Transcutol?P 15-30％
Ethanol 2-6%.
7, pharmaceutical composition according to claim 1 is characterized in that the weight of described self-micro-emulsification medicine-releasing system is formed:
Labrafac?CC 12-25％
Oleum Ricini 12-20%
Cremophor?EL 25-50％
Transcutol?P 15-30％
Ethanol 2-6%.
8, pharmaceutical composition according to claim 1 is characterized in that the weight of described self-micro-emulsification medicine-releasing system is formed:
Labrafac?CC 12-25％
Oleum Ricini 12-25%
Cremophor?RH40 25-35％
Transcutol?P 15-35％。
9, pharmaceutical composition according to claim 1 is characterized in that the weight of described self-micro-emulsification medicine-releasing system is formed:
Oleum Ricini 20-40%
Cremophor?EL 25-45％
Transcutol?P 15-30％
Ethanol 2-6%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005100133907A CN100335050C (en) | 2005-04-30 | 2005-04-30 | Compsn. of medication of silybum mariamum |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005100133907A CN100335050C (en) | 2005-04-30 | 2005-04-30 | Compsn. of medication of silybum mariamum |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1695610A CN1695610A (en) | 2005-11-16 |
| CN100335050C true CN100335050C (en) | 2007-09-05 |
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| Application Number | Title | Priority Date | Filing Date |
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| CNB2005100133907A Expired - Fee Related CN100335050C (en) | 2005-04-30 | 2005-04-30 | Compsn. of medication of silybum mariamum |
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Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101342167B (en) * | 2007-07-10 | 2012-03-21 | 陈亚玲 | Medicament composition |
| CN103285401A (en) * | 2013-05-27 | 2013-09-11 | 沈阳药科大学 | Composition capable of improving solubility and bioavailability of insoluble medicament |
| CN104688845A (en) * | 2015-03-25 | 2015-06-10 | 江苏永璋伟业健康科技有限公司 | Method for separating and preparing pyrrole butyric acid self-emulsion from radix ranunculi ternati and application of pyrrole butyric acid self-emulsion |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1316898A (en) * | 1999-07-05 | 2001-10-10 | 韩美药品工业株式会社 | Oral micro-emulsion composition of silybin |
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2005
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1316898A (en) * | 1999-07-05 | 2001-10-10 | 韩美药品工业株式会社 | Oral micro-emulsion composition of silybin |
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| CN1695610A (en) | 2005-11-16 |
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Assignee: Tianjin Pacific Pharmaceutical Co., Ltd. Assignor: Tianjin Pacific Pharmaceutical Co., Ltd. Contract record no.: 2012120000011 Denomination of invention: Compsn. of medication of silybum mariamum Granted publication date: 20070905 License type: Exclusive License Open date: 20051116 Record date: 20120312 |
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Granted publication date: 20070905 Termination date: 20130430 |