CN100389767C - Injectable stable pharmaceutical composition containing active ingredient silibinin and its salt - Google Patents
Injectable stable pharmaceutical composition containing active ingredient silibinin and its salt Download PDFInfo
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- CN100389767C CN100389767C CNB2006100035646A CN200610003564A CN100389767C CN 100389767 C CN100389767 C CN 100389767C CN B2006100035646 A CNB2006100035646 A CN B2006100035646A CN 200610003564 A CN200610003564 A CN 200610003564A CN 100389767 C CN100389767 C CN 100389767C
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Abstract
The present invention relates to an injectable stable pharmaceutical composition containing active ingredient silibinin and salt, which is characterized in that the pharmaceutical composition is composed of active ingredient silibinin, salt, a water soluble filling agent, a pH regulating agent, a stabilizing agent, water for injection and a regulating agent of osmotic pressure; the pH values of a freeze dried powder needle of a preparation, small needle injection and small transfusion in the state of water solution are from 7 to 9. The stabilizing agent disclosed by the present invention needs adding, wherein tris-hydroxymethyl aminomethane is preferable. The present invention simultaneously discloses preparation methods of a freeze dried agent, the small needle injection and the small transfusion. The injectable stable pharmaceutical composition containing active ingredient silibinin and salt, which is prepared by the present invention, is suitable for the treatment of the acute paroxysm of hepatitis.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, more particularly relate to a kind of stable pharmaceutical composition that contains the administrated by injection of active component silibinin and salt thereof.
Background technology
Hepatitis is meant the liver inflammation.It comprises the hepatitis that Different types of etiopathogenises is different.But viral hepatitis is the most common in the daily life, so people abbreviate viral hepatitis as hepatitis habitually.Viral hepatitis is that common clinically a kind of liver damage is main, the infectious disease of immune dysfunction.It has the sickness rate height, and the course of disease is long, and the patient's condition repeatability is strong, and the characteristics that hazardness is bigger if do not treat effectively and timely, very easily change hepatitis interstitialis chronica and hepatocarcinoma into.At present viral hepatitis is mainly divided five kinds of first type, B-mode, third type, fourth type and hepatitis Es, finds to have own type hepatitis and hepatitis G in recent years again.Wherein first type and hepatitis E have self limiting, generally can not transfer to chronicly, and minority can develop into liver cirrhosis.Chronic hepatitis B and primary hepatoma substantial connection arranged.Calculate that according to existing investigation there are 1.2 hundred million human hepatitis B virus in China, the chronic viral hepatitis B patient is about, and 3,000 ten thousand, 3,800 ten thousand people carry hepatitis C virus., almost be that national people ten have one only from the numeral of hepatitis B virus carriers.
Silibinin is insoluble in water very much, makes that water solublity increases behind the meglumine salt.The sheet that silibinin and salt thereof (Seeley guest amine) is arranged in the market, also have silibinin and the oral cavity disintegration tablet of salt and the patent of reporting (200410069355.2 and 02156856.1) of dispersible tablet in the document, disclose the preparation method (200410023873.0) of silibinin salt freeze-dried powder recently again.The inventor emphasizes to have used solubilizing agent in the claims, and pH value is 7-12 when emphasizing that freeze-dried powder adds equal-volume water.As everyone knows, the physiological PH value that human body tolerated in the preparation of administrated by injection is 4-9, is PH10-12 and the inventor emphasizes in example, and this certainly will cause the zest of human body, and this method is that physiology is unacceptable.Silibinin and salt thereof are unstable under alkali condition on the other hand, are easy to oxidation.So adding stabilizing agent is very important.The present invention has overcome the deficiency of above-mentioned patent, produces the ejection preparation of effective silibinin of stability and safety and salt thereof, satisfies clinical requirement.
Summary of the invention
The objective of the invention is overcoming the shortcoming and defect of above-mentioned prior art, provide and be fit to the injectable drug that clinical acute hepatopathy treatment requires, the present invention is an active component with silibinin and salt thereof, invented the stable pharmaceutical composition of drug administration by injection, especially intravenous administration has solved the demand in the treatment.
One, the content of pharmaceutical composition
The pharmaceutical composition of the administrated by injection of silibinin and salt thereof, it is characterized in that by active component be silibinin and salt thereof, adjuvant comprises: water-soluble filler, PH regulator, stabilizing agent, water for injection, osmotic pressure regulator or the like, combined by one or more adjuvants, wherein said preparation comprises freeze-dried powder, small injection and primary infusion.
1, it is characterized in that described preparation freeze-dried powder, small injection and primary infusion its pH value under aqueous solution state is 7-9.
2, the stable pharmaceutical composition of described administrated by injection is characterized in that water-soluble filler is mannitol, low molecular dextran, sorbitol, Polyethylene Glycol, tween, glucose, lactose or galactose;
The PH regulator is nonvolatile acid such as citric acid, phosphoric acid, hydrochloric acid and acceptable organic or inorganic bronsted lowry acids and bases bronsted lowry of physiology and salt such as potassium hydroxide, sodium hydroxide or hydroxide pipe, sodium carbonate, potassium carbonate or ammonium carbonate salts, sodium bicarbonate, sodium bicarbonate potassium or sodium bicarbonate ammonium salt;
Stabilizing agent is poloxamer, carbomer, sodium lauryl sulphate or Tris; Wherein preferred Tris.
Osmotic pressure regulator is one or both combination of sodium chloride, potassium chloride.
3, in the described preparation:
A. in the freeze-dried powder, the percentage by weight that active component accounts for total amount is 1-50%, preferred 10-30%.
B. in the small injection, the concentration of active component is 50mg/ml-0.5mg/ml, and preferred 5-30mg/ml comprises 2ml, 4ml, 5ml, 10ml and 20ml specification.
E. the concentration of primary infusion Chinese medicine is 1mg/ml-0.02mg/ml.The specification that comprises 50ml, 100ml, 250ml is with the compound injection of one or more compositions of sodium chloride, glucose or low molecular dextran.
Two, preparation method
The stable preparation of pharmaceutical compositions method that contains active component silibinin and salt administrated by injection thereof of the present invention is characterized in that this method comprises the following steps:
I, composition
(1) freeze-dried powder
Silibinin and salt 0.1%-50% thereof
Water-soluble filler 50%-90%
PH regulator 0.01%-10%
Stabilizing agent 0.001%-2%
Osmotic pressure regulator 0.9%
(2) small injection
Silibinin and salt 2.0%-0.05% thereof
PH regulator 0.01%-10%
Stabilizing agent 0.001%-2%
Water for injection 88%-98%
(3) primary infusion
Silibinin and salt 1%-0.002% thereof
PH regulator agent 0.01%-10%
Stabilizing agent 0.001%-2%
Osmotic pressure regulator 0.9%
Water for injection 88%-98%
The stable preparation of drug combination method of II. different administrated by injection comprises the following steps:
(1) freeze-dried powder
Get silibinin and salt thereof and water-soluble filler, stabilizing agent, osmotic pressure regulator etc., it is an amount of to add water for injection, regulates pH value and makes its dissolving to 7-9, adds water to scale, add the 0.1-0.5% active carbon, stirred 10-60 minute down at 20-50 ℃, the filtering with microporous membrane degerming is adopted in decarburization, filtrate is carried out packing, adopt freeze-drying, make the white loose block, seal promptly.
(2) small injection
Get silibinin and salt thereof, stabilizing agent, it is an amount of to add water for injection, regulates pH value and makes its dissolving to 7-9, adds water to scale, adds the 0.1-0.5% active carbon, stirs 10-60 minute decarburization, fine straining, embedding, sterilization down at 20-50 ℃.
(3) primary infusion
Get silibinin and salt thereof and stabilizing agent, osmotic pressure regulator etc., add water for injection 20%, regulate pH value and make its dissolving to 7-9, adding 0.1-0.5% active carbon stirred 10-60 minute down at 20-50 ℃, and decarburization adds water to scale, fine straining, embedding, sterilization.
We are to adding stabilizing agent and do not add the sample that stabilizing agent makes and redissolve, and investigate the visible foreign matters inspection that it was placed 0 hour, 4 hours, 8 hours.The result is as follows:
In addition, we also investigate the long-term stability of placing of sample room temperature, and the result is as follows:
| Time | 0 month | 1 month | 3 months | 6 months |
| Do not add the stabilizing agent sample | Visible foreign matters is qualified | Visible foreign matters is qualified | Visible foreign matters is qualified | There is foreign body to produce |
| Add the stabilizing agent sample | Visible foreign matters is qualified | Visible foreign matters is qualified | Visible foreign matters is qualified | Visible foreign matters is qualified |
The specific embodiment
The present invention is described further below in conjunction with embodiment, and embodiment only is indicative explanation, means that never it limits the scope of the invention by any way.
Embodiment 1
Water intaking Silybin meglumine 0.5g adds acetone 10ml.Put into 80 ℃ of heating in water bath, add water 5ml again, stir to clarify gradually.Add active carbon 30mg, stirring in water bath 5 minutes.Sucking filtration, filtrate is placed room temperature and is separated out naturally.Sucking filtration is used the suitable quantity of water flush cake, and 50 ℃ of dryings promptly get highly finished product.
Embodiment 2
Get silibinin sodium salt 0.5g, add acetone 5ml.Put into 80 ℃ of heating in water bath, add water 2.5ml again, add acetone 1ml and make clarification.Add active carbon 30mg, stirring in water bath 5 minutes.Sucking filtration, filtrate is placed room temperature and is separated out naturally.Sucking filtration is used the suitable quantity of water flush cake, and 50 ℃ of dryings promptly get highly finished product.
Embodiment 3
Get silibinin arginine salt 0.5g, add 1mol/l sodium hydroxide solution 4ml dissolving, add 2ml ethanol and 3ml water again.Add active carbon 30mg, stirring in water bath 5 minutes.Sucking filtration, 50 ℃ of rotary evaporation dryings of filtrate.Promptly get highly finished product.
Embodiment 4
Get silibinin 1g, add acetone 5ml dissolving, Dropwise 5 ml water slowly makes the solution clarification again, adds active carbon 30mg, stirring in water bath 5 minutes.Sucking filtration, 50 ℃ of rotary evaporation dryings of filtrate.Promptly get highly finished product.
Embodiment 5
Get silibinin lysinate 0.5g, add acetone 4ml dissolving, add 3ml water again, make the solution clarification.Add active carbon 30mg, stirring in water bath 5 minutes.Sucking filtration, 50 ℃ of rotary evaporation dryings of filtrate.Promptly get highly finished product.
Embodiment 6
Get embodiment 2 silibinin sodium salt 3g, place container, add stabilizing agent poloxamer 1g, water for injection 80ml, hydro-oxidation sodium 0.2g stirs and makes dissolving, and the citron acid for adjusting pH that adds 1mol/L is to 7-9.0, add mannitol 28g, lactose 22g, stir and make dissolving, mend and add water to 100ml.Add the 0.5g activated carbon, stirred 20 minutes down at 30 ℃, the filtering with microporous membrane degerming is adopted in decarburization, and filtrate is carried out packing by every 1ml, after the pre-freeze 2 hours, freezing down drying under reduced pressure 12 hours, to sample temperature after room temperature, dry 5 hours again, make the white loose block, seal and promptly get silibinin sodium salt freeze-dried powder.
Embodiment 7
Get embodiment 4 silibinin 5g, place container, add stabilizing agent Ka Baimu 2g, water for injection 180ml stirs and makes dissolving, regulates pH to 7.0-9.0 with the sodium hydroxide of 1mol/L, adds mannitol 80g, sorbitol 20g, stirs and makes dissolving, mends and adds water to 200ml.Add the 0.5g activated carbon, stirred 20 minutes down at 30 ℃, the filtering with microporous membrane degerming is adopted in decarburization, and filtrate is carried out packing by every 2ml, after the pre-freeze 2 hours, freezing down drying under reduced pressure 18 hours, to sample temperature after room temperature, dry 5 hours again, make the white loose block, seal and promptly get silybin frozen powder injection.
Embodiment 8
Get embodiment 3 silibinin arginine salt 2g, place container, hydro-oxidation sodium 0.05g adds injection water 180ml, stirring makes dissolving, hydrochloric acid or sodium hydroxide with 1mol/L are regulated pH to 7.0-9.0, add mannitol 20g, and lactose 20g stirs and makes dissolving, benefit adds water to 200ml, add the 0.5g activated carbon, stirred decarburization 40 minutes down at 20 ℃, adopt the filtering with microporous membrane degerming, filtrate is carried out packing by every 2ml, and pre-freeze is after 2 hours, freezing drying under reduced pressure down 15 hours, to sample temperature after room temperature, dry 5 hours again, make the white loose block, seal and promptly get silibinin arginine salt freeze-dried powder.
Embodiment 9
Get embodiment 4 silibinin 10g, join among the water for injection 440ml that dissolves the 5g sodium lauryl sulphate, stirring and dissolving, adding sodium bicarbonate adjusting PH is 7-9, adds the 5g active carbon, stirring at room absorption 30 minutes, carbon removal, benefit adds water to 500ml, and fine straining, with every 5ml embedding, sterilization promptly gets the silibinin injection.
Embodiment 10
Get embodiment 2 silibinin sodium salt 5g, join among the water for injection 440ml that dissolves the 10g Tris,, adding sodium bicarbonate adjusting pH is 7-9.0, mends and adds water to 500ml, add the 5g active carbon, stirring at room absorption 30 minutes, carbon removal, fine straining, with every 2ml embedding, sterilization, promptly get the silibinin sodium-salt parenteral solution.
Embodiment 11
Get embodiment 5 silibinin lysinate 1g, add among the water for injection 180ml, add 0.5 gram NaOH stirring and make dissolving, add the 0.05g Tris, stirring and dissolving, adjusting pH is 8.0-9.0, add water for injection to 200ml, add the 2g active carbon, stirring and adsorbing 30 minutes, carbon removal, fine straining, with every 2ml embedding, sterilization, promptly get silibinin glutamate, Glu injection.
Embodiment 12
Get embodiment 2 silibinin sodium salt 5g, add 15g sodium hydrogen phosphate and 90g sodium chloride, add injection water 2000ml again, stir and make dissolving, adjusting pH is 7-9.0, add the 10g active carbon, stirring and adsorbing 30 minutes, carbon removal, benefit adds water to 10000ml, fine straining, every bottle of 100ml of embedding, sterilization promptly gets the silibinin sodium chloride injection.
Embodiment 13
Get embodiment 4 silibinin 10g, add 15g sodium hydroxide and 1000g glucose, the 1g Tris, add injection water 2000ml again, stirring makes dissolving, and adjusting pH is 8.0-9.0, adds the 10g active carbon, stirring and adsorbing 30 minutes, carbon removal is mended and is added water to 10000ml, fine straining, every bottle of 100ml of embedding, sterilization promptly gets the silibinin glucose injection.
Embodiment 14
Get embodiment 1 silybin-N-methylglucamine 3.0g, add stabilizing agent poloxamer 20g, water for injection 2000ml, stirring makes dissolving, adds 15g sodium hydrogen phosphate and 500g low molecular dextran again, 15g EDTA-2Na, stirring makes dissolving, and adjusting pH is 7.0-9.0, adds the 10g active carbon, stirring and adsorbing 30 minutes, carbon removal is mended and is added water to 5000ml, fine straining, every bottle of 50ml of embedding, sterilization promptly gets silybin meglumine low molecular dextran injection.
Claims (4)
1. pharmaceutical composition that contains silibinin or its salt administrated by injection, it is characterized in that, by active component silibinin or its salt and water-soluble filler, the pH regulator agent, stabilizing agent, water for injection or osmotic pressure regulator are formed, and described compositions is a freeze-dried powder, small injection or primary infusion consist of separately:
(1) freeze-dried powder
Silibinin or its salt 0.1%-50%
Water-soluble filler 50%-90%
PH regulator agent 0.01%-10%
Stabilizing agent 0.001%-2%
Osmotic pressure regulator 0.9%;
(2) small injection
Silibinin or its salt 2.0%-0.05%
PH regulator agent 0.01%-10%
Stabilizing agent 0.001%-2%
Water for injection 88%-98%;
Each component content sum of above compositions is 100%
(3) primary infusion
Silibinin or its salt 0.1%-0.002%
PH regulator agent 0.01%-10%
Stabilizing agent 0.001%-2%
Osmotic pressure regulator 0.9%
Water for injection 88%-98%;
Described compositions its pH value under aqueous solution state is 7-9,
Described salt is to be selected from arginine salt, lysinate, proline salt, glutamate, Glu, cysteine salt, valine salt, leucine salt, methionine salt, meglumine salt, mesylate, tartrate, citrate, acetate, maleate, fumarate, succinate, cholate, dexycholate, sodium salt, potassium salt, magnesium salt, zinc salt, aluminum salt, hydrochlorate, sulfate, phosphate or nitrate
Described water-soluble filler is selected from mannitol, low molecular dextran, sorbitol, Polyethylene Glycol, tween, glucose, lactose or galactose;
Described pH regulator agent is selected from citric acid, phosphoric acid, hydrochloric acid, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate or ammonium carbonate salts, sodium bicarbonate, potassium bicarbonate or bicarbonate ammonium salt;
Stabilizing agent is selected from poloxamer, carbomer, sodium lauryl sulphate or Tris;
Osmotic pressure regulator is selected from sodium chloride or potassium chloride.
2. pharmaceutical composition as claimed in claim 1 is characterized in that:
A. the concentration of small injection Chinese medicine is 50mg/ml-0.5mg/ml;
B. the concentration of primary infusion Chinese medicine is 1mg/ml-0.02mg/ml.
3. pharmaceutical composition as claimed in claim 2 is characterized in that, described primary infusion is meant the compound injection of one or more compositions of active component and sodium chloride, glucose or low molecular dextran.
4. the preparation of drug combination method of claim 1 is characterized in that: comprise the following steps:
(1) lyophilized preparation
Get silibinin or its salt and water-soluble filler, stabilizing agent, osmotic pressure regulator, it is an amount of to add water for injection, regulates pH value and makes its dissolving to 7-9, adds water to scale, add the 0.1-0.5% active carbon, stirred 10-60 minute down at 20-50 ℃, the filtering with microporous membrane degerming is adopted in decarburization, filtrate is carried out packing, adopt freeze-drying, make the white loose block, seal promptly;
(2) small injection
Get silibinin or its salt, stabilizing agent, it is an amount of to add water for injection, regulates pH value and makes its dissolving to 7-9, adds water to scale, adds the 0.1-0.5% active carbon, stirs 10-60 minute decarburization, fine straining, embedding, sterilization down at 20-50 ℃;
(3) primary infusion
Get silibinin or its salt and stabilizing agent, osmotic pressure regulator adds water for injection 20%, regulates pH value and makes its dissolving to 7-9, and adding 0.1-0.5% active carbon stirred 10-60 minute down at 20-50 ℃, and decarburization adds water to scale, fine straining, embedding, sterilization.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006100035646A CN100389767C (en) | 2005-09-30 | 2006-02-13 | Injectable stable pharmaceutical composition containing active ingredient silibinin and its salt |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200510015289.5 | 2005-09-30 | ||
| CN200510015289 | 2005-09-30 | ||
| CNB2006100035646A CN100389767C (en) | 2005-09-30 | 2006-02-13 | Injectable stable pharmaceutical composition containing active ingredient silibinin and its salt |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1839822A CN1839822A (en) | 2006-10-04 |
| CN100389767C true CN100389767C (en) | 2008-05-28 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2006100035646A Expired - Fee Related CN100389767C (en) | 2005-09-30 | 2006-02-13 | Injectable stable pharmaceutical composition containing active ingredient silibinin and its salt |
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| Country | Link |
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Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2219642B1 (en) | 2007-11-15 | 2011-09-21 | Madaus GmbH | Silibinin component for the treatment of hepatitis |
| CN102309441B (en) * | 2010-07-09 | 2015-07-22 | 天士力制药集团股份有限公司 | Silymarin medicinal composition wrapper and preparation method thereof |
| CN102614121B (en) * | 2011-11-10 | 2013-12-11 | 上海天氏利医药科技有限公司 | Silibinin injection composition and preparation process |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6428821B2 (en) * | 1999-07-05 | 2002-08-06 | Jong-Soo Woo | Oral micro-emulsion composition of silybin |
| CN1397277A (en) * | 2002-08-16 | 2003-02-19 | 广州瑞济生物技术有限公司 | Process for preapring silymanium injection |
| CN1164269C (en) * | 2002-08-16 | 2004-09-01 | 广州瑞济生物技术有限公司 | Silybin injection containing cyclo dextrin or its derivatives |
-
2006
- 2006-02-13 CN CNB2006100035646A patent/CN100389767C/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6428821B2 (en) * | 1999-07-05 | 2002-08-06 | Jong-Soo Woo | Oral micro-emulsion composition of silybin |
| CN1397277A (en) * | 2002-08-16 | 2003-02-19 | 广州瑞济生物技术有限公司 | Process for preapring silymanium injection |
| CN1164269C (en) * | 2002-08-16 | 2004-09-01 | 广州瑞济生物技术有限公司 | Silybin injection containing cyclo dextrin or its derivatives |
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| Publication number | Publication date |
|---|---|
| CN1839822A (en) | 2006-10-04 |
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