CN101926791A - Phospholipid complex of silybin dihemisuccinate disodium and preparation method and application thereof - Google Patents
Phospholipid complex of silybin dihemisuccinate disodium and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a medicinal composition containing silybin dihemisuccinate disodium and a preparation method and application thereof. Silybin dihemisuccinate disodium and phospholipid are dissolved into an organic solvent according to a certain proportion, and a product is obtained by heating reflux, drying and concentration. The composition increases the dissolution of silybin, improves the lipid solubility, and obviously solves the problem of low bioavailability of the silybin. The composition has the effect of protecting liver, and can be used for treating acute or chronic hepatitis, fatty liver and other liver function injury.
Description
Technical field
The invention belongs to field of medicaments, particularly relate to the phosphatide complexes that contains the active component silybin dihemisuccinate disodium, specifically being characterized as increasing the water miscible while of this complex improves obviously that it is fat-soluble, improves its bioavailability, performance better therapeutic aspect hepatoprotective.
Background technology
In recent years, along with the raising of people's living standard and the variation of dietary structure, China's pathogenesis of fatty liver rate is near the hepatitis B virus carrying rate, and is obvious ascendant trend.Wherein, 30～40 years old male is " main force " in the Patients with Fatty Liver main forces, accounts for 1/4 of whole Patients with Fatty Liver substantially.According to estimates, present pathogenesis of fatty liver rate is than having increased in the past about 30 times the eighties in 20th century.It is reported that 15% Patients with Fatty Liver can develop into liver cirrhosis, 3% Patients with Fatty Liver can be died from liver failure.So fatty liver prevents early and treatment has very important significance.
Hepatitis is meant the liver inflammation owing to the different causes of disease, and viral hepatitis is the most common in the daily life, and it has the sickness rate height, and the course of disease is long, and the patient's condition repeatability is strong, the characteristics that hazardness is big, if in time do not treat, changing is possible of liver cirrhosis and hepatocarcinoma.China is again hepatitis country occurred frequently, and according to statistics, China has 1.2 hundred million people of surpassing to infect hepatitis B virus, and the chronic viral hepatitis B patient is about, and 3,000 ten thousand, 3,800 ten thousand people carry hepatitis C virus, only from the numeral of hepatitis B virus carriers, almost account for national 1/10th.
At present, though the liver disease drug kind is a lot, does not still have a kind of medicine and can really kill hepatitis B virus.The at present employing suppressed virus replication or improved symptom, two kinds of treatments of disease controlling development thinking more.Though the former can suppress virus replication fast, has the long-term prescription risk.Though hepatitis B virus can be suppressed at reduced levels (DNA＜10 as hepatopathy one line medicine lamivudine
3Copy/ml), but need long-term prescription (usually 2-3) can not arbitrarily be stopped using, and is not only costly, and long-term prescription directly causes part patient hepatitis B virus the drug resistance variant to occur, and it is complicated that the state of an illness more becomes.Therefore, develop a kind of medicine that can effectively improve the hepatopathy symptom, be fit to long-term prescription and reasonable price, be used for the prevention and the treatment of hepatic disease, meet current national conditions, meet clinical needs.
Herba Silybi mariani, Compositae is good hepatoprotective plant, its main component is silibinin (silybin).Pharmacological evaluation proves that silibinin has the protection liver plasma membrane, improves the effect of liver function, prevents the hepatic injury due to the multiple hepatotoxic agent, promotes liver cell regeneration, is mainly used in diseases such as the various acute, chronic hepatitis of treatment, the poisoning of first cirrhosis regulating liver-QI.
Silibinin is insoluble in water very much, has limited its oral absorption, and water solublity obviously increases behind the salify.At present, main research concentrates on silybin-N-methylglucamine and silibinin phosphatide complexes.The main component that the Seeley guest pacifies sheet promptly is a silybin meglumine, but still deposits the not high shortcoming of bioavailability.The good main component of water woods is a silibinin lecithin complex, though by improving the fat-soluble bioavailability that improved to a certain extent, its water solublity is still relatively poor.
Influence that the factor of bioavailability comprises dosage form factor and two aspects of physiologic factor in the body: fat-soluble, the water solublity of dosage form factor such as medicine and pKa value, the difference of the dosage form characteristic of medicine (as disintegration, dissolution rate) and some process conditions; Physiologic factor comprises the effect of liquid in the gastrointestinal tract, the transhipment situation of medicine in gastrointestinal tract, and the surface area of absorption site and regional flow, the influence of drug metabolism, intestinal bacterial strain and some influence the disease of drug absorption etc.Thus, medicine absorption in vivo situation is fat-soluble relevant with medicine itself not only, and water solublity also is a key parameter.
Silybin bis-bias succinate sodium salt (silybin dihemisuccinate disodium) is that development is at first invented by German Madaus company, the trade name Legalon, the synthetic water solublity that has obviously increased silibinin of this salt, pharmacological action shows to have the content that reduces dissociate in the serum fatty acid and triglyceride, regulates the disorder of phospholipid metabolism, removes oxygen-derived free radicals, suppress lipid peroxidation, stablize liver plasma membrane, alleviate steatosis, the function of antagonism hepatic necrosis.The ejection preparation of these product goes on the market abroad and is used for the treatment of the acute liver poisoning that Amanita phalloides causes.
The phosphatide complexes of the prepared silybin bis-bias succinate sodium salt of the present invention has not only improved its water solublity, and has improved to a great extent that it is fat-soluble, has obviously improved its bioavailability.We discover that after silibinin was made succinate, the dissolubility in water obviously was better than silybin-N-methylglucamine, the phosphatide complexes water solublity of prepared silybin bis-bias succinate sodium salt and the fat-soluble silybin-N-methylglucamine that all is better than.We are also with prepared complex and the water woods is good compares, and bioavailability obviously improves.We carry out zoopery with this complex, with Seeley guest peace with the water woods is good compares, found that its therapeutic effect obviously increases.
On this basis, we can make that a kind of bioavailability is higher, good effect, be fit to the ejection preparation or the oral formulations of phosphatide complexes of the silybin bis-bias succinate sodium salt of long term administration, storage-stable, satisfy the needs of acute and chronic liver disease clinically.
Summary of the invention
The present invention has overcome the shortcoming and defect of existing medicine, and a kind of phosphatide complexes of silybin dihemisuccinate disodium is provided, and acceptable carrier pharmaceutically.
The silybin dihemisuccinate disodium that adopts among the present invention is generally silybin bis-bias succinate sodium salt (Silybin dihemisuccinate disodium) molecular formula: C
33H
28Na
2O
16, molecular weight: 726.54536.
Structure is as follows:
The silibinin succinate that the present invention adopts can also be natrium potassium salt or di-potassium:
Constituting the used phospholipid of compositions among the present invention can be lecithin, fabaceous lecithin, natural phosphocholine two glyceride, injection soybean phospholipid, oral soybean phospholipid, is preferably lecithin.
The present invention also provides a kind of preparation method that contains the phosphatide complexes of silybin dihemisuccinate disodium, by with silybin dihemisuccinate disodium and phospholipid according to weight proportion 1: 1～3 constitutive materials, be dissolved in the organic solvent according to certain proportioning again, reflux under 50～70 ℃ of conditions, question response is 40～90 ℃ of concentrating under reduced pressure dryings in back fully, promptly get product.Described method can be directly with Rotary Evaporators or vacuum decompression enrichment facility concentrating under reduced pressure drying, under the instrument condition that does not integrate concentrating under reduced pressure and vacuum drying, can be concentrated into 5～15% with vacuum concentration equipment earlier, the reuse vacuum dryer is drying to obtain this product for 20～60 ℃.Used organic solvent can be methanol, ethanol, acetone, chloroform, ethyl acetate and dichloromethane etc. in this method.
Described complex makes the phosphatide complexes of silybin dihemisuccinate disodium by said method, this complex and after pharmaceutically the acceptable excipient substance mixes according to a certain percentage makes required dosage form according to preparation method well-known to those skilled in the art.The dosage form of the present composition can be injection and oral formulations etc.
Compositions of the present invention has increased the dissolubility in water, can make injection type, thereby increases clinical applicable scope, and is especially for emergency case or critically ill patient, significant.Injection can be liquid drugs injection, freeze-dried powder etc., and approach can be subcutaneous, intravenous injection and intravenous drip etc.
The dosage form of composition oral administration of the present invention can be selected from said oral formulations on all pharmaceuticss such as tablet, capsule, granule, powder, electuary, pill, oral liquid, buccal tablet, enteric coated tablet, sustained-release preparation, and can contain conventional excipient.Described excipient comprises diluent, binding agent, disintegrating agent, antitack agent and lubricant; Described diluent be selected from microcrystalline Cellulose, lactose, mannitol, calcium hydrogen phosphate, starch, pregelatinized Starch, and composition thereof; Described binding agent be selected from sodium alginate, sodium carboxymethyl cellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, hypromellose, methylcellulose, gelatin, polyvidone, cellulose acetate, starch, pregelatinized Starch, and composition thereof; Described disintegrating agent be selected from alginic acid, sodium alginate, sodium carboxymethyl cellulose, microcrystalline Cellulose, cellulose powder, cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, pregelatinized Starch, starch, and composition thereof; Described antitack agent be selected from micropowder silica gel, magnesium trisilicate and Pulvis Talci, and composition thereof; Described lubricant be selected from magnesium stearate, Pulvis Talci, and composition thereof.
Oral formulations described in the present invention is applicable to that the patient takes 3-4 time every day, and should there be therapeutical effect in each 1-4 preparation unit so that active component is brought into play it in patient's body.Dosage and number of times can suitably be adjusted according to patient age, body weight and disease condition.
Silybin bis-bias succinate among the present invention can be synthetic by silibinin and succinic anhydrides, and the silybin bis-bias succinate sodium salt can be made by silybin bis-bias succinate and sodium hydroxide reaction.Silibinin, succinic anhydrides, phospholipid, sodium hydroxide etc. all are product solds on the market, and raw material is easy to get.
Compositions of the present invention has not only increased the dissolubility of silibinin, and has improved fat-solublely, has obviously improved its bioavailability.The present invention selects the phospholipid composite of silybin bis-bias succinate as effective ingredient for use, its therapeutical effect is better than silybin-N-methylglucamine and silibinin phosphatide complexes, this is because making of silybin bis-bias succinate increased its water solublity, form compositions with phospholipid and make its fat-soluble also increase, phospholipid also has detoxifcation, antioxidation simultaneously, unite with silibinin and to have synergism, can increase the curative effect of silibinin.This character is that silybin-N-methylglucamine and silibinin phosphatide complexes can not possess simultaneously, and this complex combines both advantages, on the basis of the medicine that goes on the market its bioavailability has been carried out further raising.
Simultaneously, said composition has also enlarged the scope of application and the approach of administration, because of its water solublity and fat-soluble all very good, both can be made into oral formulations, also can make ejection preparation.Said composition is made the solid drug-delivery preparation, and taking convenience is fit to taking of chronic hepatitis patients.Said composition is made ejection preparation, be significant for emergency and severe disease patient's treatment.
Experiment showed, compositions of the present invention and compare with the silibinin phosphatide complexes at the medicine silybin-N-methylglucamine that goes on the market, water solublity and fat-soluble all obviously increases, bioavailability obviously improves.
Get 24 of New Zealand white rabbit, body weight is (1.90 ± 0.15kg), be divided into 4 groups at random, irritate stomach respectively in 200mg (with silibinin)/kg dosage and give silymarin, silybin-N-methylglucamine, silibinin phosphatide complexes and silybin bis-bias succinate sodium salt phosphatide complexes.Respectively at after the administration 0.5,1,1.5,2,3,4,5,6,8,10, the 12h vein is got blood system from blood plasma detection of drugs concentration, mainly is silibinin total concentration in the blood plasma.Utilize 3P97 pharmacokinetics program to calculate pharmacokinetic parameter, calculate drug level area under curve AUC with trapezoidal method.
The intravital pharmacokinetic parameter of table 1 rabbit
Zoopery shows that the present composition has the effect of hepatoprotective, can be used for the treatment of acute, chronic hepatitis, fatty liver and other liver dysfunction.Curative effect for acute, chronic hepatitis, fatty liver and other liver dysfunction significantly improves.
Get 50 body weight and be divided into 5 groups at random, be respectively the phosphatide complexes group of normal control group, model control group, silybin-N-methylglucamine group, silibinin phosphatide complexes group and silybin bis-bias succinate sodium salt for the male mice of (20 ± 2) g.Except that matched group, the carbon tetrachloride 10mlkg of equal lumbar injection 0.1%
-1Induce hepatic injury.In 250mg (with silibinin)/kg gastric infusion, and normal control group and model group are given the distilled water with equivalent respectively, one week of successive administration, behind last administration 24h, get blood, and measure ALT, AST, comparable group differences.
Table 2 different pharmaceutical is to the influence of carbon tetrachloride poisoning rat acute hepatic injury
The specific embodiment
Providing the following example makes person skilled in art's clearer understanding of energy and implements the present invention.They should not be counted as limiting the scope of the invention, and only are illustrative and representational example.
The preparation of embodiment 1 silybin dihemisuccinate disodium phosphatide complexes
Take by weighing silybin dihemisuccinate disodium 530.0g and soybean phospholipid 1000.0g and mix, be dissolved in the 20000ml methanol, 50 ℃ of heating, solution clarification behind the 1h, 75 ℃ of concentrating under reduced pressure dryings obtain the silybin dihemisuccinate disodium phosphatide complexes.
The preparation of embodiment 2 silybin dihemisuccinate disodium phosphatide complexes compressed tablets
Silybin dihemisuccinate disodium 530.0g and soybean phospholipid 500.0g are mixed, be dissolved in the 20000ml dehydrated alcohol, 50 ℃ of heating, solution clarification behind the 1h, 70 ℃ are evaporated to thick, add microcrystalline Cellulose 18.0g, lactose 450.0g, pregelatinized Starch 180g, polyvinylpolypyrrolidone 22.5g mix homogeneously is a wetting agent system soft material with the aqueous solution that contains 15% polyvidone, and 20 mesh sieves are granulated, 55 ℃ of aeration-drying 3 hours, granulate adds Pulvis Talci 13.5.0g, magnesium stearate 13.5.0g, mixing press about 10000, every contains silibinin 35mg, promptly gets compressed tablet.
The capsular preparation of embodiment 3 silybin dihemisuccinate disodium phosphatide complexes
Silybin dihemisuccinate disodium 530.0g and soybean phospholipid 1000.0g are mixed; be dissolved in the 20000ml dehydrated alcohol; 50 ℃ of heating; solution clarification behind the 1h; 70 ℃ are evaporated to thick; add lactose 450.0g, mannitol 360.0g, carboxymethylstach sodium 72g; insert among the quick mixer granulator KJZ-IO; spraying 30% ethanol water granulates; 60 ℃ of aeration-drying 3 hours, 20 mesh sieve granulate add magnesium stearate 27.0g mixing; No. 1 snap fit capsule of fill makes every capsules contain silibinin 35mg.
The preparation of embodiment 4 silybin dihemisuccinate disodium phosphatide complexes dispersible tablets
Taking by weighing silybin dihemisuccinate disodium 530.0g and lecithin 1500.0g mixes, be dissolved in the 20000ml dehydrated alcohol, 50 ℃ of heating, solution clarification behind the 1h, 40 ℃ are evaporated to thick, after adding mannitol 360.0g, lactose 1500.0g, sodium carboxymethyl cellulose 54.0g, microcrystalline Cellulose 270g, polyvidone 36g, magnesium stearate 54g mix homogeneously, dry granulation, pulverized the following sieve of 24 orders, then with 180g polyvinylpolypyrrolidone mix homogeneously, direct compression makes every to contain silibinin 35mg.
The preparation of embodiment 5 silybin dihemisuccinate disodium phosphatide complexes Film coated tablets
The sheet of embodiment 1 compacting is wrapped film-coat with stomach dissolution type OPADRY-85G II, promptly get every and contain silybin dihemisuccinate disodium 53mg, Film coated tablets.
The particulate preparation of embodiment 6 silybin dihemisuccinate disodium phosphatide complexes
Taking by weighing silybin dihemisuccinate disodium 530.0g and soybean phospholipid 1000.0g mixes, be dissolved in the 20000ml acetone, 30 ℃ of heating, solution clarification behind the 5h, 60 ℃ are evaporated to 2000ml, 40 ℃ of vacuum dryings obtain the silybin dihemisuccinate disodium phosphatide complexes, add lactose 2250.0g, mannitol 1600.0g, gelatin 22.5.0g, aspartame 22.5g Fructus Citri tangerinae essence 22.5.0g mixing, spray 10% alginic acid aqueous solution system soft material, 14 orders are granulated, dry 3 hours of convection oven, 12 mesh sieve granulate, measure content, quantitatively be divided in the PVC clad aluminum foil bag, make every bag to contain silibinin 70mg.
The preparation of embodiment 7 silybin dihemisuccinate disodium phosphatide complexes oral cavity disintegration tablets
Taking by weighing silybin dihemisuccinate disodium 530.0g and lecithin 1500.0g mixes, be dissolved in the 20000ml ethyl acetate, 70 ℃ of heating, solution clarification behind the 5h, 80 ℃ are evaporated to 2000ml, 50 ℃ of vacuum dryings obtain the silybin dihemisuccinate disodium phosphatide complexes, add mannitol 3000.0g, carboxymethylstach sodium 120.0g, carmellose 60.0g, flavoring orange essence 20.0g, Aspartame 20.0g, water or ethanol moistening, cross 30 mesh sieve system soft materials, 55 ℃ of oven dryings, dried granule adds micropowder silica gel 60.0g, hard fumaric acid sodium 60.0g mix homogeneously, tabletting, every contains silibinin 35mg.
The preparation of embodiment 8 silybin dihemisuccinate disodium phosphatide complexes drop pill
Taking by weighing silybin dihemisuccinate disodium 530.0g and soybean phospholipid 1000.0g mixes, be dissolved in the 20000ml methanol 100 ℃ of heating, solution clarification behind the 1h, 75 ℃ are evaporated to 2000ml, and 60 ℃ of vacuum dryings obtain the silybin dihemisuccinate disodium phosphatide complexes.Taking polyethylene glycol-600080.0g, put heating and melting in 85 ℃ of water-baths, added the silybin dihemisuccinate disodium phosphatide complexes 20.0g of 100 mesh sieves, carboxymethylstach sodium 2g stirs, and continues to put in 85 ℃ of water-baths heating, is stirred to feed liquid and becomes suspension by muddy attitude, with the dimethicone is condensing agent, condensation temperature is-5～10 ℃, drips with 50 droplets/minute and makes, and removes condensing agent, promptly get the heavily about 50mg of every drop pill, contain principal agent 10mg.
The preparation of embodiment 9 silybin dihemisuccinate disodium phosphatide complexes injections
Get the silybin dihemisuccinate disodium phosphatide complexes 10g that embodiment 1 makes, join among the water for injection 450ml of dissolved 10g Tris, stirring and dissolving, add sodium bicarbonate and regulate pH value to 7-9, add the 5g activated carbon, stirring at room absorption is after 30 minutes, de-carbon, benefit adds water to 500ml, and fine straining, with every 2ml embedding, sterilization promptly gets silybin dihemisuccinate disodium phosphatide complexes injection.
The preparation of embodiment 10 silybin dihemisuccinate disodium phosphatide complexes freeze-dried powders
Get the silybin dihemisuccinate disodium phosphatide complexes 10g that embodiment 1 makes, place container, add stabilizing agent Ka Baimu 4g, water for injection 360ml, stirring and dissolving is used 1molml
-1Sodium hydroxide is regulated pH value to 7-9, adds mannitol 160g, lactose 100g, and stirring and dissolving, moisturizing is to 400ml.Add the 0.5g activated carbon, stir 20min down at 30 ℃, the filtering with microporous membrane degerming is adopted in decarburization, and filtrate is carried out packing by every 1ml, behind the pre-freeze 2h, freezing down drying under reduced pressure 12h, reach room temperature to sample temperature after, dry again 5h, make the white loose block, seal and promptly get silybin dihemisuccinate disodium phosphatide complexes freeze-dried powder.
The preparation of embodiment 11 silybin dihemisuccinate natrium potassium salt phosphatide complexes
Take by weighing silybin dihemisuccinate natrium potassium salt 540.0g and soybean phospholipid 500.0g and mix, be dissolved in the 20000ml dehydrated alcohol, 50 ℃ of heating, solution clarification behind the 1h, 70 ℃ of concentrating under reduced pressure dryings obtain silybin dihemisuccinate natrium potassium salt phosphatide complexes.
The preparation of the compressed tablet of embodiment 12 silybin dihemisuccinate natrium potassium salt phosphatide complexes
Taking by weighing silybin dihemisuccinate natrium potassium salt 540.0g and soybean phospholipid 1000.0g mixes, be dissolved in the 20000ml methanol 50 ℃ of heating, solution clarification behind the 1h, 75 ℃ are evaporated to 2000ml, and 40 ℃ of vacuum dryings obtain silybin dihemisuccinate natrium potassium salt phosphatide complexes.Add microcrystalline Cellulose 140.0g, lactose 280.0g, starch 140g, methylcellulose 14.0g, mix homogeneously, with 30% ethanol water is wetting agent system soft material, 20 mesh sieves are granulated, 60 ℃ of aeration-drying 3 hours, granulate, add micropowder silica gel 14.0g,, magnesium stearate 14.0g, mixing press special-shaped tablets, every contains silibinin 70mg, promptly gets compressed tablet.
The capsular preparation of embodiment 13 silybin dihemisuccinate natrium potassium salt phosphatide complexes
Taking by weighing silybin dihemisuccinate natrium potassium salt 540.0g and lecithin 1500.0g mixes, be dissolved in the 20000ml ethyl acetate 50 ℃ of heating, solution clarification behind the 1h, 80 ℃ are evaporated to 2000ml, and 50 ℃ of vacuum dryings obtain silybin dihemisuccinate natrium potassium salt phosphatide complexes.Add lactose 1000g, Pulvis Talci 375g, carboxymethylstach sodium 125g mixing; insert among the quick mixer granulator KJZ-IO; spraying 30% ethanol water granulates; 60 ℃ of aeration-drying 3 hours; 20 mesh sieve granulate; add magnesium stearate 30.0g mixing, the fill capsule, every capsules contains silibinin 35mg.
The preparation of embodiment 14 silybin dihemisuccinate natrium potassium salt phosphatide complexes dispersible tablets
Take by weighing silybin dihemisuccinate natrium potassium salt 540.0g and soybean phospholipid 1000.0g and mix, be dissolved in the 20000ml ethyl acetate, 50 ℃ of heating, solution clarification behind the 1h, 70 ℃ of concentrating under reduced pressure dryings obtain silybin dihemisuccinate natrium potassium salt phosphatide complexes.Add lactose 540.0g, low-substituted hydroxypropyl cellulose sodium 90.0g, hypromellose 27g, microcrystalline Cellulose 135g mix homogeneously,, cross 24 mesh sieves, 55 ℃ of oven dryings with 30% polyethylene glycol 6000 ethanol system soft material.Dried granule adds micropowder silica gel 27g, magnesium stearate 45g, mix homogeneously, and tabletting, every contains silibinin 70mg.
The preparation of embodiment 15 silybin dihemisuccinate natrium potassium salt phosphatide complexes injections
Get the silybin dihemisuccinate natrium potassium salt phosphatide complexes 10g that embodiment 11 makes, join among the water for injection 440ml of dissolved 5g sodium lauryl sulphate, stirring and dissolving, add sodium bicarbonate and regulate pH value to 7-9, add the 5g activated carbon, stirring at room absorption is after 30 minutes, de-carbon, benefit adds water to 500ml, and fine straining, with every 1ml embedding, sterilization promptly gets silybin dihemisuccinate natrium potassium salt phosphatide complexes injection.
The preparation of embodiment 16 silybin dihemisuccinate natrium potassium salt phosphatide complexes freeze-dried powders
Get the silybin dihemisuccinate natrium potassium salt phosphatide complexes 10g that embodiment 11 makes, place container, add stabilizing agent Ka Baimu 4g, water for injection 360ml, stirring and dissolving is used 1molml
-1Sodium hydroxide is regulated pH value to 7-9, adds mannitol 160g, sorbitol 40g, and stirring and dissolving, moisturizing is to 400ml.Add the 0.5g activated carbon, stir 20min down at 30 ℃, the filtering with microporous membrane degerming is adopted in decarburization, and filtrate is carried out packing by every 2ml, behind the pre-freeze 2h, freezing down drying under reduced pressure 18h, reach room temperature to sample temperature after, dry again 5h, make the white loose block, seal and promptly get silybin dihemisuccinate natrium potassium salt phosphatide complexes freeze-dried powder.
The preparation of embodiment 17 silybin dihemisuccinate di-potassium phosphatide complexes
Take by weighing silybin dihemisuccinate di-potassium 550.0g and soybean phospholipid 1000.0g and mix, be dissolved in the 20000ml dehydrated alcohol, 50 ℃ of heating, solution clarification behind the 1h, 70 ℃ of concentrating under reduced pressure dryings obtain silybin dihemisuccinate di-potassium phosphatide complexes.
The preparation of embodiment 18 silybin dihemisuccinate di-potassium phosphatide complexes compressed tablets
Taking by weighing silybin dihemisuccinate di-potassium 550.0g and soybean phospholipid 500.0g mixes, be dissolved in the 20000ml methanol 50 ℃ of heating, solution clarification behind the 1h, 75 ℃ are evaporated to 2000ml, and 40 ℃ of vacuum dryings obtain silybin dihemisuccinate di-potassium phosphatide complexes.Add microcrystalline Cellulose 900.0g, calcium hydrogen phosphate 360.0g, micropowder silica gel 36.0g mix homogeneously, 30% alcoholic solution with hypromellose is a wetting agent system soft material, 20 mesh sieves are granulated, 55 ℃ of aeration-drying 4 hours, granulate, add sodium carboxymethyl cellulose 45.0g, magnesium stearate 45.0g mixing tabletting, press about 10000, every contains silibinin 35mg.
The preparation of embodiment 19 silybin dihemisuccinate di-potassium phosphatide complexes dispersible tablets
Take by weighing silybin dihemisuccinate di-potassium 550.0g and lecithin 1500.0g and mix, be dissolved in the 20000ml ethyl acetate, 50 ℃ of heating, solution clarification behind the 1h, 80 ℃ of concentrating under reduced pressure dryings obtain silybin dihemisuccinate di-potassium phosphatide complexes.Add mannitol 360.0g, lactose 1080.0g, polyvinylpolypyrrolidone 180.0g, polyvidone 36g, microcrystalline Cellulose 180g, magnesium stearate 18g mix homogeneously, dry granulation.Pulverize, cross 24 mesh sieves, add carboxymethyl starch sodium 72g, magnesium stearate 18g mix homogeneously again, press 10000, every contains silibinin 35mg.
The capsular preparation of embodiment 20 silybin dihemisuccinate di-potassium phosphatide complexes
Take by weighing silybin dihemisuccinate di-potassium 550.0g and soybean phospholipid 1000.0g and mix, be dissolved in the 20000ml ethyl acetate, 50 ℃ of heating, solution clarification behind the 1h, 70 ℃ of concentrating under reduced pressure dryings obtain silybin dihemisuccinate di-potassium phosphatide complexes.Adding lactose 1000.0g, mannitol 800.0g, Pulvis Talci 375g, carboxymethylstach sodium 125g insert among the quick mixer granulator KJZ-IO; spraying 30% ethanol water granulates; 60 ℃ of aeration-drying 3 hours; 20 mesh sieve granulate; add magnesium stearate 60.0g mixing; No. 1 snap fit capsule of fill, every capsules contains silibinin 35mg.
The preparation of embodiment 21 silybin dihemisuccinate di-potassium phosphatide complexes injections
Get the silybin dihemisuccinate di-potassium phosphatide complexes 10g that embodiment 17 makes, join among the water for injection 440ml of dissolved 10g Tris, stirring and dissolving, add sodium bicarbonate and regulate pH value to 7-9, add the 5g activated carbon, stirring at room absorption is after 30 minutes, de-carbon, benefit adds water to 500ml, and fine straining, with every 2ml embedding, sterilization promptly gets silybin dihemisuccinate di-potassium phosphatide complexes injection.
The preparation of embodiment 22 silybin dihemisuccinate di-potassium phosphatide complexes freeze-dried powders
Get the silybin dihemisuccinate di-potassium phosphatide complexes 10g that embodiment 17 makes, place container, add stabilizing agent poloxamer 4g, water for injection 300ml, stirring and dissolving is regulated pH value to 7-9 with sodium hydroxide, adds mannitol 160g, sorbitol 40g, stirring and dissolving, moisturizing is to 400ml.Add the 0.5g activated carbon, stir 20min down at 30 ℃, the filtering with microporous membrane degerming is adopted in decarburization, and filtrate is carried out packing by every 2ml, behind the pre-freeze 2h, freezing down drying under reduced pressure 12h, reach room temperature to sample temperature after, dry again 5h, make the white loose block, seal and promptly get silybin dihemisuccinate di-potassium phosphatide complexes freeze-dried powder.
Although the present invention has done detailed description in conjunction with its special embodiment, clearly concerning the skilled people in present technique field, still can make various changes and improvements, can not depart from spirit of the present invention and protection domain.
Claims (10)
1. the phosphatide complexes of a silybin dihemisuccinate disodium, wherein, the weight proportion of silybin dihemisuccinate disodium and phospholipid is 1: 0.8～6, silybin dihemisuccinate disodium is all by silybin bis-bias succinate weight.
2. the described phosphatide complexes of claim 1, wherein silybin dihemisuccinate disodium can be pharmaceutically acceptable salt of silybin dihemisuccinate disodium, silybin dihemisuccinate di-potassium, silybin dihemisuccinate natrium potassium salt and other, is preferably silybin dihemisuccinate disodium.
3. the described complex of claim 1-2, phospholipid wherein is selected from lecithin, fabaceous lecithin, natural phosphocholine two glyceride, injection soybean phospholipid, oral soybean phospholipid; Be preferably lecithin.
4. the described complex of claim 1, the weight proportion that it is characterized in that wherein said silybin dihemisuccinate disodium and phospholipid is 1: 1～3, silybin dihemisuccinate disodium is all by silybin bis-bias succinate weight.
5. complex as claimed in claim 1, its preparation method comprises the steps:
A. get an amount of silybin dihemisuccinate disodium and phospholipid, be dissolved in the suitable organic solvent, make the solution clarification 30～100 ℃ of reflux.
B. get 40～90 ℃ of concentrating under reduced pressure of the above-mentioned solution of gained, drying, obtain the phosphatide complexes of silybin dihemisuccinate disodium.
6. the method for claim 5, wherein, the described organic solvent of step a can be selected from methanol, ethanol, acetone, chloroform, ethyl acetate and dichloromethane, and described reflux temperature is preferably 50～70 ℃.
7. the phosphatide complexes of the silybin dihemisuccinate disodium that makes of claim 1-4 is made injection and oral formulations.
8. the described oral formulations of claim 7 comprises tablet, capsule, granule, powder, electuary, pill, oral liquid, buccal tablet, enteric coated tablet, sustained-release preparation.
9. the described ejection preparation of claim 7 comprises injection freeze-dried powder, injection liquid drugs injection, injection powder pin and infusion solutions, primary infusion.
10. the complex among the claim 1-4 can be used for preparing the medicine for the treatment of acute, chronic hepatitis, fatty liver and other hepatic injury.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102406636A (en) * | 2011-10-28 | 2012-04-11 | 西安安健药业有限公司 | Pharmaceutical composition for treating liver disease |
| CN104383547A (en) * | 2014-08-26 | 2015-03-04 | 新疆维吾尔自治区药物研究所 | Saussurea involucrate extractive phytosome, oral cavity disintegrating tablet and preparation methods of two |
| CN105853374A (en) * | 2016-04-26 | 2016-08-17 | 江苏中兴药业有限公司 | Preparation method of silybin-phospholipid complex |
| CN107875121A (en) * | 2017-11-06 | 2018-04-06 | 大连理工大学 | A kind of preparation method of 2,3 dehydro-silibinin phosphatide complexes nano suspension |
| US10307395B2 (en) * | 2015-03-23 | 2019-06-04 | Tasly Pharmaceutical Group Co., Ltd. | Pharmaceutical composition containing silybin and L-carnitine |
| CN111925394A (en) * | 2020-09-25 | 2020-11-13 | 嘉兴金派特生物科技有限公司 | Silybin derivative or pharmaceutically acceptable salt thereof, and preparation method and application thereof |
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- 2008-12-25 CN CN2008101544483A patent/CN101926791A/en active Pending
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102406636A (en) * | 2011-10-28 | 2012-04-11 | 西安安健药业有限公司 | Pharmaceutical composition for treating liver disease |
| CN104383547A (en) * | 2014-08-26 | 2015-03-04 | 新疆维吾尔自治区药物研究所 | Saussurea involucrate extractive phytosome, oral cavity disintegrating tablet and preparation methods of two |
| CN104383547B (en) * | 2014-08-26 | 2017-11-14 | 新疆维吾尔自治区药物研究所 | Herba Saussureae Involueratae extract phosphatide complexes, oral disnitegration tablet and preparation method thereof |
| US10307395B2 (en) * | 2015-03-23 | 2019-06-04 | Tasly Pharmaceutical Group Co., Ltd. | Pharmaceutical composition containing silybin and L-carnitine |
| US10307396B2 (en) * | 2015-03-23 | 2019-06-04 | Tasly Pharmaceutical Group Co., Ltd. | Pharmaceutical composition containing silybin, VE and L-carnitine |
| US10376491B2 (en) * | 2015-03-23 | 2019-08-13 | Tasly Pharmaceutical Group Co., Ltd. | Pharmaceutical composition containing silibinin and pueraria root extract |
| CN105853374A (en) * | 2016-04-26 | 2016-08-17 | 江苏中兴药业有限公司 | Preparation method of silybin-phospholipid complex |
| CN107875121A (en) * | 2017-11-06 | 2018-04-06 | 大连理工大学 | A kind of preparation method of 2,3 dehydro-silibinin phosphatide complexes nano suspension |
| CN111925394A (en) * | 2020-09-25 | 2020-11-13 | 嘉兴金派特生物科技有限公司 | Silybin derivative or pharmaceutically acceptable salt thereof, and preparation method and application thereof |
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