CN1201746C - Erigeron breviscapus liposome and its freeze dried powder injection fluid and preparation method - Google Patents
Erigeron breviscapus liposome and its freeze dried powder injection fluid and preparation method Download PDFInfo
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- CN1201746C CN1201746C CN 03113037 CN03113037A CN1201746C CN 1201746 C CN1201746 C CN 1201746C CN 03113037 CN03113037 CN 03113037 CN 03113037 A CN03113037 A CN 03113037A CN 1201746 C CN1201746 C CN 1201746C
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Abstract
The present invention relates to a breviscapine liposome and a frozen dried powder injection and an industrial applicable preparation method thereof. The weight ratio of breviscapine to phospholipid material is 1: 2 to 65 (portion), and 1 to 15 portions of cholesteryl can be added. The frozen dried powder injection is prepared according to the proportion that 0.2 to 4.0 portions of frozen dried protectant is added to 1 portion of phosphatide, which can visibly enhance the storage stability and can make the frozen dried powder of the breviscapine liposome diluted with transfusion according to arbitrary ratio to carry out administration after dissolved in water for injection, but deposits and degraded products can not be generated. The encapsulation efficiency is from 60% to 90%, the particle diameter is from 20 nm to 1 mu m, and the biological availability of the injection of the present invention is 10 times more than that of a common injection.
Description
Technical field
The invention belongs to the liposome and lyophilized injectable powder and the preparation method that contain Chinese herbal medicine effective site, be specially the liposome, its lipidosome freeze-dried injection and the corresponding preparation method that contain breviscapine.
Background technology
Herba Erigerontis belongs to annual herb plant (Erigron brevi-scapus (vaniot) HandMazz) for the Compositae Erigeron breviscapus (Vant.) Hand.-Mazz., and the main effective ingredient of its blood circulation promoting and blood stasis dispelling is scutellarin (Scutellarein-7-O-glucuronide).Except that main effective ingredient scutellarin, a small amount of breviscapine and other multiple composition are arranged still in the present Herba Erigerontis extract.Its chemical constitution of scutellarin is a glycosides million, and itself is unstable and be insoluble in water.Generally injection is prepared in dissolving under alkaline pH, but is subjected to the influence of multicomponent and degraded, and clarity and stability all are difficult to guarantee.The small injection of existing clinical use, adopt the method solubilising that adds surfactants such as Tween 80 in the production, when injection being joined in the transfusion dilution when injecting to venous patient, because Tween 80 is diluted and the change of pH value, solubilizing effect descends, transfusion often produces precipitation, and is especially even more serious when dosage is big, brings unsafe factor.Domestic Breviscapini injection has been carried out galenic pharmacy research, held the nationwide Breviscapini injection symposium of secondary, facts have proved that this product can not directly be prepared into infusion solution, can prepare injection powder pin with Freeze Drying Technique, to improving bin stability certain effect is arranged, but can not solve dissolving and safety issue in the dilution.On the other hand, in clinical application, the dosage of breviscapine is 50-100mg/ day, is about to breviscapine injection 20-40ml and adds 5% glucose injection or the instillation of 0.9% sodium chloride injection, and 10-20 days was 1 course of treatment, dosage is big, dosing interval is short, and its indication all is some chronic diseases, therefore, patient's is poor along doctor's property, has had a strong impact on its curative effect and clinical practice.
Summary of the invention
The technical problem to be solved in the present invention is to study a kind of clinical suitable breviscapine liposome and injection freeze-dried powder thereof, can significantly improve bin stability, can make the breviscapine lipid freeze-dry powder again after adding that water for injection is molten again and loosing, can not produce precipitation and catabolite with transfusion dilution administration with arbitrary proportion, especially under the big situation of dosage, reduce the unsafe factor of clinical application to greatest extent.In addition, make the medicine in the liposome continue to discharge, improve blood drug level, prolong circulation time in blood, to improve the bioavailability of medicine active ingredient.
But the present invention also will solve the preparation method of the suitability for industrialized production of described breviscapine liposome and injection freeze-dried powder thereof.
For addressing the above problem, the invention provides following technical scheme.
A kind of breviscapine liposome is characterized in that: the weight ratio of breviscapine, phospholipid, cholesterol is 1: 2-65: 0-15 part.
Its preferably ratio be: 1 part of breviscapine, phosphatidase 13 0-60 part, cholesterol 5-10 part.
Described breviscapine liposome, it is characterized in that: breviscapine mainly is made up of scutellarin, can contain a small amount of breviscapine (specification commonly used is a scutellarin labelled amount 80-105% content range in the dry product, and surplus is breviscapine and a small amount of composition of being correlated with); Phospholipid is soybean phospholipid, lecithin or synthetic phospholipid.
A kind of preparation method of breviscapine liposome is characterized in that: through following step preparation,
1) gets phosphatidase 12-65 part and cholesterol 1-15 part by weight, be dissolved in chloroform and/or the methanol solvate, remove and desolvate; The phosphate buffer that adds the pH6-8 that is dissolved with 1 part of breviscapine again; Form suspension, homogenize; Perhaps
2) in the phosphate buffer of pH6-8, feed nitrogen, by weight 1 part of breviscapine is dissolved in wherein, add phosphatidase 12-65 part, mixing and emulsifying, homogenize again; Perhaps
3) get by weight in the phosphate buffer that 1 part of breviscapine adds pH6-8, get phosphatidase 12-65 part and cholesterol 1-15 part and be dissolved in low polar organic solvent, mix two liquid, organic solvent is removed in emulsifying; Perhaps
4) get phosphatidase 12-65 part by weight and be dissolved in low polar organic solvent with cholesterol 1-15 part, add the phosphate buffer of pH6-8, mixing and emulsifying is removed solvent.
The preparation method of breviscapine liposome preferably is characterized in that:
1) get phosphatidase 13 0-60 part and cholesterol 5-10 part by weight, be dissolved in the chloroform/methanol mixed solvent, heating boils off solvent; The phosphate buffer that adds the pH6-8 that is dissolved with 1 part of breviscapine again; Form suspension, homogenize; Perhaps
2) in the phosphate buffer of pH6-8, feed nitrogen,, add phosphatidase 13 0-60 part again, mixing and emulsifying, homogenize by weight 1 part of breviscapine is dissolved in wherein; Perhaps
3) get by weight in the phosphate buffer that 1 part of breviscapine adds pH6-8, get phosphatidase 13 0-60 part and cholesterol 5-10 part is dissolved in ether, mix two liquid, organic solvent is removed in emulsifying; Perhaps
4) get phosphatidase 13 0-60 part by weight and cholesterol 5-10 part is dissolved in ether, add the phosphate buffer of pH6-8, mixing and emulsifying is removed solvent; Mix with the phosphate buffer of the pH6-8 that contains 1 part of breviscapine.
The preparation method of aforementioned breviscapine liposome, it is characterized in that: when breviscapine is dissolved in the phosphate buffer of pH6-8, add sodium hydroxide, phosphate, carbonate, citrate, cysteine, nicotiamide, Benzoylamide, urea, thiourea, ethylenediamine, diethylamine, ethanolamine, diethanolamine, triethanolamine, triethylamine, meglumine and/or Tris.
The lyophilized injectable powder of described breviscapine liposome is characterized in that: be made up of liposome and dextran, monosaccharide, disaccharidase and/or polysaccharide substantially; The amount by phospholipase weight ratio of dextran, monosaccharide, disaccharidase and/or polysaccharide is calculated, and 1 part of phospholipid adds 0.2-4.0 part dextran, monosaccharide, disaccharidase and/or polysaccharide.
The lyophilized injectable powder of breviscapine liposome preferably, it is characterized in that: monosaccharide is mannitol, glucose, and disaccharidase is lactose, sucrose, and polysaccharide is a trehalose, its amount by phospholipase weight ratio is calculated, and 1 part of phospholipid adds dextran, monosaccharide, disaccharidase and/or the polysaccharide of 0.5-1.0 part.
A kind of preparation method of breviscapine lipidosome freeze-dried injection is characterized in that: with aforementioned breviscapine liposome cool to room temperature, add dextran, monosaccharide, disaccharidase and/or polysaccharide, the weight ratio of its amount by phospholipase is calculated, 1 part of phospholipid adds 0.2-4.0 part, after the filtration, and lyophilization.Monosaccharide is mannitol, glucose, and disaccharidase is lactose, sucrose, and polysaccharide is a trehalose, and it is measured preferably to the by phospholipase weight ratio and calculates, and 1 part of phospholipid adds 0.5-1.0 dextran, monosaccharide, disaccharidase and/or polysaccharide.
The lyophilized injectable powder of described breviscapine liposome is characterized in that: after diluting with arbitrary proportion and transfusion, envelop rate is 60%～90%, and particle diameter is 20nm～1 μ m.Described arbitrary proportion and transfusion dilution are meant pharmaceutically to be suitable for ratio and transfusion dilution.
In order to finish the present invention's purpose, particularly a kind of breviscapine liposome and lyophilized powder and their preparation method is characterized in that: the weight ratio of breviscapine and phospholipid is 1: 2-60, with the weight ratio of cholesterol be 1: 0-10.Can use phospholipid commonly used according to the present invention, as soybean phospholipid or lecithin or synthetic phospholipid.Phosphatidylcholine purity can be between 76%-100%, preferred purity＞93%.When phosphatidylcholine purity was high, its consumption can suitably reduce.
Preferred in the described liposome: as to contain the 1-5mg breviscapine in every ml liposome turbid liquor.Add pH regulator agent such as sodium hydroxide, phosphate, carbonate, citrate, cysteine and organic amine, as nicotiamide, Benzoylamide, urea, thiourea, ethylenediamine, diethylamine, ethanolamine, diethanolamine, triethanolamine, triethylamine, meglumine, Tris, regulate pH value to 6-8, can increase the envelop rate of breviscapine in liposome.Adding freeze drying protectant such as mannitol, lactose, sucrose, glucose, trehalose etc. help the reorganization of lipid freeze-dry powder and stablize.Wherein mannitol, glucose and trehalose are good especially.Freeze drying protectant is 0.2-4 with the ratio of phospholipid: 1, and with 0.5-1: 1 is good.
Liposome of the present invention can be used method preparations such as rotary evaporation method, reverse phase evaporation, high pressure homogenize method, pH gradient method.
Breviscapine content height in the unit volume of breviscapine liposome of the present invention has shown that prescription of the present invention and technology both can make liposome reach high envelop rate, had stable drug loading again.Medicine in the liposome continues to discharge, and has significantly improved blood drug level, and prolong drug is circulation time in blood.The clinical suitable breviscapine liposome injection freeze-dried powder of the present invention, can significantly improve bin stability, can make the breviscapine lipid freeze-dry powder again after adding that water for injection is molten again and loosing, can not produce precipitation and catabolite with transfusion dilution administration with arbitrary proportion, especially under the big situation of dosage, thereby reduce the unsafe factor of clinical application to greatest extent.The bioavailability of breviscapine liposome freeze-dried powder injection of the present invention is 8 times of the normal injection agent, thereby can reduce dosage.
But the present invention has also solved the preparation method of the suitability for industrialized production of described breviscapine liposome and injection freeze-dried powder thereof.
Description of drawings
Fig. 1, breviscapine liposome and the injection of commercially available normal injection agent rabbit auricular vein through the time curve (n=3)
The specific embodiment
Raw material sources: commercially available breviscapine, can extract from Herba Erigerontis, Herba Erigerontis or other plant according to a conventional method.Allowing specification is scutellarin labelled amount 80-105% content range in the dry product, and surplus is breviscapine and a small amount of composition of being correlated with.
Embodiment 1
Taking by weighing 600mg soybean phospholipid (purity＞76% phosphatidylcholine) and 100mg cholesterol is dissolved in chloroform/methanol (1: 1) (chloroform is 1 with the ratio of methanol: 0.5-2) in the mixed solvent, this solution is placed the ground round-bottomed flask, in under the condition of 100rpm and decompression, boiling off organic solvent with Rotary Evaporators in the 26-28 ℃ of water bath with thermostatic control, make filmogen such as phospholipid form an even lipid membrane at drag, place vacuum desiccator, it is standby that room temperature condition is placed 4 hours (4-12 hour) down.In addition with the 10mg breviscapine, the 2mg sodium hydroxide adds in 5ml (2-10ml) the pH7.4 phosphate buffer, it is joined in the above-mentioned round-bottomed flask again, under 32 ℃, wash film with the Rotary Evaporators rotation, become the milky liposome turbid liquor until the hydration of lipoid thin film, high pressure homogenize (Avestin homogenizer) reduces particle diameter (5000psi, 3 times) promptly.300mg mannitol is dissolved in the liposome, and (membrane filter aperture 0.2 μ m) will finally disperse in the thing packing cillin bottle lyophilization then after the aseptic filtration.
With cryodesiccated liposome 40 ℃ store 3 months after, breviscapine content is 95.5%, and the liposome encapsulation that the reorganization of adding 2ml water for injection obtains is 80%, and particle diameter is 600nm, dilutes not have in back 10 hours to precipitate with 5% glucose injection or 0.9% sodium chloride injection and separates out.
Embodiment 2
In 20ml pH6.8 phosphate buffer, fed nitrogen 10 minutes.Behind the logical nitrogen 100mg breviscapine and 40mg ethanolamine are dissolved in wherein, add 800mg soybean phospholipid (purity＞93% phosphatidylcholine) then.Use homogenizer this mixture to be disperseed to reach 10 minutes at 65 ℃.After replenishing transpiring moisture, pre-dispersed thing is transferred in the high pressure homogenizer.5000psi and 65 ℃ of following homogenizes 3 times, liposome is cooled to room temperature.The 1.2g glucose is dissolved in the liposome, after the aseptic filtration (membrane filter aperture 0.2 μ m), will finally disperses the thing branch to pack in the cillin bottle lyophilization then into.
With cryodesiccated liposome 40 ℃ store 3 months after, breviscapine content is 96.5%, and the liposome encapsulation that the reorganization of adding 2ml water for injection obtains is 90%, and particle diameter is 100nm, dilutes not have in back 10 hours to precipitate with 5% glucose injection or 0.9% sodium chloride injection and separates out.
Embodiment 3
30mg breviscapine, 12mg sodium bicarbonate are added the dissolving of 10ml pH6.8 phosphate buffer, again 900mg lecithin (purity＞93% phosphatidylcholine), 100mg cholesterol are dissolved in the 20ml ether, again the breviscapine aqueous solution is added in the phospholipid ether solution, emulsifying is carried out in the two mixing, organic solvent is removed in decompression then, and the ultrasonic 0.5min of probe-type gets final product.The 900mg trehalose is dissolved in the liposome, after the aseptic filtration (membrane filter aperture 0.2 μ m), will finally disperses the thing branch to pack in the cillin bottle lyophilization then into.
With cryodesiccated liposome 40 ℃ store 3 months after, breviscapine content is 97.5%, and the liposome encapsulation that the reorganization of adding 2ml water for injection obtains is 85%, and particle diameter is 25nm, dilutes not have in back 10 hours to precipitate with 5% glucose injection or 0.9% sodium chloride injection and separates out.
Embodiment 4
Take by weighing 900mg synthetic phospholipid (DMPC, purity＞93% phosphatidylcholine), the 100mg cholesterol is dissolved in the 20ml ether, again 5ml pH8.0 phosphate buffer is added in the phospholipid ether solution, emulsifying is carried out in the two mixing, organic solvent is removed in decompression then, the ultrasonic 0.5min of probe-type, standby, as blank liposome.In addition 30mg breviscapine and 18mg aminothiopropionic acid are added in the 5ml pH8.0 phosphate buffer and dissolve, mixes usefulness 0.1M HCL adjust pH to 7.0, balance 30min (15-60min) in 37 ℃ of water-baths afterwards again with blank liposome.After liposome is cooled to room temperature, the 600mg lactose is dissolved in the liposome, after the aseptic filtration (membrane filter aperture 0.2 μ m), will finally disperses the thing branch to pack in the cillin bottle lyophilization then into.
With cryodesiccated liposome 40 ℃ store 3 months after, breviscapine content is 98.5%, and the liposome encapsulation that the reorganization of adding 2ml water for injection obtains is 88%, and particle diameter is 200nm, dilutes not have in back 10 hours to precipitate with 5% glucose injection or 0.9% sodium chloride injection and separates out.
Embodiment 5
Breviscapine liposome rabbit body giving drugs into nose is for the examination of kinetic property:
A. administration with get the blood scheme:
3 of ash rabbits, male and female are not limit, body weight (1.87 ± 0.058kg), provided by this school Experimental Animal Center, inject commercially available breviscapine injection by an ear vein respectively, injection finishes in the 2min, after the administration respectively at 5,15,30,45,60,120,180,300,420,540min gets blood from the opposite side auricular vein, each 0.5ml.Institute's blood-sample withdrawal is all used anticoagulant heparin, and separated plasma immediately.After one week, at the first-class dosage of same animal (4mg/kg) injection breviscapine liposome turbid liquor of the present invention (freeze-dried powder is disperseed with the water for injection dissolving), after the administration respectively at 5,15,30,45,60,120,180,300,540,720,1440min gets blood, places the centrifuge tube of heparinization.
B. through the time curve, referring to Fig. 1.
C. the moving parameter of relevant medicine
| V parameter (c)/ml t 1/2β/min AUC/ug·min·ml -1CL (s)/ml·min -1 | Liposome 209.9441 ± 212.9016 301.5101 ± 68.3577 1416.7370 ± 284.4667 4.0172 ± 0.9402 | Commercially available normal injection agent 401.1532 ± 266.5517 1.5125 ± 0.1379 137.7837 ± 32.6111 42.5394 ± 17.1946 |
Claims (9)
1, a kind of breviscapine liposome is characterized in that: the weight ratio of breviscapine, phospholipid, cholesterol is 1: 2-65: 0-15 part, and contain the pH regulator agent.
2, according to the described breviscapine liposome of claim 1, it is characterized in that: the weight ratio of breviscapine, phospholipid, cholesterol is 1: 30-60: 5-10 part; Breviscapine mainly is made up of scutellarin, can contain a small amount of breviscapine; Phospholipid is soybean phospholipid, lecithin or synthetic phospholipid; The pH regulator agent is sodium hydroxide, phosphate, carbonate, citrate, cysteine, nicotiamide, Benzoylamide, urea, thiourea, ethylenediamine, diethylamine, ethanolamine, diethanolamine, triethanolamine, triethylamine, meglumine and/or Tris.
3, a kind of preparation method of breviscapine liposome is characterized in that: through following step preparation,
1) gets phosphatidase 12-65 part and cholesterol 1-15 part by weight, be dissolved in chloroform and/or the methanol solvate, remove and desolvate; The phosphate buffer that adds the pH6-8 that is dissolved with 1 part of breviscapine and pH regulator agent again; Form suspension, homogenize; Perhaps
2) in the phosphate buffer of pH6-8, feed nitrogen, by weight 1 part of breviscapine and pH regulator agent are dissolved in wherein, add phosphatidase 12-65 part, mixing and emulsifying, homogenize again; Perhaps
3) get 1 part of breviscapine by weight and add in the phosphate buffer of pH6-8 with the pH regulator agent, get phosphatidase 12-65 part and cholesterol 1-15 part and be dissolved in low polar organic solvent, mix two liquid, organic solvent is removed in emulsifying; Perhaps
4) get phosphatidase 12-65 part by weight and be dissolved in low polar organic solvent with cholesterol 1-15 part, add the phosphate buffer of pH6-8, mixing and emulsifying is removed solvent, and contains 1 part of breviscapine and mixes with the phosphate buffer of the pH6-8 of pH regulator agent.
4, according to the preparation method of the described breviscapine liposome of claim 3, it is characterized in that:
1) get phosphatidase 13 0-60 part and cholesterol 5-10 part by weight, be dissolved in the chloroform/methanol mixed solvent, heating boils off solvent; The phosphate buffer that adds the pH6-8 that is dissolved with 1 part of breviscapine and pH regulator agent again; Form suspension, homogenize; Perhaps
2) in the phosphate buffer of pH6-8, feed nitrogen,, add phosphatidase 13 0-60 part again, mixing and emulsifying, homogenize by weight 1 part of breviscapine and pH regulator agent are dissolved in wherein; Perhaps
3) get 1 part of breviscapine by weight and add in the phosphate buffer of pH6-8 with the pH regulator agent, get phosphatidase 13 0-60 part and cholesterol 5-10 part is dissolved in ether, mix two liquid, organic solvent is removed in emulsifying; Perhaps
4) get phosphatidase 13 0-60 part by weight and cholesterol 5-10 part is dissolved in ether, add the phosphate buffer of pH6-8, mixing and emulsifying is removed solvent; With contain 1 part of breviscapine and mix with the phosphate buffer of the pH6-8 of pH regulator agent.
5, according to the preparation method of the described breviscapine liposome of claim 4, it is characterized in that: when breviscapine was dissolved in the phosphate buffer of pH6-8, the pH regulator agent of adding was sodium hydroxide, phosphate, carbonate, citrate, cysteine, nicotiamide, Benzoylamide, urea, thiourea, ethylenediamine, diethylamine, ethanolamine, diethanolamine, triethanolamine, triethylamine, meglumine and/or Tris.
6, according to the lyophilized injectable powder of claim 1 or 2 described breviscapine liposomees, it is characterized in that: form by liposome and dextran, monosaccharide, disaccharidase and/or polysaccharide substantially; The amount by phospholipase weight ratio of dextran, monosaccharide, disaccharidase and/or polysaccharide is calculated, and 1 part of phospholipid adds 0.2-4.0 part dextran, monosaccharide, disaccharidase and/or polysaccharide.
7, according to the lyophilized injectable powder of the described breviscapine liposome of claim 6, it is characterized in that: monosaccharide is mannitol, glucose, and disaccharidase is lactose, sucrose, and polysaccharide is a trehalose, and its amount by phospholipase weight ratio is calculated, and 1 part of phospholipid adds 0.5-1.0 part.
8, a kind of preparation method of breviscapine lipidosome freeze-dried injection, it is characterized in that: with claim 1 or 2 described breviscapine liposome cool to room temperature, add dextran, monosaccharide, disaccharidase and/or polysaccharide, the weight ratio of its amount by phospholipase is calculated, 1 part of phospholipid adds 0.2-4.0 part, after the filtration, lyophilization.
9, the preparation method of lyophilized injectable powder according to Claim 8, it is characterized in that: described monosaccharide is mannitol, glucose, and disaccharidase is lactose, sucrose, and polysaccharide is a trehalose, and its amount by phospholipase weight ratio is calculated, and 1 part of phospholipid adds 0.5-1.0.
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| CN1843368B (en) * | 2005-04-06 | 2010-04-28 | 清华大学 | Breviscapinum long-circulating nanoliposome and its preparation method |
| CN102344475A (en) * | 2010-07-30 | 2012-02-08 | 昆明制药集团股份有限公司 | Scutellarin derivative and preparation method and application thereof |
| CN104800171B (en) * | 2015-05-05 | 2017-09-19 | 临沂大学 | Phase gelation multivesicular liposome freeze-dried powder and preparation method thereof in a kind of Breviscapinun |
| CN106265519B (en) * | 2016-08-30 | 2019-03-29 | 上海交通大学 | A kind of Scutellarein Liposomal formulation and preparation method thereof |
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Assignee: Zhejiang Fengan Biopharmaceutical Co., Ltd. Assignor: China Pharmaceutical University Contract fulfillment period: 2009.5.4 to 2023.3.23 contract change Contract record no.: 2009330000964 Denomination of invention: Erigeron breviscapus liposome and its freeze dried powder injection fluid and preparation method Granted publication date: 20050518 License type: Exclusive license Record date: 2009.5.13 |
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