CN103120645A - Irinotecan or irinotecan hydrochloride lipidosome and preparation method thereof - Google Patents
Irinotecan or irinotecan hydrochloride lipidosome and preparation method thereof Download PDFInfo
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Abstract
The invention discloses an irinotecan or irinotecan hydrochloride lipidosome and a preparation method thereof. The lipidosome contains irinotecan or irinotecan hydrochloride, neutral phospholipid and cholesterol, wherein the weight ratio of the cholesterol to the neutral phospholipid is 1:(3-5), and the irinotecan or irinotecan hydrochloride lipidosome is prepared by an ion gradient method.
Description
The application is that application number is 200980154026.9, and the applying date is December in 2009 3 days, and denomination of invention is divided an application for the Chinese patent application of " irinotecan or irinotecan hydrochloride liposome and preparation method thereof ".
Technical field
The present invention relates to a kind of irinotecan or irinotecan hydrochloride liposome and preparation method thereof, and contain injection of this liposome and preparation method thereof.
Background technology
Irinotecan is the semi-synthetic derivant of camptothecine.Camptothecine can be combined with topoisomerase I specifically, and the latter induces the reversibility single-strand break, thereby the DNA double chain structure is untwisted; Irinotecan and active metabolite SN-38 thereof can be combined with topoisomerase I-DNA complex, thereby stop the connection again of fracture strand.Existing research prompting, the cytotoxicity of irinotecan are owing in the DNA building-up process, and replicative enzyme and topoisomerase I-DNA-irinotecan (or SN-38) three complex interact, thereby cause the DNA double chain interruption.
The irinotecan hydrochloride pharmacological action is obvious, clinical efficacy is definite, be widely used in treating malignant tumor, but, it is the same with other camptothecines, and a same problem that exists is exactly that the saturated lactonic ring in its structure has the pH dependency, understand reversible its carboxylate form that changes under physiological condition, and anti-tumor activity is weakened.The existing commercial preparation of irinotecan hydrochloride is irinotecan hydrochloride injection and freeze-dried powder thereof, clinically after intravenously administrable, free drug directly is in the physiological environment of meta-alkalescence, hydrolysis easily occurs and changes carboxylate form in the lactonic ring in its structure, thereby lose activity, indirectly reduced the curative effect of medicine.And the toxic and side effects of preparation is larger, and main manifestations is that neutrophilic granulocyte reduces and Delayed onset diarrhoea.
Liposome is as Recent study a kind of pharmaceutical carrier comparatively widely, and its main feature is to protect encapsulated medicine, increases medicine stability, changes medicine distribution behavior in vivo, and carrying medicaments is passive or initiatively be targeted to diseased region.Liposome can effectively improve curative effect of medication as the good carrier of antitumor drug, reduces toxic and side effects.
International Application No. WO 2005/117878 discloses prescription and the preparation method of irinotecan liposome, contains irinotecan or irinotecan hydrochloride in said preparation, is selected from HSPC, phospholipid, the cholesterol such as PHOSPHATIDYL ETHANOLAMINE, lecithin, cuorin.Equally, Chinese patent application CN1994279A also discloses prescription and the preparation method of irinotecan liposome, and wherein the use phosphatidylcholine of embodiment 5 has prepared liposome as phospholipid.
Although the prescription of putting down in writing in above-mentioned patent documentation has had better effects, be fit to if be prepared into the preparation that human body uses, this liposome still can not be satisfactory at aspects such as stability, particle diameters.
Summary of the invention
The purpose of this invention is to provide a kind of drug loading higher, and it is high to satisfy simultaneously envelop rate, good stability, is fit to be prepared into irinotecan or the irinotecan hydrochloride liposome of preparation.
Form and preparation method although put down in writing at present the liposome of irinotecan in some documents (for example International Application No. WO 2005/117878 and CN1994279A), wherein the part index number of individual program is better.But the control for aspects such as stability, particle diameters does not provide any information.The applicant is through further studying liposome, wonderful discovery is when the adjuvant of selecting prescription and consumption relation meet some condition, the consumption of special cholesterol has certain impact to liposome particle diameter and stability, ratio between controlling both on the basis of selecting neutral phosphor and cholesterol, can make the particle diameter of liposome become little and even, and improve the stability of liposome.Compare with other prescriptions, the indexs such as stability of the application's liposome obviously improve.The present invention compares with technology such as CN1994279A with International Application No. WO 2005/117878 in addition, alkali-free functional compounds and cation lipid in product, prescription forms simple, and drug loading is high, good stability, liposome of the present invention has good antitumous effect.
Liposome of the present invention contains irinotecan or irinotecan hydrochloride, neutral phospholipid and cholesterol, and the part by weight of wherein said cholesterol and neutral phospholipid is 1:3～5, and preferred proportion is 1:3.5～4.5, most preferably is 1:4.
The optional materials such as hydrogenated soy phosphatidyl choline (HSPC), egg yolk lecithin (EPC), soybean phospholipid (SPC) of selecting of neutral phospholipid used in the present invention, particularly when neutral phospholipid used hydrogenated soy phosphatidyl choline, its effect was best.When the weight proportion relation between further control medicine and phospholipid was following the relation, the drug loading of liposome greatly improved:
1 part of irinotecan or irinotecan hydrochloride
Liposome of the present invention can prepare according to the method for preparing lipidosome of this area routine, for liposome of the present invention, preferably uses the ion gradient legal system standby.When using the ion gradient method, has the ion gradient that buffer agent forms in described liposome between water and outer water, in preferred described liposome, water has the high ion gradient of ion concentration than outer water, this particle diameter that can improve the lay up period liposome is stable, better keep drug effect, it is little and even that this can control the liposome mean diameter, can make the liposome particle diameter be reduced to minimum level in the variation of storage period.
The present invention can make the liposome particle diameter be reduced to minimum level in the variation of storage period by the lipid derivate that adds hydrophilic macromolecule in formula, can extend liposome circulation time in vivo adding of polyethyleneglycol derivative simultaneously.Polyethyleneglycol derivative is selected from the hard ester acyl PHOSPHATIDYL ETHANOLAMINE (DSPE-PEG of Macrogol 2000-two
2000) Polyethylene Glycol 5000-DSPE, Macrogol 2000-DPPE, Polyethylene Glycol 5000-DPPE.Therefore in order to improve the long-lasting of medicine, the application preferably adds the lipid derivate of hydrophilic macromolecule in liposome, on this prescription ratio basis, uses DSPE-PEG
2000That effect is the most obvious.The weight ratio of preferred lipid derivate and irinotecan or irinotecan hydrochloride is 0.2～0.4.
Liposome can further contain electrically charged phospholipid, electrically charged phospholipid is selected from one or more in PE, DPPG, DSPG, GLYCEROL,DIMYRISTOYL PHOSPHATIDYL, two oleic acid Phosphatidylserine, DOPG, two lauroyl phosphatidic acid, two myristoyl phosphatidic acid or G 12S3P, and the part by weight of electrically charged phospholipid and neutral phospholipid is 1:5～1:100.
The preferred liposome of the present invention contains the composition of following weight proportion:
And the ratio of cholesterol and hydrogenated soy phosphatidyl choline is 1:4.
The application also provides the preparation method of irinotecan or irinotecan hydrochloride liposome, and liposome of the present invention can select common method for preparing lipidosome to prepare.Those skilled in the art can according to the prescription of liposome provided by the invention, select the whole bag of tricks to prepare.For the selected prescription of liposome of the present invention, preferred preparation method is the ion gradient method.This preparation method comprises following step:
1) prepare blank liposome by following A any method to the D:
A, select neutral phospholipid, cholesterol to be dissolved in dehydrated alcohol or dehydrated alcohol-tert-butyl alcohol mixed solvent according to formula, mix with buffer agent, obtain the blank liposome crude product after ethanol is removed in decompression, adopt high pressure homogenizer afterwards or/and extrusion equipment prepares blank liposome to required granularity;
B, select neutral phospholipid, cholesterol to be dissolved in chloroform or chloroform-methanol mixed solvent according to formula, rotary evaporation forms lipid film, add the buffer agent aquation to obtain the blank liposome crude product, adopt high pressure homogenizer afterwards or/and extrusion equipment prepares blank liposome to required granularity;
C, select neutral phospholipid, cholesterol to mix with buffer agent according to formula, adopt high pressure homogenizer afterwards or/and extrusion equipment prepares blank liposome to required granularity;
D, select neutral phospholipid, cholesterol to be dissolved in dehydrated alcohol or dehydrated alcohol-tert-butyl alcohol mixed solvent according to formula, mix with buffer agent, adopt high pressure homogenizer afterwards or/and extrusion equipment prepares blank liposome to required granularity;
2) generation of the inside and outside water ion gradient of liposome membrane: the outer water of displacement blank liposome makes water and outer water generation ion gradient in liposome;
3) pastille liposome preparation: preparation irinotecan hydrochloride aqueous solution, join in the blank liposome dispersion liquid with ion gradient, heated and stirred is hatched certain hour and get final product.
After step 3) " preparation of pastille liposome " step, also can comprise following steps:
4) removal of free drug and sample is concentrated: add buffer medium in the irinotecan hydrochloride liposome, adopt the slipstream device to remove non-encapsulated medicine, simultaneously with sample concentration to suitable volume.
The application also provides the lipidosome injection that contains above-mentioned liposome.When liposome being prepared into the injection that is fit to use, it is useful adding stabilizing agent.Stabilizing agent used in the present invention also can be selected normally used stabilizing agent, such as vitamin E, ethylenediaminetetraacetic acid etc., and these stabilizing agents are stable helpful to preparation all.For above-mentioned prescription, by the research of stabilizing agent being found ethylenediaminetetraacetic acid or its salt are best with respect to other stabilizing agent effects, the most beneficial for the stability that improves liposome, therefore can select one or more in ethylenediaminetetraacetic acid, disodium EDTA, ethylenediaminetetraacetic acid two calcium salts, and the additional proportion of stabilizing agent is that 0%～0.5w/v% and lower limit are not 0%.
Preferably contain antioxidant in compositions of the present invention, described antioxidant can be selected from water solublity antioxidant or oil-soluble antioxidant, described oil-soluble antioxidant is selected from alpha-tocopherol, α-tocopheryl acid succinate, α-tocopheryl acetate or its mixture, described water solublity antioxidant is selected from ascorbic acid, sodium sulfite, sodium sulfite, sodium pyrosulfite, Cys or its mixture, and the additional proportion of antioxidant is that 0%～0.5w/v% and lower limit are not 0%.
Injection can be injection or freeze-dried powder form.Can contain osmotic pressure regulator in preparation, described osmotic pressure regulator is selected from one or more in glucose, sucrose, sorbitol, mannitol, sodium chloride, glycerol, histidine and hydrochloride thereof, glycine and hydrochloride thereof, lysine, serine, glutamic acid, arginine or valine, and the additional proportion of osmotic pressure regulator is that 0%～5w/v% and lower limit are not 0%.
For the preparation of lyophilized powder form, injection further contains freeze drying protectant, carries out making liposome freeze-drying powder injection after lyophilization.Freeze drying protectant is selected from one or more in glucose, sucrose, trehalose, mannitol, dextran or lactose.
The preferred injection liposome of the present invention contains the composition of following weight proportion:
And the ratio of cholesterol and hydrogenated soy phosphatidyl choline is 1:4.
The preparation method of above-mentioned injection comprises following step:
1) prepare blank liposome by following A any method to the D:
A, select neutral phospholipid, cholesterol to be dissolved in dehydrated alcohol or dehydrated alcohol-tert-butyl alcohol mixed solvent according to formula, mix with buffer agent, obtain the blank liposome crude product after ethanol is removed in decompression, adopt high pressure homogenizer afterwards or/and extrusion equipment prepares blank liposome to required granularity;
B, select neutral phospholipid, cholesterol to be dissolved in chloroform or chloroform-methanol mixed solvent according to formula, rotary evaporation forms lipid film, add the buffer agent aquation to obtain the blank liposome crude product, adopt high pressure homogenizer afterwards or/and extrusion equipment prepares blank liposome to required granularity;
C, select neutral phospholipid, cholesterol to mix with buffer agent according to formula, adopt high pressure homogenizer afterwards or/and extrusion equipment prepares blank liposome to required granularity;
D, select neutral phospholipid, cholesterol to be dissolved in dehydrated alcohol or dehydrated alcohol-tert-butyl alcohol mixed solvent according to formula, mix with buffer agent, adopt high pressure homogenizer afterwards or/and extrusion equipment prepares blank liposome to required granularity;
2) generation of the inside and outside water ion gradient of liposome membrane: the outer water of displacement blank liposome makes water and outer water generation ion gradient in liposome;
3) pastille liposome preparation: preparation irinotecan hydrochloride aqueous solution, join in the blank liposome dispersion liquid with ion gradient, heated and stirred is hatched certain hour and get final product.
After step 3) " preparation of pastille liposome " step, also can comprise following steps:
4) removal of free drug and sample is concentrated: add buffer medium in the irinotecan hydrochloride liposome, adopt the slipstream device to remove non-encapsulated medicine, simultaneously with sample concentration to suitable volume.
After obtaining liposome, also can be by adjustment liposomal body substrate concentration, standardize solution, filtration sterilization, embedding get lipidosome injection in bottle; Perhaps add freeze drying protectant in the liposomal body matter sample, adjust drug level, standardize solution, filtration sterilization, embedding are in bottle, and lyophilization gets freeze-dried powder.
Beneficial effect of the present invention:
Irinotecan hydrochloride is made Liposomal formulation, overcome the deficiency of existing product and technology, pharmaceutical pack is wrapped in aqueous phase in liposome, improve medicine stability, medicine is existed with the state of lactonic ring in vivo, can keep for a long time the concentration of active metabolite SN-38 in blood plasma, increase the preparation curative effect to reach, reduce the toxic and side effects of medicine.
Irinotecan of the present invention or irinotecan hydrochloride Liposomal formulation are by controlling the proportionate relationship of specific medicine, phospholipid and cholesterol, can reach the low problem of liposome drug loading that solves, medicine fat can reach more than 0.25 than (w/w), entrapment efficiency can reach more than 90% simultaneously, and preferred prescription can reach more than 95%; The present invention is by further selecting the magnitude relation of using of cholesterol and phospholipid, and the liposome particle diameter of preparation is less, has improved the stability of liposome.The present invention also by the screening to stabilizing agent, optimizes the stability that adds a certain proportion of edetate obviously to improve liposome; The particle diameter of liposome is evenly distributed between 10nm-220nm; Stable in properties, irinotecan or irinotecan hydrochloride lipidosome injection influence factor experimental result show, place 10 days under 40 ℃ of degree conditions, and particle diameter and envelop rate are all without significant change, and indices meets the requirements; Irinotecan or irinotecan hydrochloride lipidosome injection are compared with the commercial preparation, and tumour inhibiting rate significantly improves, and toxicity significantly reduces.
Description of drawings
Fig. 1 shows the particle size distribution of irinotecan of the present invention or irinotecan hydrochloride lipidosome injection.
Fig. 2 shows the aspect graph of irinotecan of the present invention or irinotecan hydrochloride lipidosome injection.
Fig. 3 shows the result of the anti-tumor in vivo test of pesticide effectiveness of irinotecan of the present invention or irinotecan hydrochloride lipidosome injection.
The specific embodiment
Following embodiment is used for further illustrating the present invention, but the present invention is not limited to this embodiment.
Embodiment 1
Prescription
Preparation method:
Hydrogenated soy phosphatidyl choline (HSPC), the cholesterol (CHOL) of recipe quantity is dissolved in appropriate dehydrated alcohol gets lipid soln, mix with the 100ml ammonium sulfate, decompression is removed ethanol and is obtained the blank liposome crude product.Adopt afterwards 5 circulations of high pressure homogenizer 1000bar homogenizing, extrude liposome by extrusion equipment afterwards and control its particle diameter (2 0.1 μ m extruded films of extruder paving are extruded 5 times).Add afterwards the DSPE-PEG for preparing
2000Aqueous solution stirs and hatched 20 minutes.Adopt tangential flow ultra-filtration unit dialysis blank liposome, middle continual supplementary injection water namely gets blank liposome.
With water for injection preparation irinotecan hydrochloride aqueous solution, be that 1:3.5 joins in above-mentioned blank liposome dispersion liquid with ion gradient according to the part by weight of irinotecan hydrochloride and HSPC, 60 ℃ of heated and stirred are hatched and were namely got drug-loaded liposome in 20 minutes.Adopt tangential flow ultra-filtration unit to remove non-encapsulated medicine, simultaneously with sample concentration to about 50ml, add 0.45g sodium chloride to regulate osmotic pressure.Adjust drug level, standardize solution, 0.22 μ m membrane filtration degerming, the inflated with nitrogen embedding namely gets the irinotecan hydrochloride lipidosome injection in bottle.
The change of size of respectively writing out a prescription of preparation is as shown in the table, and result shows, sample particle diameter minimum when phospholipid and cholesterol weight ratio are 4:1.
The sample of different phospholipid and the preparation of cholesterol weight ratio is placed under 25 ℃ of conditions, investigated stability.Result such as following table were placed under 25 ℃ of conditions 60 days, and phospholipid and cholesterol weight ratio are that 4:1 sample particle diameter and envelop rate are without significant change, the sample particle diameter of other ratio increases, envelop rate also descends to some extent, and as seen, phospholipid and cholesterol weight ratio are that the sample stability of 4:1 is better.
Conclusion: comprehensive indices, the proportion control between result proof C/PL can reach reasonable result of use in 1:3～5, and best proportioning is 1:4.
Prescription
Preparation method:
Hydrogenated soy phosphatidyl choline, the cholesterol of recipe quantity is dissolved in appropriate dehydrated alcohol gets lipid soln, mix with the 100ml ammonium sulfate, decompression is removed ethanol and is obtained the blank liposome crude product.Adopt afterwards 5 circulations of high pressure homogenizer 1000bar homogenizing, extrude liposome by extrusion equipment afterwards and control its particle diameter (2 0.1 μ m extruded films of extruder paving are extruded 5 times).Add afterwards the DSPE-PEG for preparing
2000Aqueous solution stirs and hatched 20 minutes.Adopt tangential flow ultra-filtration unit dialysis blank liposome, middle continual supplementary injection water namely gets blank liposome.
With water for injection preparation irinotecan hydrochloride aqueous solution, be that 1:3.5 joins in above-mentioned blank liposome dispersion liquid with ion gradient according to the part by weight of irinotecan hydrochloride and HSPC, 60 ℃ of heated and stirred are hatched and were namely got drug-loaded liposome in 20 minutes.Adopt tangential flow ultra-filtration unit to remove non-encapsulated medicine, simultaneously with sample concentration to about 50ml, add 0.45g sodium chloride to regulate osmotic pressure.Adjust drug level, standardize solution, 0.22 μ m membrane filtration degerming, the inflated with nitrogen embedding namely gets the irinotecan hydrochloride lipidosome injection in bottle.
Embodiment 3
Blank liposome prescription and preparation method are identical with embodiment 2, different is is respectively as 1:1.5,1:2,1:3.5,1:4 and 1:5 are prepared liposome according to the part by weight of irinotecan hydrochloride and HSPC, and irinotecan hydrochloride liposomal samples envelop rate and particle diameter see the following form.
Presentation of results, envelop rate significantly reduces when the ratio of irinotecan hydrochloride and HSPC is 1:1.5, and drug loading descends obviously when its ratio is 1:5, is not suitable for being prepared into the preparation of clinical practice, and envelop rate and drug loading are all higher when its ratio is between 1:2 and 1:4.
Embodiment 4
Consumption according to prescription component in embodiment 2 prepares blank liposome and drug-loaded liposome, preparation method is with the described method of embodiment 2, and difference is that the HSPC that adopts respectively high-purity egg yolk lecithin (EPC), high-purity soybean phospholipid (SPC) to replace in prescription prepares.The liposomal samples of preparation is placed in investigation stability under 25 ℃ of conditions.The results are shown in following table.Result of the test shows, adopts the liposomal samples stability of HSPC preparation best, places 2 months leading indicators under 25 ℃ of conditions without significant change.
Embodiment 5
Prescription
Preparation method＜1 〉:
Alcohol injection: with hydrogenated soy phosphatidyl choline, the DSPE-PEG of recipe quantity
2000, cholesterol is dissolved in appropriate dehydrated alcohol and gets lipid soln, is injected in the normal saline solution of irinotecan hydrochloride, decompression is removed ethanol and is obtained the liposome crude product.Adopt afterwards 5 circulations of high pressure homogenizer 1000bar homogenizing, extrude liposome by extrusion equipment afterwards and control its particle diameter (2 0.1 μ m extruded films of extruder paving are extruded 5 times).Adjust drug level, standardize solution, 0.22 μ m membrane filtration degerming, the inflated with nitrogen embedding namely gets the irinotecan hydrochloride lipidosome injection in bottle.
Preparation method＜2 〉:
Film dispersion method: with hydrogenated soy phosphatidyl choline, the DSPE-PEG of recipe quantity
2000, cholesterol is dissolved in appropriate chloroform and gets lipid soln, with lipid soln rotary evaporation film forming, eliminate chloroform and then add the normal saline solution aquation of irinotecan hydrochloride to hatch approximately 1h.Adopt afterwards 5 circulations of high pressure homogenizer 1000bar homogenizing, then extrude liposome by extrusion equipment and control its particle diameter (2 0.1 μ m extruded films of extruder paving are extruded 5 times).Adjust drug level, standardize solution, 0.22 μ m membrane filtration degerming, the inflated with nitrogen embedding namely gets the irinotecan hydrochloride lipidosome injection in bottle.
Measure preparation method＜1 〉,＜2 and irinotecan hydrochloride liposome encapsulation and the particle diameter of embodiment 2 preparations.
Result shows, when adopting Passive loading method such as alcohol injection and film evaporation method to prepare the irinotecan hydrochloride liposome, can prepare the purpose product.But its sample envelop rate is lower, and most of medicine does not all enter into liposome; And adopt sample (embodiment 2) envelop rate of active loading method preparation high, and drug loading is high, and particle diameter is little and even, so adopt active loading method.Namely adopt the standby irinotecan hydrochloride liposome of ion gradient legal system that extraordinary effect is arranged in the present invention.
Preparation method:
Blank liposome: with the lipid ethanol injection.Homogenizing 1000bar, 6 times; 200nm extrudes 3 times, and 100nm extrudes 5 times; Add PEG
2000-DSPE gives 30min for 60 ℃.Slipstream dialysis 3 times adds 50ml at every turn.Wherein VE is added in the phospholipid organic solvent, and EDTA is added in ammonium sulfate.
Drug-loaded liposome: preparation is the irinotecan hydrochloride aqueous solution of 10mg/ml approximately, adds in blank liposome, gives 15min for 60 ℃.To about 50ml, be the 5mg/ml sample with the slipstream concentrating sample.
Stability result sees the following form, and as seen, adds separately disodiumedetate sample indices without significant change, can significantly improve the stability of liposome, and other stabilizing agent does not obviously improve the stability of liposome.
Prescription (1)
Preparation method:
Hydrogenated soy phosphatidyl choline, the cholesterol of recipe quantity is dissolved in appropriate dehydrated alcohol gets lipid soln, mix with the 100ml manganese sulfate solution, decompression is removed ethanol and is obtained the blank liposome crude product.Extrude liposome by extrusion equipment afterwards and control its particle diameter (2 0.1 μ m extruded films of extruder paving are extruded 5 times).Adopt tangential flow ultra-filtration unit dialysis blank liposome, middle continual supplementary injection water namely gets blank liposome.With water for injection preparation irinotecan hydrochloride aqueous solution, join in the blank liposome dispersion liquid with ion gradient, 50 ℃ of heated and stirred are hatched and were namely got drug-loaded liposome in 20 minutes.Adopt tangential flow ultra-filtration unit to remove non-encapsulated medicine, simultaneously with sample concentration to about 50ml, add 2.5g mannitol to regulate osmotic pressure.Adjust drug level, standardize solution, 0.22 μ m membrane filtration degerming, the inflated with nitrogen embedding namely gets the irinotecan hydrochloride lipidosome injection in bottle.Recording liposome particle size through the nano particle size analyzer is 89.3nm, and envelop rate is 97.5%.
Prescription (2)
Preparation method:
Hydrogenated yolk lecithin, the cholesterol of recipe quantity is dissolved in appropriate dehydrated alcohol gets lipid soln, mix with the 100ml Adlerika.Extrude liposome by extrusion equipment afterwards and control its particle diameter (2 0.1 μ m extruded films of extruder paving are extruded 5 times).Adopt tangential flow ultra-filtration unit dialysis blank liposome, middle continual supplementary injection water namely gets blank liposome.With water for injection preparation irinotecan hydrochloride aqueous solution, join in the blank liposome dispersion liquid with ion gradient, 50 ℃ of heated and stirred are hatched and were namely got drug-loaded liposome in 20 minutes.Adopt tangential flow ultra-filtration unit to remove non-encapsulated medicine, simultaneously with sample concentration to about 50ml, add the 2.5g histidine to regulate osmotic pressure.Adjust drug level, standardize solution, 0.22 μ m membrane filtration degerming, the inflated with nitrogen embedding namely gets the irinotecan hydrochloride lipidosome injection in bottle.Recording liposome particle size through the nano particle size analyzer is 87.6nm, and envelop rate is 98.1%.
Prescription (3)
Preparation method:
Hydrogenated soy phosphatidyl choline, the cholesterol of recipe quantity is dissolved in appropriate dehydrated alcohol gets lipid soln, mix with the 100ml ammonium sulfate, decompression is removed ethanol and is obtained the blank liposome crude product.After adopting afterwards 5 circulations of high pressure homogenizer 1000bar homogenizing, add afterwards the DSPE-PEG for preparing
2000Aqueous solution stirs and hatched 20 minutes.Adopt tangential flow ultra-filtration unit dialysis blank liposome, middle continual supplementary injection water namely gets blank liposome.With water for injection preparation irinotecan hydrochloride aqueous solution, join in the blank liposome dispersion liquid with ion gradient, 60 ℃ of heated and stirred are hatched and were namely got drug-loaded liposome in 20 minutes.Adopt tangential flow ultra-filtration unit to remove non-encapsulated medicine, simultaneously with sample concentration to about 50ml, add 0.45g sodium chloride to regulate osmotic pressure.Adjust drug level, standardize solution, 0.22 μ m membrane filtration degerming, the inflated with nitrogen embedding namely gets the irinotecan hydrochloride lipidosome injection in bottle.Recording liposome particle size through the nano particle size analyzer is 87.3nm, and envelop rate is 99.2%.
Embodiment 8
Prescription
Preparation method:
Hydrogenated soy phosphatidyl choline, cardiolipin, DSPE-PEG with recipe quantity
5000, cholesterol, alpha-tocopherol be dissolved in appropriate dehydrated alcohol and get lipid soln, mixes with the 100ml citric acid solution, decompression is removed ethanol and is obtained the blank liposome crude product.Adopt afterwards high pressure homogenizer 1000bar, homogenizing 5 times.Adopt tangential flow ultra-filtration unit dialysis blank liposome, the middle continual 0.9% sodium chloride solution 400ml that replenishes namely gets blank liposome.With water for injection preparation irinotecan hydrochloride solution, join in the blank liposome dispersion liquid with ion gradient, 60 ℃ of heated and stirred are hatched and were namely got drug-loaded liposome in 20 minutes.Adopt tangential flow ultra-filtration unit to remove non-encapsulated medicine, simultaneously with sample concentration to about 50ml.Adjust drug level, standardize solution, 0.22 μ m membrane filtration degerming, the inflated with nitrogen embedding namely gets the irinotecan hydrochloride lipidosome injection in bottle.Recording liposome particle size through the nano particle size analyzer is 85.8nm, and envelop rate is 98.6%.
Embodiment 9
Prescription
Preparation method:
DPPC, DPPG, the cholesterol of recipe quantity is dissolved in appropriate dehydrated alcohol gets lipid soln, mix with 100ml ammonium sulfate (containing disodiumedetate), decompression is removed ethanol and is obtained the blank liposome crude product.Adopt afterwards high pressure homogenizer 1000bar, homogenizing 5 times.Adopt tangential flow ultra-filtration unit dialysis blank liposome, the middle continual 0.9% sodium chloride solution 400ml that replenishes namely gets blank liposome.With water for injection preparation irinotecan hydrochloride solution, join in the blank liposome dispersion liquid with ion gradient, 60 ℃ of heated and stirred are hatched and were namely got drug-loaded liposome in 20 minutes.Adopt tangential flow ultra-filtration unit to remove non-encapsulated medicine, simultaneously with sample concentration to about 50ml, add ascorbic acid.Adjust drug level, standardize solution, 0.22 μ m membrane filtration degerming, the inflated with nitrogen embedding namely gets the irinotecan hydrochloride lipidosome injection in bottle.Recording liposome particle size through the nano particle size analyzer is 89.4nm, and envelop rate is 97.2%.
Prescription
Preparation method:
Hydrogenated soy phosphatidyl choline, cholesterol, the alpha-tocopherol of recipe quantity is dissolved in appropriate dehydrated alcohol gets lipid soln, mix with the 100ml ammonium sulfate, decompression is removed ethanol and is obtained the blank liposome crude product.Adopt afterwards high pressure homogenizer 1000bar, homogenizing 5 times, then extrude liposome (5 100nm extruded films of extruder paving are extruded 5 times) by extrusion equipment, add afterwards the DSPE-PEG for preparing
5000Aqueous solution stirs and hatched 20 minutes.Adopt tangential flow ultra-filtration unit dialysis blank liposome, the middle continual 0.9% sodium chloride solution 400ml that replenishes namely gets blank liposome.With water for injection preparation irinotecan hydrochloride solution, join in the blank liposome dispersion liquid with ion gradient, 60 ℃ of heated and stirred are hatched and were namely got drug-loaded liposome in 20 minutes.Adopt tangential flow ultra-filtration unit to remove non-encapsulated medicine, simultaneously with sample concentration to about 50ml, add sucrose and mannitol to make mix homogeneously.Adjust drug level, standardize solution, 0.22 μ m membrane filtration degerming, canned in cillin bottle, lyophilization namely gets the irinotecan hydrochloride liposome freeze-drying powder injection.Be 90.8nm with measuring liposome particle size after the liposome freeze-drying powder injection aquation, envelop rate is 97.5%.
Test example 1
The physicochemical characteristics of the finished product that makes according to the present invention (pressing embodiment 2):
It is appropriate that [particle size distribution] gets this product, to measure with dynamic light scattering method after the water dilution.Measure wavelength X=633nm, measure 173 ° of angles, 25 ℃ of temperature.Size is with intensity footpath (Intensity) data representation.Particle size distribution figure sees Fig. 1, and mean diameter is 85.9nm.
It is appropriate that [morphology investigation] draws liposomal samples, and copper mesh is placed on clean filter paper, drips sample on copper mesh, with 2% phosphotungstic acid dyeing, to be dried rear in the lower this product of observing of JEM2010 transmission electron microscope (Jeol Ltd.).Aspect graph is seen Fig. 2.Through transmission electron microscope observing, the irinotecan liposome form is typical bilayer structure, and the particle diameter major part matches with the result of dynamic light scattering determination below 200nm.
[entrapment efficiency determination] medicine assay method: chromatographic column: Agilent ZORBAX Eclipse XDB-C18(4.6 * 150mm, 5 μ m); Mobile phase: acetonitrile-0.05M potassium phosphate buffer (pH4 contains 1% triethylamine)=20:80; Column temperature: 40 ℃; Sampling volume: 20 μ L; Flow velocity: 1.0mL/min.
The entrapment efficiency determination method: draw the 1mL sample solution to the 10mL measuring bottle, add entry and be diluted to scale, shake up, put 8010 type ultrafilters (MILLIPORE company) ultrafiltration, discard just filtrate, getting subsequent filtrate is need testing solution.Draw respectively need testing solution, reference substance solution 20 μ L injection liquid chromatographies, record chromatogram, calculate preparation free drug content with external standard method, be designated as W; The another medicine total content of pressing method calculating book product under the assay item is designated as W
0Be calculated as follows the envelop rate of sample.
Measurement result: this product envelop rate is 99.4.
[influence factor's test] got this product and is placed in and carries out factors influencing under different condition, and result is as shown in the table:
Result shows, sample is responsive to illumination, and through the flavescence of strong illumination sample appearance, content descends, and related substance obviously increases; Envelop rate and particle diameter are without significant change when 40 ° of C of high temperature for sample, but related substance slightly increases; Low temperature and freeze cycle test show that sample produces macroparticle.Consider the unstability of phospholipid under the condition of high temperature, in conjunction with influence factor's result of the test, this product answers low-temperature dark to store.
[the anti-tumor in vivo test of pesticide effectiveness]
Medicine name: the irinotecan hydrochloride liposome (CPT-11 liposome) by embodiment 2 preparations is provided by Hengrui Pharmaceutical Co., Ltd., Shanghai, irinotecan hydrochloride injection (CPT-11, Hengrui Medicine Co., Ltd., Jiangsu Prov. provides)
Compound method: all be made into desired concn with normal saline.
Laboratory animal: the BALB/cA-nude nude mouse, 6-7 week,
Available from Shanghai Slac Experimental Animal Co., Ltd..The quality certification number: SCXK(Shanghai) 2007-0005.Feeding environment: SPF level.
Test method: nude mouse subcutaneous vaccination human colon carcinoma Ls-174t cell, treat that tumor growth is to 150-300mm
3After, with animal random packet (d0).Dosage and dosage regimen see the following form.Survey weekly the tumor volume 2-3 time, claim Mus heavy, record data.Gross tumor volume (V) computing formula is:
V=1/2 * a * b
2Wherein a, b represent respectively length and width.
D0: administration time for the first time; RTV: relative tumour volume; The P value refers to compared with the control.
Matched group n=12, treatment group n=6.Vehicle: blank medium.
Experimental result:
CPT-11 liposome and CPT-11 all obviously suppress the growth of human colon carcinoma Ls-174t Nude Mice, the CPT-11 liposome suppresses the Ls-174t growth obvious dose dependent, during high dose (3mg/kg) administration, there is 4/14 tumor section to disappear, suitable when the curative effect during low dosage (1mg/kg) administration and CPT-1110mg/kg administration, the curative effect of prompting CPT-11 liposome might improve 10 times at least than its injection, and concrete outcome is seen Fig. 3.
Claims (20)
1. an irinotecan or irinotecan hydrochloride liposome, it is characterized in that described liposome contains irinotecan or irinotecan hydrochloride, neutral phospholipid and cholesterol, the part by weight of wherein said cholesterol and neutral phospholipid is 1:3～5, described neutral phospholipid is hydrogenated soy phosphatidyl choline, and described neutral phospholipid and irinotecan or irinotecan hydrochloride meet following weight proportion:
1 part of irinotecan or irinotecan hydrochloride
Neutral phosphatidase 12～5 parts, preferred 2.5-4 part.
2. liposome according to claim 1, is characterized in that the ratio of described cholesterol and neutral phospholipid is 1:3.5～4.5, most preferably is 1:4.
3. according to the described liposome of aforementioned any one claim, it is characterized in that obtaining by the ion gradient legal system is standby at described liposome.
4. liposome according to claim 3 is characterized in that having the ion gradient that buffer agent forms between water and outer water in described liposome, and in preferred described liposome, water has the high ion gradient of ion concentration than outer water.
5. according to the described liposome of aforementioned any one claim, it is characterized in that described liposome also contains the lipid derivate of hydrophilic macromolecule, preferably DSPE-PEG
2000
6. liposome according to claim 5, is characterized in that the lipid derivate of described hydrophilic macromolecule and the weight ratio of irinotecan or irinotecan hydrochloride are 0.2～0.4.
7. according to the described liposome of aforementioned any one claim, it is characterized in that described liposome further contains electrically charged phospholipid, described electrically charged phospholipid is selected from one or more in PE, DPPG, DSPG, GLYCEROL,DIMYRISTOYL PHOSPHATIDYL, two oleic acid Phosphatidylserine, DOPG, two lauroyl phosphatidic acid, two myristoyl phosphatidic acid or G 12S3P, and the part by weight of electrically charged phospholipid and neutral phospholipid is 1:5～1:100.
8. liposome according to claim 1 is characterized in that described liposome contains the composition of following weight proportion:
And the ratio of cholesterol and hydrogenated soy phosphatidyl choline is 1:4.
9. the preparation method of the described liposome of claim 1-8 any one is characterized in that this preparation method comprises following step:
1) prepare blank liposome by following A any method to the D:
A. select neutral phospholipid, cholesterol to be dissolved in dehydrated alcohol or dehydrated alcohol-tert-butyl alcohol mixed solvent according to formula, mix with buffer agent, obtain the blank liposome crude product after ethanol is removed in decompression, adopt high pressure homogenizer afterwards or/and extrusion equipment prepares blank liposome to required granularity;
B. select neutral phospholipid, cholesterol to be dissolved in chloroform or chloroform-methanol mixed solvent according to formula, rotary evaporation forms lipid film, add the buffer agent aquation to obtain the blank liposome crude product, adopt high pressure homogenizer afterwards or/and extrusion equipment prepares blank liposome to required granularity;
C. select neutral phospholipid, cholesterol to mix with buffer agent according to formula, adopt high pressure homogenizer afterwards or/and extrusion equipment prepares blank liposome to required granularity;
D. select neutral phospholipid, cholesterol to be dissolved in dehydrated alcohol or dehydrated alcohol-tert-butyl alcohol mixed solvent according to formula, mix with buffer agent, adopt high pressure homogenizer afterwards or/and extrusion equipment prepares blank liposome to required granularity;
2) generation of the inside and outside water ion gradient of liposome membrane: the outer water of displacement blank liposome makes water and outer water generation ion gradient in liposome;
3) pastille liposome preparation: preparation irinotecan hydrochloride aqueous solution, join in the blank liposome dispersion liquid with ion gradient, heated and stirred is hatched, and get final product.
10. preparation method according to claim 9, is characterized in that 3) after pastille liposome preparation process, also comprise following steps:
4) removal of free drug and sample is concentrated: add buffer medium in the irinotecan hydrochloride liposome, adopt the slipstream device to remove non-encapsulated medicine, simultaneously with sample concentration to suitable volume.
11. according to claim 9-10 described preparation methoies of any one, it is characterized in that described buffer agent is selected from contains Na
+, K
+, Fe
2+, Ca
2+, Ba
2+, Mn
2+, Mg
2+, Li
+, NH
4 +Or H
+One or more of ion salt.
12. contain the lipidosome injection of the described irinotecan of claim 1-8 any one or irinotecan hydrochloride liposome.
13. lipidosome injection according to claim 12, it is characterized in that described injection contains stabilizing agent, described stabilizing agent is selected from one or more in ethylenediaminetetraacetic acid, disodium EDTA, ethylenediaminetetraacetic acid two calcium salts, the additional proportion of stabilizing agent is that 0%～0.5w/v% and lower limit are not 0%, preferably disodiumedetate.
14. lipidosome injection according to claim 12 is characterized in that described injection is injection or freeze-dried powder.
15. lipidosome injection according to claim 12, it is characterized in that described injection contains osmotic pressure regulator, described osmotic pressure regulator is selected from one or more in glucose, sucrose, sorbitol, mannitol, sodium chloride, glycerol, histidine and hydrochloride thereof, glycine and hydrochloride thereof, lysine, serine, glutamic acid, arginine or valine, and the additional proportion of osmotic pressure regulator is that 0%～5w/v% and lower limit are not 0%.
16. lipidosome injection according to claim 12, it is characterized in that described injection further contains antioxidant, described antioxidant is selected from water solublity antioxidant or oil-soluble antioxidant, described oil-soluble antioxidant is selected from alpha-tocopherol, α-tocopheryl acid succinate, α-tocopheryl acetate or its mixture, described water solublity antioxidant is selected from ascorbic acid, sodium sulfite, sodium sulfite, sodium pyrosulfite, Cys or its mixture, and the additional proportion of antioxidant is that 0%～0.5w/v% and lower limit are not 0%.
17. lipidosome injection according to claim 14 is characterized in that described injection is freeze-dried powder, wherein contains freeze drying protectant, is the liposome freeze-drying powder injection that makes by lyophilization.
18. lipidosome injection according to claim 12 is characterized in that described injection liposome contains the composition of following weight proportion::
And the ratio of cholesterol and hydrogenated soy phosphatidyl choline is 1:4.
19. the preparation technology of the described lipidosome injection of claim 12-18 any one is characterized in that described technique comprises the preparation method of claim 9-10 any one.
20. preparation technology according to claim 19 is characterized in that described technique also comprises:
Standardize solution, degerming, packing: adjust the liposomal body substrate concentration, standardize solution, filtration sterilization, embedding get lipidosome injection in bottle; Perhaps
Add freeze drying protectant in the liposomal body matter sample, adjust drug level, standardize solution, filtration sterilization, embedding are in bottle, and lyophilization gets freeze-dried powder.
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