CN102961335A - Camptothecin medical lipidosome composition and preparation method thereof - Google Patents
Camptothecin medical lipidosome composition and preparation method thereof Download PDFInfo
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- CN102961335A CN102961335A CN2012105196620A CN201210519662A CN102961335A CN 102961335 A CN102961335 A CN 102961335A CN 2012105196620 A CN2012105196620 A CN 2012105196620A CN 201210519662 A CN201210519662 A CN 201210519662A CN 102961335 A CN102961335 A CN 102961335A
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Abstract
The invention provides a camptothecin medical lipidosome composition. The camptothecin medical lipidosome composition is prepared from the following raw materials and supplementary materials in parts by weight: 5 to 25 parts of camptothecin medicine, 40 to 100 parts of phospholipid, 6 to 50 parts of cholesterol, 1 to 8 parts of vitamin E, and 10 to 100 parts of amino compound. According to a preparation method of the camptothecin medical lipidosome composition, the camptothecin medical lipidosome composition is prepared in a multi-emulsion way and an inverted evaporation way. The aqueous solution of the amino compound has a solubilizing effect respect to the camptothecin medicine, and can generate a water-soluble compound under the effect of intermolecular interaction or ionic bond effect. The compound is stable in physiological pH (Potential of Hydrogen) and higher in solution concentration, and can be wrapped in the inner cavity of lipidosome, therefore, the amount of the medicine in transfer can be increased, and the problem that the lactonic-ring type camptothecin medicine is subjected to high ring opening to result in leakage due to the influence of the pH and the plasma proteins can be avoided. The compound is stably wrapped in the lipidosome, and can reach the tumor part under the targeting effect of the lipidosome and then act in form of lactonic ring under the acidic condition of the tumor cells; and the compound has the advantages of increasing effect and reducing toxicity.
Description
Technical field
The present invention relates to the camptothecine field, relate in particular to camptothecine liposome composition and manufacture method thereof.
Background technology
Camptothecine is the alkaloid that extracts from the distinctive Nyssaceae plant camptotheca acuminata of China, and camptothecin analogues can suppress copying and transcribing of typeⅠtopoisomerase interference DNA by selectivity, thereby reaches the effect of killer cell.The advantage of camptothecine be anticancer spectrum wide, without crossing drug resistant, all effective to Several Kinds of Malignancies such as primary hepatocarcinoma, gastric cancer, incidence epidermal carcinoma, chronic myelocytic leukemia, rectal cancer and bladder cancer.Based on above characteristics, camptothecine is counted as the phytogenic anticarcinogen that has appreciable impact power behind paclitaxel at world wide.
From molecular structure, the precursor structure of camptothecine by be in conplane A, B, C, D, the E five rings consists of, wherein the AB ring is the quinoline ring, the C ring is pyrrole ring, the D ring is pyridine ring, the E ring is the hydroxy-lactone ring.The hydroxy-lactone ring is the active anticancer center of such medicine, but its structural instability, to sensitivities such as heat, light, alkali, pH7 or when above most lactone structure open loop become the hydroxycarboxylate, activity significantly reduces, side effect increases.Usually, camptothecine also presents the characteristics of pharmacokinetics that quick distribution is eliminated, and the half-life only has a few minutes or dozens of minutes, needs repetitively administered or extends the period for the treatment of.The existence of the problems referred to above has affected the clinical use of camptothecine to a certain extent.
Adopt liposome technology to solve existing more document and the patent of research of the problems referred to above of camptothecine, because liposome has potential advantages aspect the characteristics of pharmacokinetics of improving camptothecine and the tumor-targeting, and better than administration nano-drug administration systems such as Emulsion, nanoparticles aspect the safety and stability of preparation.At present; what existing patent was paid close attention to mostly is the lactonic ring of protection camptothecine; (application number: what 200310112772.6) " camptothecine, hydroxy camptothecin lipid composition and preparation method thereof ", this invention related to is anticarcinogen camptothecine, hydroxy camptothecin lipid composition and preparation method thereof such as Chinese patent.Camptothecine, hydroxy camptothecin lipid composition advantage are both can solve the principal agent water-insoluble, simultaneously, can protect again in the principal agent chemical constitution active function δ of group lactone not make open loop and affect the treatment.Chinese patent (application number: 200410084647.3) " 10-hydroxycamptothecine long circulating liposomes and lyophilized formulations thereof " and for example, this invention belongs to field of pharmaceutical preparations, relate to the 10-hydroxycamptothecine long circulating liposomes, lyophilized formulations of long circulating liposomes and preparation method thereof.But this disclosure of the Invention the method for industrializing implementation of said preparation, the lipid of modifying with lecithin, soybean phospholipid or hydrolecithin and PEG is the film material, uses the cholesterol used as stabilizers, makes freeze drying protectant with trehalose or sucrose, makes solvent with ethanol and dichloromethane.This invention 10-hydroxycamptothecine long circulating liposome preparation has the high anti-cancer effect, and its toxicity is little, patient's better tolerance, water solublity and stability improves, relative cost is lower.
In above-mentioned two patent documentations, the technology of employing is camptothecine to be embedded in be prepared into liposome in the phospholipid bilayer.Because camptothecine shipwreck fat melting indissoluble and in common solvent dissolubility limited, therefore the drug loading of the liposome of above-mentioned technology preparation is less, is difficult to reach the dosage of clinical requirement.In fact, the open loop of camptothecine and closed loop are reversible, and camptothecine mainly is to exist with closed loop when pH≤5; Intracellular pH has ready conditions in the cell and the camptothecine of open loop is changed into the activity form of closed loop about 5.Because the camptothecine good water solubility of open loop, can make higher concentration, so drug encapsulation water in liposome can be improved the drug loading of camptothecine, then the targeting by liposome changes into lactone at tumor locus and obtains stronger drug effect.But another problem deserving of attention is, what we must guarantee that the medicine in the liposome can be stable is wrapped in the liposome, can be with drug leakage before arriving tumor locus.Studies show that, hydroxycarboxylate after the camptothecine open loop and the binding ability of plasma protein are very strong, cause camptothecine liposome to produce prominent [" Influence of serum and albumins from different species on stability of camptothecin-loaded micelles " (" the Journal of Controlled Release that releases, Volume104, Issue2,18May2005, Pages313321 ") and " preparation of Hydroxycamptothecin liposome and quality evaluation research " (" pharmacy and clinical research " the 4th phase in 2008 4 pages of 274-277 pages or leaves)], medicine is eliminated very soon, often is difficult to arrive tumor locus performance drug effect.At present, improve camptothecine in liposome drug loading and guarantee that stable in liposome of medicine is the emphasis of studying in the field.
Summary of the invention
The purpose of this invention is to provide a kind of liposome composition with camptothecin cancer therapy drug of efficient stable feature, can directly disperse for intravenously administrable with normal saline or glucose solution.
Furtherly, the camptothecine liposome composition of efficient stable provided by the invention is by camptothecine being distributed in the amino-compound solution, both form water miscible medicinal composition by intermolecular or ionic bond effect, then this medicinal composition solution are wrapped in the liposome inner chamber.This medicinal composition can form higher solution concentration, and the lactonic ring form of comparing its slightly solubility can be increased by 1 ~ 2 times by the dose that bag carries in the unit Liposomal formulation, have higher transmission dosage.Because the lactonic ring of camptothecine is easily open loop under physiological pH, and open-loop products and plasma protein have very strong affinity, thus the ring-like camptothecine of lactone by bag be loaded in when being applied in the body in the liposome open loop balance destroyed cause leaking serious.The medicine of liposome inner chamber parcel of the present invention-amino complex is difficult for passing the phospholipid bilayer of liposome, dissociation equilibrium stable to physiological pH, medicinal composition can keep stable in vivo.Therefore liposome of the present invention has the antileakaging characteristics of stablizing in vivo the time, thereby guaranteed liposome with the targeted drug delivery of high dose to tumor locus, then medicine can be transformed into lactonic ring activity form performance drug effect under the acid condition of tumor cell.By above-described technological means, liposome of the present invention not only has the characteristics of efficient stable in the body, can also reduce in addition the toxic and side effects of cancer therapy drug, has good clinical value.
Another object of the present invention has provided the preparation method for preparing above-mentioned efficient stable camptothecine liposome.By adopting multiple emulsion process or reverse phase evaporation to produce liposome, can realize several large-scale industrial productions that rise to hectolitre.
Purpose of the present invention is achieved through the following technical solutions:
A kind of camptothecine liposome composition is comprised of following weight proportioning raw material and adjuvant: 10 ~ 100 parts of 5 ~ 25 parts of camptothecines, 0 ~ 100 part of phosphatidase 14,6 ~ 50 parts in cholesterol, vitamin e1 ~ 8 part, amino-compounds.
Described camptothecine is at least a of similar camptothecine, 10-hydroxycamptothecine, SN38, or at least a in the similar irinotecan, topotecan, lurtotecan.
Described phospholipid is at least a in soybean phospholipid, Ovum Gallus domesticus Flavus lecithin, the hydrogenated soya phosphatide.
Described amino-compound is at least a in meglumine, glycine, alanine, serine, arginine, lysine, chitosan, water-solubility chitosan derivative, polymine and derivant thereof, PAMAM and the derivant thereof.
Described amino-compound is at least a in meglumine, the lysine.
Described arbitrary camptothecine liposome composition is characterized in that: described liposome water is the aqueous solution that camptothecine and amino-compound form; The amido number ratio of single amino-compound molecule is 1:1 ~ 1:10 in the molecular number of camptothecine and the amino-compound.
The preparation method of described camptothecine liposome composition adopts multiple emulsion process, may further comprise the steps:
(1) phospholipid, cholesterol and vitamin E are dissolved in organic solvent altogether, as forming organic facies in one or both the mixed solvent in chloroform, dichloromethane, ethanol or the ether;
(2) in saturated amino-compound aqueous solution, be that the ratio of 1:1 ~ 1:10 adds camptothecine in the amido number of single amino-compound molecule in the molecular number of camptothecine and the amino-compound, stir to clarify in 25 ~ 100 ℃, be chilled to after the room temperature as water;
(3) solution with step (1) and step (2) is that 1:1 ~ 20:1 mixes by organic facies and water volume ratio, and 8000 ~ 14000 rev/mins of high-speed stirred made the W/O colostrum in 1 ~ 5 minute;
(4) fast with the purified water of 1 ~ 100 times of volume of colostrum impouring, stir 10 ~ 30 minutes second emulsifyings with 1000 ~ 5000 rev/mins rotating speeds;
(5) reduction vaporization is removed organic solvent, forms liposome turbid liquor;
(6) with suspension with high pressure homogenizer homogenizing 3 times under 30 ~ 120MPa, be chilled to room temperature, adding with accounting for the liposome solutions mass percent is 2 ~ 15% freeze drying protectant;
(7) heat sterilization, fill obtains the camptothecine liposome composition finished product after the lyophilization.
The freeze drying protectant of wherein said step (6) is selected from least a among mannitol, sorbitol, trehalose, sucrose, glucose, lactose, fructose, dextran, Polyethylene Glycol and the PVP.
The preparation method of described camptothecine liposome composition adopts reverse phase evaporation, may further comprise the steps:
((1) is dissolved in organic solvent with phospholipid, cholesterol and vitamin E, as forming organic facies in a kind of in chloroform, dichloromethane, ethanol or the ether or both mixed solvents;
(2) in saturated amino-compound aqueous solution, be that the ratio of 1:1 ~ 1:10 adds camptothecine in the amido number of single amino-compound molecule in the molecular number of camptothecine and the amino-compound, stir to clarify in 25 ~ 100 ° of C, be chilled to after the room temperature as water;
(3) solution with step (1) and step (2) is that 1:1 ~ 8:1 stirs mix and blend emulsifying in 1 ~ 10 minute with 500 ~ 5000 rev/mins by organic facies and water volume ratio;
(4) emulsion goes to Rotary Evaporators, bath temperature be 35 ~ 60 ° of C, pressure be-0.06 ~-0.02MPa, the evaporation organic solvent, emulsion becomes first the micelle shape, continues the dissolving of rotation micelle and namely forms liposome turbid liquor with opalescence;
(5) suspension is chilled to room temperature with high pressure homogenizer homogenize 3 times under 30 ~ 120MPa, and adding with accounting for the liposome solutions mass percent is 2 ~ 15% freeze drying protectant;
(6) heat sterilization, fill obtains the camptothecine liposome composition finished product after the lyophilization.
The preparation method of described camptothecine liposome composition, the freeze drying protectant of wherein said step (6) are selected from least a among mannitol, sorbitol, trehalose, sucrose, glucose, lactose, fructose, dextran, Polyethylene Glycol and the PVP.
Description of drawings
Fig. 1 is for adopting the flow chart of the standby camptothecine liposome composition of emulsion legal system.
Fig. 2 is for adopting reverse phase evaporation to prepare the flow chart of camptothecine liposome composition.
Fig. 3 be the liposome for preparing of the present invention with by the 10-hydroxycamptothecine liposome of general thin dispersion method preparation respectively at the PBS of pH7.4 with contain releasing curve diagram among the pH7.4PBS of 0.5% people source blood plasma.
Blood drug level-time graph comparison diagram in the rat body of the liposome of Fig. 4 the present invention preparation and commercial preparation, membrane process liposome.
The specific embodiment
The preparation camptothecine liposome composition adopts multiple emulsion process, may further comprise the steps:
(1) soybean phospholipid 56g, cholesterol 8g and vitamin E2 .8g are dissolved in an amount of dichloromethane solvent, as organic facies altogether;
(2) add 10-hydroxycamptothecine 5g in the saturated meglumine solution of 25mL, stir to clarify in 50 ℃, be chilled to room temperature as water;
(3) solution with step (1) and step (2) is that 2:1 mixes by organic facies and water volume ratio, and 8000 rev/mins of high-speed stirred made the W/O colostrum in 1 minute;
(4) fast with W/O colostrum impouring 450ml water for injection second emulsifying, stirred 10 minutes with 5000 rev/mins rotating speeds;
(5) on Rotary Evaporators, remove organic solvent with 35 ℃ of constant temperature reduction vaporizations, form liposome turbid liquor;
(6) with suspension with high pressure homogenizer homogenizing 3 times under 75MPa, be chilled to room temperature, add glucose 15g and be dissolved in the suspension, adding water for injection, to adjust volume be 500mL;
(7) heat sterilization, filtrate are pressed the 2mL/ bottle under aseptic condition, and embedding is in cillin bottle, and lyophilization namely gets light yellow loose block Liposomal formulation.
Every bottle of freeze-dried lipidosome redissolves with 5mL water for injection, hands jolting more than 10 times, but rapid dispersion becomes liposome solutions, and mean diameter is 160nm, and envelop rate is 87%.
The preparation camptothecine liposome composition adopts multiple emulsion process, may further comprise the steps:
(1) hydrogenated soya phosphatide 72g, cholesterol 33g and vitamin e1 .0g are dissolved in an amount of dichloromethane solvent, as organic facies altogether;
(2) in the saturated meglumine aqueous solution of 50mL, add 10-hydroxycamptothecine 9.0g, stir to clarify in 50 ℃, be chilled to room temperature as water;
(3) solution with step (1) and step (2) is that 10:1 mixes by organic facies and water volume ratio, and 14000 rev/mins of high-speed stirred made the W/O colostrum in 1 minute;
(4) fast with W/O colostrum impouring 4L water for injection second emulsifying, stirred 30 minutes with 5000 rev/mins rotating speeds;
(5) on Rotary Evaporators, remove organic solvent with 60 ℃ of constant temperature reduction vaporizations, form liposome turbid liquor;
(6) with suspension with high pressure homogenizer homogenizing 3 times under 75MPa, be chilled to room temperature, add mannitol 255g and be dissolved in the suspension, inject the water adjusted volume to 5L;
(7) heat sterilization, filtrate are pressed the 2mL/ bottle under aseptic condition, and embedding is in cillin bottle, and lyophilization namely gets light yellow loose block Liposomal formulation.
Every bottle of freeze-dried lipidosome redissolves with 5mL water for injection, hands jolting more than 10 times, but rapid dispersion becomes liposome solutions, and mean diameter is 85nm, and envelop rate is 95%.
The preparation camptothecine liposome composition adopts multiple emulsion process, may further comprise the steps:
(1) Ovum Gallus domesticus Flavus lecithin 48g, cholesterol 15g and vitamin E2 .5g are dissolved in an amount of dichloromethane solvent, as organic facies altogether;
(2) in the saturated meglumine aqueous solution of 20mL, add irinotecan 5g, stir to clarify in 50 ℃, be chilled to room temperature as water;
(3) solution with step (1) and step (2) is that 5:1 mixes by organic facies and water volume ratio, and 8000 rev/mins of high-speed stirred made the W/O colostrum in 1 minute;
(4) fast with W/O colostrum impouring 450mL water for injection second emulsifying, stirred 10 minutes with 5000 rev/mins rotating speeds;
(5) on Rotary Evaporators, remove organic solvent with 35 ℃ of constant temperature reduction vaporizations, form liposome turbid liquor;
(6) with suspension with high pressure homogenizer homogenizing 3 times under 75MPa, be chilled to room temperature, add glucose 50g and be dissolved in the suspension, inject the water adjusted volume to 500mL;
(7) heat sterilization, filtrate are pressed the 2ml/ bottle under aseptic condition, and embedding is in cillin bottle, and lyophilization namely gets light yellow loose block Liposomal formulation.
Every bottle of freeze-dried lipidosome redissolves with 5mL water for injection, hands jolting more than 10 times, but rapid dispersion becomes liposome solutions, and mean diameter is 175nm, and envelop rate is 85%.
The preparation camptothecine liposome composition adopts multiple emulsion process, may further comprise the steps:
(1) soybean phospholipid 60g, cholesterol 10g and vitamin E 6g are dissolved in an amount of dichloromethane solvent, as organic facies altogether;
(2) in the saturated lysine solution of 10mL, add 10-hydroxycamptothecine 10g, stir to clarify in 60 ℃, be chilled to room temperature as water;
(3) solution with step (1) and step (2) is that 10:1 mixes by organic facies and water volume ratio, and 8000 rev/mins of high-speed stirred made the W/O colostrum in 1 minute;
(4) fast with W/O colostrum impouring 450mL water for injection second emulsifying, stirred 10 minutes with 5000 rev/mins rotating speeds;
(5) on Rotary Evaporators, remove organic solvent with 35 ℃ of constant temperature reduction vaporizations, form liposome turbid liquor;
(6) with suspension with high pressure homogenizer homogenizing 3 times under 75MPa, be chilled to room temperature, add mannitol 30g and be dissolved in the suspension, add the water for injection adjusted volume to 500mL;
(7) heat sterilization, filtrate are pressed the 2ml/ bottle under aseptic condition, and embedding is in cillin bottle, and lyophilization namely gets light yellow loose block Liposomal formulation.
Every bottle of freeze-dried lipidosome redissolves with 5mL water for injection, hands jolting more than 10 times, but rapid dispersion becomes liposome solutions, and mean diameter is 205nm, and envelop rate is 82%.
The preparation camptothecine liposome composition adopts reverse phase evaporation, may further comprise the steps:
(1) hydrogenated soya phosphatide 75g, cholesterol 20g and vitamin e1 .5g are dissolved in an amount of dichloromethane solvent form organic facies;
(2) adding 10-hydroxycamptothecine 15g in the 80mL meglumine saturated solution stirs to clarify in 50 ° of C;
(3) solution with step (1) and step (2) is that 1:1 mixes by organic facies and water volume ratio, and 5000 rev/mins are stirred mix and blend emulsifying in 1 minute;
(4) emulsion goes to Rotary Evaporators, bath temperature be 60 ° of C, pressure be-0.06 ~-0.02MPa, the evaporation organic solvent, emulsion becomes first the micelle shape, continues the dissolving of rotation micelle and namely forms liposome turbid liquor with opalescence;
(5) suspension is chilled to room temperature with high pressure homogenizer homogenize 3 times under 120MPa, adds freeze drying protectant glucose 15g, adds the water for injection adjusted volume to 500mL;
(6) heat sterilization, filtrate are pressed the 2ml/ bottle under aseptic condition, and embedding is in cillin bottle, and lyophilization namely gets light yellow loose block Liposomal formulation.
Every bottle of freeze-dried lipidosome redissolves with 5mL water for injection, hands jolting more than 10 times, but rapid dispersion becomes liposome solutions, and mean diameter is about 145nm, and envelop rate is 85%.
The preparation camptothecine liposome composition adopts reverse phase evaporation, may further comprise the steps:
(1) Ovum Gallus domesticus Flavus lecithin 100g, cholesterol 50g and vitamin E 3g are dissolved in an amount of dichloromethane solvent form organic facies;
(2) add 10-hydroxycamptothecine 10g in the 20mL lysine saturated solution and stir to clarify in 60 ° of C, be chilled to room temperature as water;
(3) solution with step (1) and step (2) is that 8:1 stirs mix and blend emulsifying in 1 minute with 2000 rev/mins by organic facies and water volume ratio;
(4) emulsion goes to Rotary Evaporators, bath temperature be 60 ° of C, pressure be-0.06 ~-0.02MPa, the evaporation organic solvent, emulsion becomes first the micelle shape, continues the dissolving of rotation micelle and namely forms liposome turbid liquor with opalescence;
(5) suspension is chilled to room temperature with high pressure homogenizer homogenize 3 times under 120MPa, adds freeze drying protectant mannitol 150g, injects the water adjusted volume to 1.5L;
(6) heat sterilization, filtrate are pressed the 2ml/ bottle under aseptic condition, and embedding is in cillin bottle, and lyophilization namely gets light yellow loose block Liposomal formulation.
Every bottle of freeze-dried lipidosome redissolves with 5mL water for injection, hands jolting more than 10 times, but rapid dispersion becomes liposome solutions, and mean diameter is about 120nm, and envelop rate is 87%.
(1) soybean phospholipid 80g, cholesterol 20g and vitamin E 4g are dissolved in form organic facies in the dichloromethane solvent;
(2) add topotecan 15g in the 30mL lysine saturated solution and stir to clarify in 60 ° of C, be chilled to room temperature as water;
(3) solution with step (1) and step (2) is that 5:1 stirs mix and blend emulsifying in 1 minute with 5000 rev/mins by organic facies and water volume ratio;
(4) emulsion goes to Rotary Evaporators, bath temperature be 60 ° of C, pressure be-0.06 ~-0.02MPa, the evaporation organic solvent, emulsion becomes first the micelle shape, continues the dissolving of rotation micelle and namely forms liposome turbid liquor with opalescence;
(5) suspension is chilled to room temperature with high pressure homogenizer homogenize 3 times under 120MPa, adds freeze drying protectant mannitol 75g, injects the water adjusted volume to 1L;
(6) heat sterilization, filtrate are pressed the 2ml/ bottle under aseptic condition, and embedding is in cillin bottle, and lyophilization namely gets light yellow loose block Liposomal formulation.
Every bottle of freeze-dried lipidosome redissolves with 5mL water for injection, hands jolting more than 10 times, but rapid dispersion becomes liposome solutions, and mean diameter is about 130nm, and envelop rate is 90%.
The preparation camptothecine liposome composition adopts the normal film dispersion method, may further comprise the steps:
(1) 10-hydroxycamptothecine 5g, hydrogenated soya phosphatide 150g, cholesterol 10g and vitamin e1 .0g are dissolved in an amount of dichloromethane-ethanol (5:1, v/v) mixed solvent altogether, put on the Rotary Evaporators;
(2) under 60 ° of C, pressure is-0.06 ~-0.02MPa is spin-dried for film forming, improves negative pressure again and drains remaining solvent, and with 500mL water for injection eluting lipid film, hydration is carried out in insulation, and fully hydration namely obtains liposome turbid liquor;
(3) with suspension with high pressure homogenizer homogenize 3 times under 75MPa, be chilled to room temperature, add glucose 12.5g and be dissolved in the liposome solutions;
(4) heat sterilization, filtrate are pressed the 2mL/ bottle embedding are in cillin bottle under aseptic condition, and lyophilization namely gets light yellow loose block Liposomal formulation.
Every bottle of freeze-dried lipidosome redissolves with 5mL water for injection, hands jolting more than 10 times, but rapid dispersion becomes liposome solutions, and mean diameter is about 240nm, and envelop rate is 57%.
Test method: get respectively a certain amount of lipidosome freeze-dried powder of 10-hydroxycamptothecine that prepare by the present invention and that prepare by the general thin dispersion method and be added in the bag filter, tighten bag mouth; Then turn the basket method by Chinese Pharmacopoeia 2010 editions, the powder charge bag filter is packed into turns basket, and the PBS with 900mL pH7.4 makes dissolution medium simulation investigation Liposomal formulation release behavior in vivo with the pH7.4PBS that has added 0.5% people source blood plasma respectively.The results are shown in accompanying drawing 3, wherein solid line represents the release profiles by the lipid freeze-dry powder of the inventive method preparation, and dotted line then represents the release profiles by the lipid freeze-dry powder of general thin dispersion method preparation.Comparative study shows that the lipid stability of pressing the inventive method preparation is good, is difficult for leaking, and is easier to leakage by the 10-hydroxycamptothecine liposome of common film dispersion method preparation, is unfavorable for the performance of drug effect.
Blood drug level in the rat body of the inventive method liposome and commercial preparation, membrane process liposome-time graph relative analysis
Test method: be that the SOD male rat of 220 ± 20g is divided into three groups at random with body weight, give respectively the method liposome of the present invention of 10-hydroxycamptothecine by 10mg/kg dosage tail vein injection, happiness (is opened up in the commercial preparation of 10-hydroxycamptothecine, Wuhan Li Shizhen (1518-1593 A.D.) pharmaceutcal corporation, Ltd) and three kinds of the membrane process of 10-hydroxycamptothecine self-control liposomees be subjected to test preparation, respectively 0.083,0.25,0.5,0.75,1.5,2.5,4,6,8,12h equi-time point vena ophthalmica clump is got 6 rats of each time point of blood 200 μ L(, n=6), the centrifuging and taking upper plasma, the concentration of the 10-hydroxycamptothecine in the HPLC method analysed for plasma is drawn plasma drug level-time graph.With two chamber models fitting time front of blood concentration, calculate main pharmacokinetic parameters.
The main pharmacokinetic parameters (n=6) of three kinds of preparations of table 1
Such as blood drug level-time graph comparison diagram in the rat body of the liposome of accompanying drawing 4 the present invention preparation and commercial preparation, membrane process liposome, reach the main pharmacokinetic parameters (n=6) of three kinds of preparations of table 1; The result as can be known, the AUC of Liposomal formulation of the present invention has improved about 5 times than the commercial preparation, MRT has improved about 6 times, it is eliminated speed and compares and reduced about 5 times.Compare with membrane process self-control liposome, the liposome AUC of the present invention's preparation and MRT have improved 2-3 doubly, have eliminated rate reduction about 2 times.To sum up, the liposome composition preparation that obtains of prescription of the present invention and preparation method has long-acting Circulation.
Claims (10)
1. camptothecine liposome composition is characterized in that: be comprised of following weight proportioning raw material and adjuvant: 10 ~ 100 parts of 5 ~ 25 parts of camptothecines, 0 ~ 100 part of phosphatidase 14,6 ~ 50 parts in cholesterol, vitamin e1 ~ 8 part, amino-compounds.
2. camptothecine liposome composition as claimed in claim 1 is characterized in that: described camptothecine is at least a in camptothecine, 10-hydroxycamptothecine, SN38, irinotecan, topotecan, the lurtotecan.
3. camptothecine liposome composition as claimed in claim 1 is characterized in that: described phospholipid is at least a in soybean phospholipid, Ovum Gallus domesticus Flavus lecithin, the hydrogenated soya phosphatide.
4. camptothecine liposome composition as claimed in claim 1 is characterized in that: described amino-compound is at least a in meglumine, glycine, alanine, histidine, arginine, lysine, chitosan, water-solubility chitosan derivative, polymine and derivant thereof, PAMAM and the derivant thereof.
5. camptothecine liposome composition as claimed in claim 4 is characterized in that: described amino-compound is at least a in meglumine, the lysine.
6. such as the described arbitrary camptothecine liposome composition of claim 1 ~ 5, it is characterized in that: described liposome water is the aqueous solution that camptothecine and amino-compound form; The amido number ratio of single amino-compound molecule is 1:1 ~ 1:10 in the molecular number of camptothecine and the amino-compound.
7. the preparation method of camptothecine liposome composition as claimed in claim 1 adopts multiple emulsion process, may further comprise the steps:
(1) phospholipid, cholesterol and vitamin E are dissolved in organic solvent altogether, as forming organic facies in one or both the mixed solvent in chloroform, dichloromethane, ethanol or the ether;
(2) in saturated amino-compound aqueous solution, be that the ratio of 1:1 ~ 1:10 adds camptothecine in the amido number of single amino-compound molecule in the molecular number of camptothecine and the amino-compound, stir to clarify in 25 ~ 100 ℃, be chilled to after the room temperature as water;
(3) solution with step (1) and step (2) is that 1:1 ~ 20:1 mixes by organic facies and water volume ratio, and 8000 ~ 14000 rev/mins of high-speed stirred made the W/O colostrum in 1 ~ 5 minute;
(4) fast with the purified water of 1 ~ 100 times of volume of colostrum impouring, stir 10 ~ 30 minutes second emulsifyings with 1000 ~ 5000 rev/mins rotating speeds;
(5) reduction vaporization is removed organic solvent, forms liposome turbid liquor;
(6) with suspension with high pressure homogenizer homogenizing 3 times under 30 ~ 120MPa, be chilled to room temperature, adding with accounting for the liposome solutions mass percent is 2 ~ 15% freeze drying protectant;
(7) heat sterilization, fill obtains the camptothecine liposome composition finished product after the lyophilization.
8. the preparation method of camptothecine liposome composition as claimed in claim 7, the freeze drying protectant of wherein said step (6) are selected from least a among mannitol, sorbitol, trehalose, sucrose, glucose, lactose, fructose, dextran, Polyethylene Glycol and the PVP.
9. the preparation method of camptothecine liposome composition as claimed in claim 1 adopts reverse phase evaporation, may further comprise the steps:
(1) phospholipid, cholesterol and vitamin E are dissolved in organic solvent, as forming organic facies in a kind of in chloroform, dichloromethane, ethanol or the ether or both mixed solvents;
(2) in saturated amino-compound aqueous solution, be that the ratio of 1:1 ~ 1:10 adds camptothecine in the amido number of single amino-compound molecule in the molecular number of camptothecine and the amino-compound, stir to clarify in 25 ~ 100 ° of C, be chilled to after the room temperature as water;
(3) solution with step (1) and step (2) is that 1:1 ~ 8:1 stirs mix and blend emulsifying in 1 ~ 10 minute with 500 ~ 5000 rev/mins by organic facies and water volume ratio;
(4) emulsion goes to Rotary Evaporators, bath temperature be 35 ~ 60 ° of C, pressure be-0.06 ~-0.02MPa, the evaporation organic solvent, emulsion becomes first the micelle shape, continues the dissolving of rotation micelle and namely forms liposome turbid liquor with opalescence;
(5) suspension is chilled to room temperature with high pressure homogenizer homogenize 3 times under 30 ~ 120MPa, and adding with accounting for the liposome solutions mass percent is 2 ~ 15% freeze drying protectant;
(6) heat sterilization, fill obtains the camptothecine liposome composition finished product after the lyophilization.
10. the preparation method of camptothecine liposome composition as claimed in claim 9, the freeze drying protectant of wherein said step (6) are selected from least a among mannitol, sorbitol, trehalose, sucrose, glucose, lactose, fructose, dextran, Polyethylene Glycol and the PVP.
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