CN1326525C - 10-hydroxy camptothecin long cyclic liposome and its freeze aried preparation - Google Patents
10-hydroxy camptothecin long cyclic liposome and its freeze aried preparation Download PDFInfo
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- CN1326525C CN1326525C CNB2004100846473A CN200410084647A CN1326525C CN 1326525 C CN1326525 C CN 1326525C CN B2004100846473 A CNB2004100846473 A CN B2004100846473A CN 200410084647 A CN200410084647 A CN 200410084647A CN 1326525 C CN1326525 C CN 1326525C
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Abstract
The present invention belongs to the field of a medicinal preparation. The present invention relates to 10-hydroxy camptothecin long cyclic liposome, a freeze dried preparation of the long cyclic liposome and a preparation method thereof. The present invention discloses a method of the preparation, which can be industrially implemented. Phosphatidyl choline/soybean phospholipid or hydrolecithin and lipid modified by PEG are used as membrane material; cholesterol is used as a stabilizing agent; trehalose dihydrate or sucrose is used as a freeze dried protective agent; ethanol and methylene chloride are used as solvent. The 10-hydroxy camptothecin long cyclic liposome of the present invention has the good antitumoral effect and has the advantages of low toxicity, good patients' tolerance, water solubility and stability enhancement, and low relative cost.
Description
Technical field
The 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.
Background technology
(Hydrocamptothecin HCPT) is the strongest micro-alkaloid of antitumaous effect in the similar antitumor monomer that extracts in the 60-70 age in this century to 10-hydroxycamptothecine from Chinese Fructus seu radix camptothecae acuminatae (Fructus Camptothecae Acuminatae), be S-phase specificity cancer therapy drug.Its anticancer mechanism of the pharmacological research of system is for suppressing Topo I, clinical ascitic type liver cancer, tumor of head and neck, gastric cancer and bladder cancer and the leukemia of mainly applying to, the toxic reaction of HCPT mainly shows the inhibition of urinary system, digestive system and hemopoietic function etc., but its toxicity is starkly lower than camptothecine, particularly the urinary system reaction is few, easily is accepted clinically.At present, the subject matter that this medicine exists has: the half-life short (5min-1h), need repetitively administered, so toxic and side effects is bigger; Fat-soluble strong, and the active anticancer reduction by 90% of making the water solublity sodium salt; Poor stability, the lactonic ring of medicine are lost pharmacologically active to light, thermo-responsive after the lactonic ring open loop.At present, domesticly clinically be form (patent 02138930.6 and 02114913.5) with the salt of the open loop of HCPT with preparation, such preparation drug effect significantly descends, and toxicity increases, thereby has limited clinical practice.Research is one of main direction of its research to the 10-hydroxycamptothecine novel form at present.
The half-life of 10-hydroxycamptothecine is short, only be about 5min-1h, on the treatment characteristics, such medicine is in concentration that affects the treatment and time factor, time is principal element, belong to the time-dependent medicine, be mainly used in poky tumor treatment, so this mechanism of action requires its long-term prescription.Many studies show that, administration nano-drug administration system have good targeting and slow releasing function, are particularly conducive to the anticancer therapy of such time-dependent sexual type medicine and the fast medicine of metabolism.Employing absorption-packs such as domestic Zhang Zhi's honor have prepared the 10-hydroxycamptothecine PBCA nanoparticle of polyvinyl pyridine alkane ketone bag quilt, experimental results show that this medicine carrying nanoparticle has tangible liver targeting and slow releasing function.Domestic patent 03152834.1 discloses the Emulsion and the Emulsion of 10-hydroxycamptothecine, has increased stability of drug, has changed medicine distribution in vivo, has improved the curative effect of medicine.Domestic patent 01138252.X has prepared 10-hydroxycamptothecine glucosan nanoparticle, 01133700.1 prepared polylactic acid nano particle, 03113179.4 prepared the liposome of HCPT, these preparations show to have the higher selectivity of reticuloendothelial system (liver, spleen etc.), better to treatment hepatocarcinoma, but not in other tumors of reticuloendothelial system, such preparation does not only have targeting, has also increased the toxicity of medicine to reticuloendothelial system as if lesions position.
Summary of the invention
The object of the present invention is to provide the long circulating liposomes of 10-hydroxycamptothecine and the freeze-dried preparation of long circulating liposomes.Preparation of the present invention can disperse with normal saline or glucose injection, is used for intravenously administrable.
Characteristics of the present invention are to use the lipid of PEGization to come modified liposome, and it is bigger to solve the traditional liposomal particle diameter on the one hand, poor stability, the problem of easily leakage, fusion and lyophilization difficulty; Surface of liposome is modified by PEG, form a kind of spatial " conformation cloud ", the absorption of opsonic identification and plasma protein in the prevention blood, reduce liposome engulfing by reticuloendothelial system, thereby the removing speed of liposome is slowed down, and residence time prolongs in the blood, helps it and enters tumor tissues, and promote its infiltration and delay effect (EPR effect), thereby reach cancer target and efficacy enhancing and toxicity reducing effect to tumor tissues.
The lipid of PEGization involved in the present invention comprises the phospholipid such as the hard ester acyl PHOSPHATIDYL ETHANOLAMINE (PEG-DSPE) of Polyethylene Glycol-two of PEGization; Block or friendship graft copolymer class such as polyethylene glycol-caprolactone (PEG-PCL), polyethylene glycol-Acetic acid, hydroxy-, bimol. cyclic ester lactide (PEG-PLGA), polyethylene glycol-lactic acid (PEG-PLA), polyethylene glycol-cetyl cyanoacrylate (PEG-PHDCA) etc.; Surfactant-based as poloxamer 188 (Pluronic F68), polyoxyethylene fatty acid ester class (Mrij), polyoxyethylene fatty acid ether (Brij), polyoxyethylene hydrogenated Oleum Ricini (Cremophor) etc.Its common trait is that an end is hydrophilic Polyethylene Glycol, because PEG has hydrophilic and pliability preferably, is proved to be best face finish material at present; The other end then is lipophilic hydrophobic side, can well be embedded in the double-layer of lipoid of liposome to form lipid film jointly with phospholipid.
The present invention carries out around the preparation of 10-hydroxycamptothecine, but also can be used for other water insoluble camptothecins such as camptothecine, 9-aminocamptothecin, 9-nitrocamptothecin etc., the 10-hydroxycamptothecine of treatment cancer prepared in accordance with the present invention is compared with existing clinical dosage form, toxicity is less and more stable, and its anti-tumor activity improves greatly.
Purpose of the present invention is achieved through the following technical solutions:
The 10-hydroxycamptothecine long circulating liposome preparation is characterized in that following weight proportion medicine is a raw material: 10-hydroxycamptothecine 1-5 part, phosphatidase 11 0-100 part, lipid 10-100 part, cholesterol 2-50 part, trehalose or sucrose 10-400 part that PEG modifies.
Described phospholipid is lecithin, soybean phospholipid or hydrogenated soya phosphatide;
Described PEGization lipid is the hard ester acyl PHOSPHATIDYL ETHANOLAMINE (PEG-DSPE) of Polyethylene Glycol-two, polyethylene glycol-caprolactone (PEG-PCL), polyethylene glycol-Acetic acid, hydroxy-, bimol. cyclic ester lactide (PEG-PLGA), polyethylene glycol-lactic acid (PEG-PLA), polyethylene glycol-cetyl cyanoacrylate (PEG-PHDCA), poloxamer 188 (Pluronic F68), polyoxyethylene fatty acid ester class (Mrij), polyoxyethylene fatty acid ether (Brij), polyoxyethylene castor oil ether (Cremophor) wait one of them or any combining form.
Technical solution of the present invention also relates to the preparation method of described 10-hydroxycamptothecine long circulating liposome preparation, it is characterized in that following weight proportion medicine is a raw material: 10-hydroxycamptothecine 1-5 part, phosphatidase 11 0-100 part, cholesterol 2-50 part, trehalose or sucrose 10-400 part.The process preparation of freeze-dried preparation by may further comprise the steps: phospholipid, cholesterol and HCPT are dissolved in certain mixed organic solvents, remove organic solvent, constant temperature removes and desolvates, vacuum drying, adding is dissolved with in the trehalose or aqueous sucrose solution of aforementioned proportion, after the aquation dissolving, available ultrasound wave or high pressure dispersing emulsification machine are handled, divide in the container of packing into, lyophilization, the lyophilizing long circulating liposome preparation of 10-hydroxycamptothecine.Seal or can use nitrogen, helium, carbon dioxide or argon during gland.
Described phospholipid is lecithin, soybean phospholipid or hydrogenated soya phosphatide or wherein any two kinds of mixture.
Described PEGization lipid is the hard ester acyl PHOSPHATIDYL ETHANOLAMINE (PEG-DSPE) of Polyethylene Glycol-two, polyethylene glycol-caprolactone (PEG-PCL), polyethylene glycol-Acetic acid, hydroxy-, bimol. cyclic ester lactide (PEG-PLGA), polyethylene glycol-lactic acid (PEG-PLA), polyethylene glycol-cetyl cyanoacrylate (PEG-PHDCA), poloxamer 188 (Pluronic F68), polyoxyethylene fatty acid ester class (Mrij), polyoxyethylene fatty acid ether (Brij), polyoxyethylene hydrogenated Oleum Ricini (Cremophor) wait one of them or any combining form.
It is 40-60 ℃ that used constant temperature is removed solvent temperature.
Used organic solvent can be dichloromethane, chloroform, ethanol, methanol, oxolane, dimethyl sulfoxide and composition thereof.
Used hydration temperature can be 10-80 ℃.
Used freeze drying protectant also can be trehalose, sucrose, glucose, lactose, dextran, mannitol, F68 (poloxamer 188) and composition thereof.
Beneficial effect of the present invention shows: can stablize the Alpha-hydroxy lactonic ring of 10-hydroxycamptothecine, it is existed with closed loop, increase stability of drug; Can increase the water solublity of 10-hydroxycamptothecine, improve the suitable pin of injection; Can increase the half-life of 10-hydroxycamptothecine, increase its blood circulation time; Can improve the effect of target tumor, improve the curative effect of medicine, reduce toxicity; The lyophilized preparation of the present invention's preparation aquation again forms liposome solutions, increases stability of formulation; The present invention adopts membrane process preparation, technology simple possible.
Description of drawings
The release in vitro of the liposome that Fig. 1 .Brij-40 modifies: discharge percentage rate-time graph.
Fig. 2. the particle size distribution figure of liposome.
Fig. 3. with haemoconcentration (cpm/0.5ml) time graph of the lipid-modified liposome of various PEGization.
The specific embodiment
Embodiment 1.
With 10-hydroxycamptothecine 1g, phosphatidase 15 0g, cholesterol 15g, hard ester acyl PHOSPHATIDYL ETHANOLAMINE (PEG-DSPE) 5g of Polyethylene Glycol-two is dissolved in chloroform: in the methanol (2: 1), rotary evaporation is removed organic solvent, vacuum drying, adding is dissolved with in the trehalose and sucrose water (1: 1) solution of 100g aquation 30min, use ultrasonic Treatment, promptly get the long circulating liposomes solution of 10-HCPT.
Embodiment 2.
With 10-hydroxycamptothecine 2g, phosphatidase 15 0g, cholesterol 10g, polyethylene glycol-caprolactone (PEG-PCL) 10g is dissolved in chloroform: in the methanol (2: 1), rotary evaporation is removed organic solvent, vacuum drying, adding is dissolved with in the aqueous trehalose of 100g aquation 30min, handle with the high pressure dispersing emulsification machine, promptly get the long circulating liposomes solution of 10-HCPT.
Embodiment 3.
With 10-hydroxycamptothecine 4g, phosphatidase 15 0g, cholesterol 20g, polyethylene glycol-Acetic acid, hydroxy-, bimol. cyclic ester lactide (PEG-PLGA) 8g is dissolved in dichloromethane: in the ethanol (2: 1), rotary evaporation is removed organic solvent, vacuum drying, adding is dissolved with in the mannose and sucrose water (1: 1) solution of 70g aquation 30min, with handling, promptly get the long circulating liposomes solution of 10-HCPT with the high pressure dispersing emulsification machine.
Embodiment 4.
With 10-hydroxycamptothecine 1g, phosphatidase 15 0g, cholesterol 25g, polyethylene glycol-lactic acid (PEG-PLA) 5g is dissolved in chloroform: in the methanol (2: 1), rotary evaporation is removed organic solvent, vacuum drying, adding is dissolved with in the mannose and sucrose water (1: 1) solution of 100g aquation 30min, use ultrasonic Treatment, promptly get the long circulating liposomes solution of 10-HCPT.The liposome branch is packed in the container, lyophilization, the lyophilizing long circulating liposome preparation of 10-hydroxycamptothecine.Logical nitrogen seals.
Embodiment 5.
With 10-hydroxycamptothecine 4g, phosphatidase 15 0g, cholesterol 15g, poloxamer 188 (Pluronic F68) 10g is dissolved in dichloromethane: in the ethanol (2: 1), rotary evaporation is removed organic solvent, vacuum drying, adding is dissolved with in the trehalose and sucrose water (1: 1) solution of 100g aquation 30min, use ultrasonic Treatment, promptly get the long circulating liposomes solution of 10-HCPT.The liposome branch is packed in the container, lyophilization, the lyophilizing long circulating liposome preparation of 10-hydroxycamptothecine.Logical nitrogen seals.
With 10-hydroxycamptothecine 1g, phosphatidase 15 0g, cholesterol 15g, polyoxyethylene fatty acid ester (Mrij-100) 5g is dissolved in chloroform: in the methanol (2: 1), rotary evaporation is removed organic solvent, vacuum drying, adding is dissolved with in the trehalose and sucrose water (1: 1) solution of 100g aquation 30min, use ultrasonic Treatment, promptly get the long circulating liposomes solution of 10-HCPT.The liposome branch is packed in the container, lyophilization, the lyophilizing long circulating liposome preparation of 10-hydroxycamptothecine.Logical nitrogen seals.
Embodiment 7.
With 10-hydroxycamptothecine 1g, phosphatidase 15 0g, cholesterol 15g, polyoxyethylene fatty acid ether (Brij-40) 5g is dissolved in chloroform: in the methanol (2: 1), rotary evaporation is removed organic solvent, vacuum drying, adding is dissolved with in the trehalose and sucrose water (1: 1) solution of 100g aquation 30min, use ultrasonic Treatment, promptly get the long circulating liposomes solution of 10-HCPT.The liposome branch is packed in the container, lyophilization, the lyophilizing long circulating liposome preparation of 10-hydroxycamptothecine.Logical nitrogen seals.Again after disperseing with normal saline, be suspended from the bag filter, be positioned in the commentaries on classics basket of digestion instrument.At 37 ℃, constant temperature vibration under the 60rmin-1 condition, different time points sampling 0.5ml, add 0.5ml release medium (the PBS buffer of pH7.4) simultaneously, sample carries out acidify through the 10ulHCL of 0.1M, and sample introduction 20ul carries out HPLC and measures, and calculates cumulative release percent (%).See Fig. 1.
Embodiment 8.
With 10-hydroxycamptothecine 1g, phosphatidase 15 0g, cholesterol 15g, polyoxyethylene hydrogenated Oleum Ricini (Cremophor) 5g is dissolved in chloroform: in the methanol (2: 1), rotary evaporation is removed organic solvent, vacuum drying, adding is dissolved with in the trehalose and sucrose water (1: 1) solution of 100g aquation 30min, use ultrasonic Treatment, promptly get the long circulating liposomes solution of 10-HCPT.The liposome branch is packed in the container, lyophilization, the lyophilizing long circulating liposome preparation of 10-hydroxycamptothecine.Logical nitrogen seals.Again after disperseing with normal saline, measure particle diameter, see Fig. 2 with Nicomp TM 380ZLS granularity and zeta potentiometer.
Embodiment 9.
HCPT's
125The I labelling adopts the Iodogen method.The HPCT that takes by weighing 3.3mg is dissolved in the 1mL methanol, therefrom gets 100 μ L solution and places the Iodogen pipe, adds 1～2mCi Na
125I is transferred to little centrifuge tube behind the slight oscillating reactions 5min, and the effective 300 μ L redistilled water washed twice of Iodogen are incorporated in the small test tube.HPLC identifies and to show,
125The mark rate of I-HCPT is about 97%.
Get 24 of SD rats, be divided into 8 groups at random.Press 4.6875uCi/10g single dose tail vein injection HCPT aqueous solution for first group, second and third, four, five, six, seven groups press the 4.6875uCi/10g single dose respectively and inject the nanometer liposomes of modifying with Mrij-100, F68, Cremorphor RH 40, Mrij-40, F127, PEG-DSPE, get blood 0.5ml in the optical fundus respectively at 5min, 15min, 30min, 1h, 2h, 4h, 8h, 12h, 24h after the administration, gamma counter reads radiocounting.See Fig. 3.
Claims (6)
1. 10-hydroxycamptothecine long circulating liposome preparation, it is characterized in that with following weight proportion composition being that raw material is made lyophilized formulations: 10-hydroxycamptothecine 1-5 part, phosphatidase 11 0-100 part, lipid 10-100 part that PEG modifies, cholesterol 2-50 part, trehalose or sucrose 10-400 part, described PEGization lipid is the hard ester acyl PHOSPHATIDYL ETHANOLAMINE of Polyethylene Glycol-two, the polyethylene glycol-caprolactone, polyethylene glycol-Acetic acid, hydroxy-, bimol. cyclic ester lactide, polyethylene glycol-lactic acid, poloxamer 188, the polyoxyethylene fatty acid ester class, polyoxyethylene fatty acid ether or polyoxyethylene methyl Oleum Ricini ether one of them or any combining form.
2,, it is characterized in that described phospholipid is lecithin, soybean phospholipid or hydrogenated soya phosphatide and any combining form thereof according to the 10-hydroxycamptothecine long circulating liposome preparation of claim 1.
3, preparation method according to the 10-hydroxycamptothecine long circulating liposome preparation of claim 1, it is characterized in that with following weight proportion composition be raw material: 10-hydroxycamptothecine 1-5 part, phosphatidase 11 0-100 part, lipid 10-100 part that PEG modifies, cholesterol 2-50 part, trehalose or sucrose 10-400 part, with 10-hydroxycamptothecine, phospholipid, cholesterol is dissolved in dichloromethane according to the above ratio: in the methanol 2: 1, constant temperature removes and desolvates, and adds in the trehalose or aqueous sucrose solution that is dissolved with aforementioned proportion calculating, after the dissolving, ultrasonic or high-pressure homogenization is handled, divide in the container of packing into, lyophilization, the lyophilizing long circulating liposome preparation of 10-hydroxycamptothecine.
4. according to the method for claim 3, it is characterized in that described phospholipid is selected from lecithin, soybean phospholipid or hydrogenated soya phosphatide.
5. according to the method for claim 3, it is characterized in that it is 40-60 ℃ that described constant temperature removes the temperature of desolvating.
6. according to the method for claim 3, wherein freezing back feeds nitrogen, helium or argon, rolls then and covers or seal.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN100531720C (en) * | 2006-07-07 | 2009-08-26 | 中国科学院上海药物研究所 | A long-circulating nanoliposome carrier of hydroxycamptothecine and preparation method thereof |
| CN101744767B (en) * | 2008-12-05 | 2013-02-13 | 中国人民解放军军事医学科学院毒物药物研究所 | Thermal sensitive liposome preparation containing camptothecin antineoplastic agents |
| CN102271659B (en) * | 2009-12-03 | 2013-09-18 | 江苏恒瑞医药股份有限公司 | Liposome of irinotecan or its hydrochloride and preparation method thereof |
| CN105777770B (en) * | 2014-12-26 | 2018-05-25 | 中国人民解放军第二军医大学 | A kind of the 7-Ethyl-10-hydroxycamptothecin compound and its long circulating liposome of saturated long chain fatty acid modification |
| CN106109415B (en) * | 2016-07-26 | 2019-01-29 | 金华市人民医院 | A kind of load camptothecin antineoplastic agents liposome, preparation method and applications |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1160344A (en) * | 1994-10-14 | 1997-09-24 | 药制品美国公司 | Lyophilizate of Lipid complex of water insoluble camptothecins |
| CN1376468A (en) * | 2002-03-01 | 2002-10-30 | 深圳万乐药业有限公司 | Freeze dried hydroxy camptothecin powder for injection and its preparing process |
| CN1397280A (en) * | 2002-08-15 | 2003-02-19 | 黄石李时珍药业集团武汉李时珍药业有限公司 | Freeze dried hydroxycamptothecin powder injection and its preparing process |
| CN1537534A (en) * | 2003-04-14 | 2004-10-20 | 江苏省药物研究所 | Liposome of 10-hydroxycamptothecine, and its prepn. method |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1160344A (en) * | 1994-10-14 | 1997-09-24 | 药制品美国公司 | Lyophilizate of Lipid complex of water insoluble camptothecins |
| CN1376468A (en) * | 2002-03-01 | 2002-10-30 | 深圳万乐药业有限公司 | Freeze dried hydroxy camptothecin powder for injection and its preparing process |
| CN1397280A (en) * | 2002-08-15 | 2003-02-19 | 黄石李时珍药业集团武汉李时珍药业有限公司 | Freeze dried hydroxycamptothecin powder injection and its preparing process |
| CN1537534A (en) * | 2003-04-14 | 2004-10-20 | 江苏省药物研究所 | Liposome of 10-hydroxycamptothecine, and its prepn. method |
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