CN1679575A - 10-hydroxy camptothecine long circulating vesica and its freeze-dried preparation - Google Patents
10-hydroxy camptothecine long circulating vesica and its freeze-dried preparation Download PDFInfo
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- CN1679575A CN1679575A CN 200510023115 CN200510023115A CN1679575A CN 1679575 A CN1679575 A CN 1679575A CN 200510023115 CN200510023115 CN 200510023115 CN 200510023115 A CN200510023115 A CN 200510023115A CN 1679575 A CN1679575 A CN 1679575A
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Abstract
A freeze-dried macrocyclic vesicle for preventing and treating cancer is proportionally prepared from 10-hydroxy camptothecine, PEG modified lipoid, span, cholesterol, trehalose or cane sugar, alcohol and dichloromethane. Its advantages are high water solubility and stability, and low toxin.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, relate to lyophilized formulations of 10-hydroxycamptothecine long circulating vesica, long circulating vesica 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 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.Chinese 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.Chinese patent 01138252.X discloses 10-hydroxycamptothecine glucosan nanoparticle, 01133700.1 disclose polylactic acid nano particle, 03113179.4 disclose the vesicle 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, also will increase 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 vesica and the freeze-dried preparation thereof of 10-hydroxycamptothecine.Preparation of the present invention can disperse with normal saline or glucose injection, is used for intravenously administrable.
The present invention will carry 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 the present invention's preparation is compared with existing clinical dosage form, toxicity is less and more stable, and its anti-tumor activity obviously improves.
The present invention is the film material with the span, uses the cholesterol used as stabilizers, makes freeze drying protectant with trehalose or sucrose, with ethanol and or dichloromethane make solvent.
Innovative point of the present invention and be characterised in that the utilization PEGization lipid-modified vesicle, it is bigger to solve traditional vesicle (liposome) particle diameter on the one hand, poor stability, easily leak, the problem of fusion and lyophilization difficulty, the vesicle surface is modified by PEG, form a kind of spatial " conformation cloud ", the absorption of opsonic identification and plasma protein in the prevention blood, reduce vesicle engulfing by reticuloendothelial system, thereby the removing speed of vesicle 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 the face finish material of present the best; The other end then is lipophilic hydrophobic side, can well be embedded in the double-layer of lipoid of vesicle to form lipid film jointly with spans.
Purpose of the present invention can be achieved through the following technical solutions:
10-hydroxycamptothecine long circulating vesica preparation of the present invention, adopting following weight proportion medicine is raw material: 10-hydroxycamptothecine 1-5 part, span 10-100 part, lipid 10-100 part, cholesterol 2-50 part, trehalose or sucrose 10-400 part that PEG modifies.
Described span is a span 20,40,60,80 and any combination.
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 combination.
The present invention can treat the 10-hydroxycamptothecine long circulating vesica preparation of cancer by following method and step preparation,
With following weight proportion medicine is raw material: 10-hydroxycamptothecine 1-5 part, and span 10-100 part, cholesterol 2-50 part, trehalose or sucrose 10-400 part,
Span, cholesterol and HCPT are dissolved in 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, handle with ultrasound wave or high pressure dispersing emulsification machine, divide in the container of packing into, lyophilization, the lyophilizing long circulating vesica preparation of 10-hydroxycamptothecine.Seal or can use nitrogen, helium, carbon dioxide or argon during gland.
Described span is for is characterized in that described span is a span 20,40,60,80 and any combining form.
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 described constant temperature is removed solvent temperature.
Described organic solvent can be dichloromethane, chloroform, ethanol, methanol, oxolane, dimethyl sulfoxide and composition thereof.
Described hydration temperature can be 10-80 ℃.
Described freeze drying protectant can be selected trehalose, sucrose, glucose, lactose, dextran, mannitol or F68 (poloxamer 188) and composition thereof for use.
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; But target tumor, the curative effect of raising medicine reduces toxicity; The lyophilized preparation of the present invention's preparation aquation again forms vesicle solution, increases stability of formulation; The present invention adopts membrane process preparation, technology simple possible.
Description of drawings
Fig. 1 is the release in vitro of the vesicle of PEG-PHDCA modification: discharge percentage rate-time graph.
Fig. 2 is the particle size distribution figure of vesicle.
Fig. 3 is haemoconcentration-time graph of modifying vesicle with PEG-PHDCA.
The specific embodiment
Embodiment 1.
With 10-hydroxycamptothecine 1g, span 50g, 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 vesica solution of 10-HCPT.
Embodiment 2.
With 10-hydroxycamptothecine 2g, span 50g, 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 vesica solution of 10-HCPT.
Embodiment 3.
With 10-hydroxycamptothecine 4g, span 50g, 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 vesica solution of 10-HCPT with the high pressure dispersing emulsification machine.
Embodiment 4.
With 10-hydroxycamptothecine 1g, span 50g, 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 vesica solution of 10-HCPT.The vesicle branch is packed in the container, lyophilization, the lyophilizing long circulating vesica preparation of 10-hydroxycamptothecine.Logical nitrogen seals.
Embodiment 5.
With 10-hydroxycamptothecine 4g, span 50g, 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 vesica solution of 10-HCPT.The vesicle branch is packed in the container, lyophilization, the lyophilizing long circulating vesica preparation of 10-hydroxycamptothecine.Logical nitrogen seals.
Embodiment 6.
With 10-hydroxycamptothecine 1g, span 50g, 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 vesica solution of 10-HCPT.The vesicle branch is packed in the container, lyophilization, the lyophilizing long circulating vesica preparation of 10-hydroxycamptothecine.Logical nitrogen seals.
Embodiment 7.
With 10-hydroxycamptothecine 1g, span 50g, cholesterol 15g, polyethylene glycol-cetyl cyanoacrylate (PEG-PHDCA) 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 vesica solution of 10-HCPT.The vesicle branch is packed in the container, lyophilization, the lyophilizing long circulating vesica 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 (%).
Embodiment 8.
With 10-hydroxycamptothecine 1g, span 50g, 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 vesica solution of 10-HCPT.The vesicle branch is packed in the container, lyophilization, the lyophilizing long circulating vesica preparation of 10-hydroxycamptothecine.Logical nitrogen seals.Again after disperseing with normal saline, measure particle diameter with Nicomp TM 380ZLS granularity and zeta potentiometer.
Embodiment 9.
Get 30 of SD rats, be divided into 5 groups at random.Press 2.5mg/kg single dose tail vein injection HCPT liquid drugs injection (concentration is with HCPT concentration in the nano vesicle) for first group, second and third, four groups inject the PEG-PHDCA nano vesicle that different PEG molecular weight (the PEG molecular weight is respectively 2000,5000,10000) that same dosage is loaded with HCPT are modified, get blood 0.5ml in the optical fundus respectively at 5min, 15min, 30min, 1h, 2h, 4h, 8h, 12h, 24h after the administration, handle according to a conventional method, measure, inner mark method ration.
Table 1 is the SD its pharmacokinetics in rats parameter of modifying vesicle with PEG-PHDCA.
Table 1.
t
1/2β AUC MRT
PEG
2000-PHDCA(S) 8.25 9.73 21.4951
PEG
5000-PHDCA(S) 13.03 26.54 29.6418
PEG
10000-PHDCA(S) 7.33 8.96 21.007
HCPT 0.7213 0.821 0.5883
Claims (9)
1,10-hydroxycamptothecine long circulating vesica and lyophilized formulations thereof; it is characterized in that with following weight proportion medicine be raw material: 10-hydroxycamptothecine 1-5 part; the film material is span 10-100 part; lipid 10-100 part that PEG modifies; stabilizing agent is cholesterol 2-50 part, and freeze drying protectant is trehalose or sucrose 10-400 part.
2,10-hydroxycamptothecine long circulating vesica according to claim 1 and lyophilized formulations thereof is characterized in that described film material span is a span 20,40,60,80 or any combination wherein.
3,10-hydroxycamptothecine long circulating vesica according to claim 1 and lyophilized formulations thereof, it is characterized in that the lipid that described PEG modifies is selected from 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, polyethylene glycol-cetyl cyanoacrylate, poloxamer 188, the polyoxyethylene fatty acid ester class, polyoxyethylene fatty acid ether or polyoxyethylene methyl Oleum Ricini ether or any combination wherein.
4, the 10-hydroxycamptothecine long circulating vesica of claim 1 and the preparation method of lyophilized formulations thereof, it is characterized in that 10-hydroxycamptothecine, span, cholesterol are dissolved in the organic solvent in the described ratio of claim 1, constant temperature removes and desolvates, add in the trehalose or aqueous sucrose solution that is dissolved with aforementioned proportion calculating, after the aquation dissolving, ultrasonic or high-pressure homogenization is handled, divide the container of packing into, lyophilization, get the lyophilizing long circulating vesica lyophilized formulations of 10-hydroxycamptothecine, freezing back feeds nitrogen, helium or argon, after roll lid or seal.
5, according to the method for claim 4, wherein said organic solvent can be selected from dichloromethane, chloroform, ethanol, methanol, oxolane or dimethyl sulfoxide and composition thereof.
6, according to the method for claim 4, wherein said organic solvent is a dichloromethane: methanol (2: 1).
7, according to the method for claim 4, it is 40-60 ℃ that wherein said constant temperature removes the temperature of desolvating.
8, according to the method for claim 4, wherein said hydration temperature is 10-80 ℃.
9, according to the 10-hydroxycamptothecine long circulating vesica and the lyophilized formulations thereof of claim 1, wherein said freeze drying protectant can be selected trehalose, sucrose, glucose, lactose, dextran, mannitol or poloxamer 188 and composition thereof for use.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101167725B (en) * | 2007-10-15 | 2010-06-16 | 中国药科大学 | Nimodipine long circulating vesicle and its freezing-dried preparation |
| CN101628919B (en) * | 2009-08-20 | 2011-11-23 | 浙江大学 | Camptothecin, self-emulsifying medicine precursor of derivative thereof and application thereof |
| CN106913524A (en) * | 2017-03-24 | 2017-07-04 | 清华大学 | Multifunctional load stimulation vesica based on framework induction self assembly and preparation method thereof |
| WO2019114689A1 (en) * | 2017-12-13 | 2019-06-20 | 中国人民解放军军事医学科学院毒物药物研究所 | Cyanoacrylate material for loading antitumor drug |
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2005
- 2005-01-04 CN CN 200510023115 patent/CN1679575A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101167725B (en) * | 2007-10-15 | 2010-06-16 | 中国药科大学 | Nimodipine long circulating vesicle and its freezing-dried preparation |
| CN101628919B (en) * | 2009-08-20 | 2011-11-23 | 浙江大学 | Camptothecin, self-emulsifying medicine precursor of derivative thereof and application thereof |
| CN106913524A (en) * | 2017-03-24 | 2017-07-04 | 清华大学 | Multifunctional load stimulation vesica based on framework induction self assembly and preparation method thereof |
| WO2019114689A1 (en) * | 2017-12-13 | 2019-06-20 | 中国人民解放军军事医学科学院毒物药物研究所 | Cyanoacrylate material for loading antitumor drug |
| CN109908356A (en) * | 2017-12-13 | 2019-06-21 | 中国人民解放军军事医学科学院毒物药物研究所 | Load the alpha-cyanoacrylate ester material of anti-tumor drug |
| CN109908356B (en) * | 2017-12-13 | 2021-02-12 | 中国人民解放军军事医学科学院毒物药物研究所 | Cyanoacrylate material loaded with antitumor drug |
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