CN100349570C - 10-hydoxy camptothecin self micro emulsifieation composition - Google Patents
10-hydoxy camptothecin self micro emulsifieation composition Download PDFInfo
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- CN100349570C CN100349570C CNB2004100846488A CN200410084648A CN100349570C CN 100349570 C CN100349570 C CN 100349570C CN B2004100846488 A CNB2004100846488 A CN B2004100846488A CN 200410084648 A CN200410084648 A CN 200410084648A CN 100349570 C CN100349570 C CN 100349570C
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Abstract
The present invention belongs to the field of medicinal preparations. The present invention relates to a 10-hydoxy camptothecin self micro emulsion composition and a preparation method thereof. Self micro emulsion of the present invention is prepared from an oil phase, a surface active agent and cosurfactant. The self micro emulsion can be directly used; moisture which has the noncritical ratio can also be added to the self micro emulsion, and the self micro emulsion is diluted into stable products which have the arbitrary concentration to be used. After the self micro emulsion of 10-hydoxy camptothecin arrives at a human body in an injection mode or an oral administration mode, when the self micro emulsion encounters body fluid, the present invention can lead the self micro emulsion to be automatically formed into micro emulsion which has the nanometer scale particle diameter. The dissolvability of the medicine can be obviously enhanced, the stability of the medicine is increased, and the biological availability of the medicine is enhanced.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, relate to 10-hydroxycamptothecine self-emulsion composition 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.There are some researches show that administration nano-drug administration system has good targeting and slow releasing function, be 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 has been reported 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 reticuloendothelial system such as liver, the contour selectivity of spleen.
Summary of the invention
The object of the present invention is to provide self-emulsion composition of 10-hydroxycamptothecine and preparation method thereof, said preparation can disperse with normal saline or glucose injection, make injection, also can be made into various corresponding dosage forms such as capsule, soft capsule, microemulsion, percutaneous plaster.
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 the present invention's preparation is compared with existing clinical dosage form, toxicity is little and more stable, and its anti-tumor activity obviously improves.
Purpose of the present invention is achieved through the following technical solutions:
10-hydroxycamptothecine self-emulsion composition of the present invention comprises 10-hydroxycamptothecine, oil phase, surfactant and cosurfactant,
Described 10-hydroxycamptothecine is 0.1-5mg/ml,
Described oil phase is selected from following one group of material: the Semen Maydis oil (Maisine) that Oleum Glycines, isopropyl myristate, isopropyl palmitate, sad capric acid triglyceride, ethyl laurate, ethyl myristate, olein, glyceryl linoleate, Semen Maydis oil, acyl group shift
Described surfactant is selected from following one group of material: Tween 80, and soybean phospholipid, lecithin, polyoxyethylene castor oil (Cremophor EL), polyoxyethylene hydrogenated Oleum Ricini (Cremophor RH), Polyethylene Glycol-8-glycerol is sad/decanoin (Labrasol),
Described cosurfactant is selected from following one group of material: glycerol, Polyethylene Glycol, propylene glycol, ethylene glycol monomethyl ether (Trancutol P), dehydrated alcohol.
Self-emulsion composition of the present invention can be made into various corresponding dosage forms such as capsule, soft capsule, injection, percutaneous plaster.Also can further be diluted to the microemulsion of stable any concentration, and be prepared into various corresponding dosage forms with the moisture of arbitrary proportion.
The present invention has following beneficial effect:
It is bigger that prepared self-microemulsion can solve traditional Emulsion particle diameter on the one hand, because the emulsion stability that the existence of water causes is poor, stores problems such as volume is big; Can stablize the Alpha-hydroxy lactonic ring of 10-hydroxycamptothecine on the other hand, it is existed with closed loop, increase stability of drug; Can increase the dispersibility of 10-hydroxycamptothecine, improve bioavailability; Can increase the half-life of 10-hydroxycamptothecine, increase its blood circulation time; In addition, this self-microemulsion can further add the moisture dilution of arbitrary proportion, the microemulsion that spontaneous formation is transparent or semitransparent, and this microemulsion Thermodynamically stable, but filtration sterilization are easy to preparation and preservation; Can increase the water solublity of 10-hydroxycamptothecine, improve the suitable pin of injection; But the nanometer particle size of microemulsion makes its target tumor, improves the curative effect of medicine, reduces toxicity; The present invention adopts mixing method preparation, technology simple possible.
Description of drawings
Fig. 1. the particle size distribution figure of liposome.
Fig. 2. with haemoconcentration (cpm/0.5ml) time graph of the lipid-modified liposome of various PEGization.
The specific embodiment
Embodiment 1.
10-hydroxycamptothecine 2g is dissolved among Polyethylene Glycol-200 1000ml, adds polyoxyethylene castor oil (Cremophor EL) 1000ml, isopropyl myristate 2500ml, mixing gets final product.
Embodiment 2.
10-hydroxycamptothecine 2g is dissolved among the propylene glycol 1000ml, adds polyoxyethylene castor oil (Cremophor EL) 500ml, soybean lecithin 500g, isopropyl myristate 2500ml, mixing gets final product.
Embodiment 3.
10-hydroxycamptothecine 2g is dissolved among the glycerol 1000ml, add Polyethylene Glycol-8-glycerol sad/decanoin (Labrasol) 500ml, tween 80 500ml, sad capric acid triglyceride 1000ml, glyceryl linoleate 1000ml, mixing gets final product.
Embodiment 4.
10-hydroxycamptothecine 5g is dissolved among the ethylene glycol monomethyl ether Transcutol P 1000ml, add Polyethylene Glycol-8-glycerol sad/decanoin (Labrasol) 500ml, tween 80 500ml, sad capric acid triglyceride 1000ml, glyceryl linoleate 1000ml, mixing gets final product.
10-hydroxycamptothecine 5g is dissolved among the ethylene glycol monomethyl ether Transcutol P 1000ml, add polyoxyethylene hydrogenated Oleum Ricini (Cremophor RH) 500ml, tween 80 500ml, sad capric acid triglyceride 1000ml, glyceryl linoleate 1000ml, mixing gets final product.
Embodiment 6.
10-hydroxycamptothecine 5g is dissolved among the ethylene glycol monomethyl ether Transcutol P 1000ml, add Polyethylene Glycol-8-glycerol sad/decanoin (Labrasol) 500ml, soybean lecithin 500g, sad capric acid triglyceride 1000ml, Oleum Glycines 1000ml, mixing gets final product.
Embodiment 7.
10-hydroxycamptothecine 5g is dissolved among Polyethylene Glycol-200 1000ml, add Polyethylene Glycol-8-glycerol sad/decanoin (Labrasol) 500ml, polyoxyethylene castor oil (Cremophor EL) 500ml, ethyl laurate 1000ml, Oleum Glycines 1000ml, mixing gets final product.
Embodiment 8.
10-hydroxycamptothecine 5g is dissolved among Polyethylene Glycol-200 1000ml, add Polyethylene Glycol-8-glycerol sad/decanoin (Labrasol) 500ml, polyoxyethylene castor oil (Cremophor EL) 500ml, ethyl laurate 1000ml, Oleum Glycines 1000ml, mixing gets final product.
Embodiment 9.
10-hydroxycamptothecine 5g is dissolved among the ethylene glycol monomethyl ether Transcutol P 1000ml, add polyoxyethylene hydrogenated Oleum Ricini (Cremophor RH) 500ml, Polyethylene Glycol-8-glycerol is sad/decanoin (Labrasol) 500ml, ethyl laurate 1000ml, glyceryl linoleate 1000ml, mixing gets final product.
10-hydroxycamptothecine 5g is dissolved among the ethylene glycol monomethyl ether Transcutol P 1000ml, add polyoxyethylene hydrogenated Oleum Ricini (Cremophor RH) 500ml, Polyethylene Glycol-8-glycerol is sad/decanoin (Labrasol) 500ml, isopropyl palmitate 1000ml, sad capric acid triglyceride 1000ml, mixing gets final product.With Nicomp TM 380ZLS granulometry particle diameter, as Fig. 1.
Embodiment 11.
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, press the 4.6875uCi/10g single dose for second group and inject 10 preparation self-microemulsion with embodiment, 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. 2.
Claims (5)
1, a kind of 10-hydroxycamptothecine self-emulsion composition is characterized in that comprising 10-hydroxycamptothecine, oil phase, surfactant and cosurfactant, prepares by following method:
10-hydroxycamptothecine is dissolved in the cosurfactant, adds surfactant, oil phase, mixing gets final product;
Described 10-hydroxycamptothecine is 0.1-5mg/ml, and consumption is 2g;
Described cosurfactant is selected from Polyethylene Glycol-200 or propylene glycol, and consumption is 1000ml;
Described surfactant is selected from polyoxyethylene castor oil, and consumption is 500 or 1000ml;
Described oil phase is selected from isopropyl myristate, and consumption is 2500ml.
2,10-hydroxycamptothecine self-emulsion composition according to claim 1 is characterized in that described surfactant also is selected from soybean lecithin, and consumption is 500g.
3,10-hydroxycamptothecine self-emulsion composition according to claim 1 is characterized in that,
Described oil phase also is selected from: the Semen Maydis oil that Oleum Glycines, isopropyl palmitate, sad capric acid triglyceride, ethyl laurate, ethyl myristate, olein, glyceryl linoleate, Semen Maydis oil or acyl group shift;
Described surfactant also is selected from: Tween 80, and polyoxyethylene hydrogenated Oleum Ricini or Polyethylene Glycol-8-glycerol is sad/decanoin;
Described cosurfactant also is selected from: glycerol, ethylene glycol monomethyl ether or dehydrated alcohol.
4,10-hydroxycamptothecine self-emulsion composition according to claim 1 and 2 is characterized in that further being diluted to the microemulsion of stable any concentration with the moisture of arbitrary proportion, and is prepared into corresponding dosage form.
5,10-hydroxycamptothecine self-emulsion composition according to claim 1 and 2 is characterized in that making capsule, soft capsule, injection or percutaneous plaster.
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| CN101185638B (en) * | 2004-10-09 | 2011-04-06 | 山西中医学院 | Microemulsion preparation and preparation method thereof |
| CN101473998B (en) * | 2008-12-17 | 2011-09-28 | 华宝食用香精香料（上海）有限公司 | Sustained-release cassia leaf oil microemulsion, preparation method and use thereof |
| CN101708156B (en) * | 2009-12-10 | 2011-11-09 | 中国人民解放军第二军医大学 | Camptothecin medicament injection solution and injection and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1493289A (en) * | 2003-08-26 | 2004-05-05 | 袁建华 | Hydroxy camptothecin emulsion and its preparation method |
| CN1555799A (en) * | 2003-12-30 | 2004-12-22 | 张钧寿 | Fatly emulsion of camptothecin kind antitumour medicine and its preparation method |
| CN1593417A (en) * | 2004-07-06 | 2005-03-16 | 中国药科大学 | Lipid emulsions of camptothecin derivative and its preparation |
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| CN1493289A (en) * | 2003-08-26 | 2004-05-05 | 袁建华 | Hydroxy camptothecin emulsion and its preparation method |
| CN1555799A (en) * | 2003-12-30 | 2004-12-22 | 张钧寿 | Fatly emulsion of camptothecin kind antitumour medicine and its preparation method |
| CN1593417A (en) * | 2004-07-06 | 2005-03-16 | 中国药科大学 | Lipid emulsions of camptothecin derivative and its preparation |
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