CN1303994C - Taxol vesicle injection and its prepn - Google Patents
Taxol vesicle injection and its prepn Download PDFInfo
- Publication number
- CN1303994C CN1303994C CNB031050484A CN03105048A CN1303994C CN 1303994 C CN1303994 C CN 1303994C CN B031050484 A CNB031050484 A CN B031050484A CN 03105048 A CN03105048 A CN 03105048A CN 1303994 C CN1303994 C CN 1303994C
- Authority
- CN
- China
- Prior art keywords
- injection
- paclitaxel
- solution
- vesicle
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention relates to a taxol vesicle injection and a preparing method thereof. The vesicle injection is composed of taxol and auxiliary materials. The used auxiliary materials comprise SPC (granulesten), PVPk15 (polyvidone k15) or PVPk30 (polyvidone k30), F68 (poloxamer 188), PEG400 (polyethyleneglycol-400 for injection), 1, 2-propanediol(for injection) and ethanol (for injection). The vesicle injection the vesicle of which is smaller than 200 nm is prepared by compounding and emulsifying the taxol and the auxiliary materials. The medicine carrying quantity of the vesicle injection (the taxol) is from 5 mg/ ml of injection to 50 mg / ml of injection. The preparing method of the present invention is suitable for industrialized production.
Description
The invention belongs to pharmaceutical chemistry and field of pharmaceutical preparations thereof, particularly, the present invention relates to a kind of paclitaxel vesicle injection and preparation method thereof.
Paclitaxel (Paclitaxel, trade name Taxol) is the chemical constitution novelty that is found and proves at the beginning of the seventies, and the kinds of tumors model is had good anti-cancer activity and the unique mechanism of action [Proc.Natl.Acad.Sci., 1980,77:1561; J.Pharmacol.Exp.Ther., 1987,243:692] antitumor drug.It can combine with the cell tubulin, when cancerous cell divides, induce and promote tubulin polymerization, suppress its depolymerization, cell mitogen is blocked, play microtubule assembling and microtubule Stabilization, thereby stop the growth of tumor cell, ovarian cancer, breast carcinoma, incidence cancer, lung cancer in non-cellule type, carcinoma of prostate etc. are all had the good anticancer effect.At the beginning of the eighties, institute of Materia Medica,Chinese Academy of Medical Sciences begins Paclitaxel is studied, and discovers that the anti-tumor activity of Paclitaxel taxane (Taxane) compounds from natural origin is the strongest.And carried out the research of pharmacodynamics, toxicity and the pharmacokinetics of Paclitaxel on this basis.Test is levied bright: Paclitaxel has obvious inhibitory action to the growth of the human ovarian cancer xenotransplantation tumor of nude mice.The first official approval Paclitaxel of December in 1992 U.S. Food and Drug Admistraton (FDA) on the 29th is used for the treatment of the transitivity advanced ovarian cancer of initial therapy or other chemotherapeutics refractory, and December in 1993 FDA on the 15th ratifies the metastatic breast cancer that Paclitaxel can be used for treating the platinum medicine refractory again.In addition, the U.S.'s II of JohnsHopkins tumor center phase clinical effectiveness shows that Paclitaxel is that single drug is treated the best medicine of incidence cancer effect up to now.
The Paclitaxel molecular formula is C
47H
51NO
14, molecular weight 853.92 is insoluble in water and many medicinal solvents (be dissolved in ethanol, methanol slightly, the utmost point is insoluble in ether), and fat-soluble strong, dissolubility only is 0.006mg/ml in the water.From the eighties, people promptly are devoted to improve its water solublity, at first be on Paclitaxel, to have connected some polar groups to form prodrug, as [J.Nat.Prod. such as Zhao, 1991,54 (6): 1607] prepare the water-soluble prodrug of Paclitaxel by structure of modification, and make it under physiological condition, discharge Paclitaxel to reach anticancer purpose.But these prodrug are not enough because of stability, fail commercialization always.In recent years, people are connected Paclitaxel to be made it in " being brought into " water with some macromolecular water-solubility carriers, for the water solublity problem that solves TAX has been opened up the small stream warp.
The present clinical preparation of using, as Paclitaxel [U.S. Bristol-Myers-Squibb (BMS) company], Anzatax (Australian Faulding company) and in the plain of home-made purple, taxol etc. be polyoxyethylene castor oil (Cremphor EL)-dehydrated alcohol (50: 50 of Paclitaxel, v/v) oil solution is diluted to the quiet notes of 0.3～1.2mg/ml.But the Cremphor EL in the prescription can cause that in-vivo tissue amine discharges, and after the administration several minutes, causes the part patient anaphylaxiss such as medicine erythra, rapid breathing, bronchospasm, hypotension to occur.Take at present before administration a few hours to take the generation that antihistaminics such as diphenhydramine, dexamethasone, aminophylline prevented every reaction more.Research is also found, but the Cremphor EL in the injection contacts lixiviate with pvc tube with transfusion bag goes out a large amount of plasticiser phthalic acid diethyl ethyl phosphonate (DEHP), cause toxicity, therefore the clinical nitroglycerine pipe of glass, polyethylene and lined with polyethylene that uses of expert advice is infusion set [Am.J.Hosp.Pharm., 1991,48:1520].
Although the side effect of clinical employed TAX preparation can be prevented by methods such as pre-medications at present, whole process is inconvenience very, and need careful detection medication process.People still need constantly research and development to be suitable for clinical Paclitaxel novel form.
1. injectable powder: Zhang Hairu [CN1148957A, 1997] organic solution of etc. taking freeze-drying will inject the Paclitaxel of specification, phospholipid and cholate is made powder, directly adds 5% glucose or 0.9% chloride injection agent dissolving posterior vein during use and instils.
2. cyclodextrin clathrate: Sharm[J.Pharm.Sci., 1995,84 (10): 1223], Szente[WO9614872A, 1996] etc. (((enclose Paclitaxel such as CM-β-CD) all can increase the Paclitaxel dissolubility and reach 2 * 10 for HE-β-D), dimethyl-β-CD for HP-β-CD), ethoxy-β-CD with many cyclodextrin derivative such as hydroxy propyl-Beta-CD
3Doubly, and do not change its cytostatic characteristic.But during the dilution of Paclitaxel inclusion complex in solution, Paclitaxel dissociates from clathrate and enters in the water, separates out precipitation, and the drug loading of clathrate does not still reach the clinical treatment desired concn; And the different substituent group of cyclodextrin is influential to the water solublity and the active anticancer of modified outcome.
3. liposome: Sharm[Pharm.Res., 1994,11:889; Cancer.Res., 1993,53:5877], Riondel J[In Vivo, 1992,6:23] etc. utilize the liposome technology to carry out a series of researchs to improving the Paclitaxel water solublity, studies show that its active anticancer of Paclitaxel liposome obviously is better than injection, and toxic and side effects reduces.
4. millimicro crystalline substance (Insoluble Drug Delivery, IDD): [Pharm.Res. such as Merisko-Liversidge, 1996,13:272] use wet grinding under aseptic condition, selecting glue-linked polymers such as Pluronic F127, F108 is that stabilizing agent has prepared particle diameter less than the brilliant aqueous suspension of the Paclitaxel millimicro of 400nm.Although the IDD microparticle formulation of Paclitaxel still is in the preliminary study stage, it is not difficult to visualize, along with the continuous development of this technology, IDD will become a kind of effective means that development comprises the multiple insoluble drug injection of Paclitaxel.
5. polyethyleneglycol derivative: Polyethylene Glycol (PEG) is a kind of amphiphilic macromolecular, and can effectively increase water solublity after hydrophobic drug combines, and can reduce the immunogenicity of conjugate.Greenwald[Bioorg.Med.Chem.Lett., 1994,4:2465] etc. coupling in the presence of diethyl propyl carbodiimide diimine (DIPC) and dimethylamino pyridine gets 2`-PEG China fir alcohol ester with acidifying Polyethylene Glycol and Paclitaxel, its dissolubility 〉=666mg/ml, external test confirmation derivatives active and Paclitaxel are similar.Enzon company has also developed Paclitaxel-polyethylene glycol conjugate PEG-paclitaxel.Preclinical study shows that this conjugate has reduced the cytotoxicity of Paclitaxel.
6. the common breast of vein: Tarr BD[Pharm.Res., 1987,4:162; J.Parenter.Sci.Technol., 1987,4:31] etc. be emulsifying agent with L-α-lecithin (2%), tween 80, Pluronic F68 (1.5%) and ethyl oleate (2%), glycerol triacetate consumption 50%, glycerol consumption 10%, making the emulsion droplet mean diameter is 1 μ m, and content is the vein breast of 10～15mg/ml.The vein breast is diluted to volume ratio＞15% with 5% dextran, and it is stable that Emulsion keeps in 4h, can be used for intravenous drip.But the physical stability of Paclitaxel vein breast is bad, stores 6 months for 4 ℃, layering occurs, and particle diameter can return to (0.8～5 μ m) about 2 μ m after the violent jolting.And, the quiet subject matter of annotating the back appearance of Paclitaxel vein breast is absorbed by reticuloendothelial system in the body (RES), medicine is difficult to arrive target site, and the immune system of damage body, therefore it is very crucial to control emulsion droplet particle diameter and stability, need to use special emulsifying device, as: microjet (Microfluidizer).
7. mixed micelle: Alkan-onynksel H[Pharm.Res., 1994,11:206] etc. the employing coprecipitation prepare Paclitaxel water-soluble epoxy glue bundle preparation, can be used for intravenous administration.Thereby solved the difficult problem of preparation long preservation.Before the clinical use, only use the 0.02MTris-HCl buffer, can further form liposome solutions, be used for intravenously administrable.Anticancer experiment in vitro shows that the mixed micelle dosage form has kept the active anticancer of Paclitaxel.
8. quiet notes submicron emulsion: Lundberg etc. [Int.J.Pharm., 1997,49:1] the quiet notes submicron emulsion of modifying through PEG of phospholipid (PEG-PE) preparation Paclitaxel.Its mean diameter is 40nm, can stablize the several months in 4 ℃.If it is disperseed the back lyophilizing with 5% glucose solution, then dried frozen aquatic products can be dissolved in the distilled water fully.Owing to added PEG-PE, can weaken combination, the picked-up ability to emulsion droplet such as protein, macrophage at the three-dimensional barrier of the outer formation of emulsion droplet, prolong circulation time.And when using glycerol triacetate to make oil phase, PEG-PE can participate in forming the outer albumen analog of lipoprotein in the monolayer phospholipid layer of emulsion droplet outer wrapping, make emulsion droplet stable, have certain targeting and do not have immunity rejection property [J.Pharm.Sci., 1994,83 (11): 1558].
9. nanoparticle: STS company and Unimed company have developed Paclitaxel milli granule product (Medisperse ), are the water solublity suspension of particle diameter less than 0.2 μ m.Entered clinical research in 1996.Experiment shows that drug effect is suitable with Taxol injection, does not have irritated reaction through zoopery and takes place.
10. poly type microsphere: the poly type prescription that can directly inject influenced joint of Canadian Angiotech company exploitation, can be at the appointed time release of active ingredients gradually.
In sum, in order to solve the side-effect problem of present clinical use Paclitaxel preparation, though about studying report, patent a lot, ubiquitous problem is that the drug loading of preparation is low, and stability is undesirable, therefore is difficult to actual clinically applying.
The present invention makes the vesicle injection of vesicle less than 200nm with Paclitaxel through the compound emulsifying agent effect, vesicle injection drug loading is from 5mg/ml to 50mg/ml, preparation method is applicable to suitability for industrialized production, with 50 times of 0.5% glucose dilutions, intravenous drip used up in 6 hours the vesicle injection with preceding.
Therefore, the purpose of this invention is to provide a kind of paclitaxel vesicle injection;
Another object of the present invention provides a kind of method for preparing paclitaxel vesicle injection.
Purpose of the present invention can realize by following technical scheme.
The inventor finds, increases by the drug loading of selecting the paclitaxel vesicle injection that proper supplementary material makes, and stability improves, and can reduce toxic and side effects.
Therefore, the invention provides a kind of paclitaxel vesicle injection, it contains as the paclitaxel of active component and adjuvant, and wherein adjuvant comprises paclitaxel (Paclitaxel), soybean phospholipid (SPC), polyvidone-30 (PVP
K15Or PVP
K30), poloxamer-188 (Poloxamer188, F
68), or Polyethylene Glycol-400 (PEG
400).
The composition and the consumption of the preferred paclitaxel vesicle of the present invention (Vesicle) injection are as follows:
The every ml injection of material content
Paclitaxel (Paclitaxel) 5mg～50mg
Soybean phospholipid (SPC) 16mg～32mg
Polyvidone-30 (PVP
K15Or PVP
K30) 8mg～16mg
Poloxamer-188 (Poloxamer188, F
68) 16mg～32mg
Polyethylene Glycol-400 (PEG
400) 100mg～300mg
1,2-propylene glycol 200mg～600mg
Ethanol 0.1ml～0.3ml
The water for injection surplus
Further specify the preparation method of injection of the present invention below.
The explanation of the relevant reagent that the present invention uses:
Paclitaxel (paclitaxel, Shenzhen ZunAn Co., Ltd);
SPC (soybean phospholipid, the safe big pharmaceutcal corporation, Ltd in Shanghai);
PVP
K15(polyvidone k
15, Shanghai chemical formula agent company, Japan and the import packing of light Co., Ltd.) or PVP
K30(polyvidone k30, Shanghai chemical formula agent company, Japan and the import packing of light Co., Ltd.);
F
68(poloxamer 188, U.S. BASF);
PEG
400(Polyethylene Glycol-400, injection);
1,2-propylene glycol (injection);
Ethanol (injection).
Paclitaxel vesicle injection preparation method one comprises the steps:
A. prepare solution I: get paclitaxel 50～500mg, add PEG
4001～3g makes solution I;
B. the preparation of soybean phospholipid film: get soybean phospholipid 160～320mg, Poloxamer188 (F68) 160～320mg, PVP
K15(or PVP
K30) 80～160mg, add ethanol 100ml, be heated to 50 ℃ of dissolvings after, rotary evaporation reclaims ethanol, drain the soybean phospholipid film, weigh.
C. prepare solution II: in the SPC film, add the injection water (for SPC film weight 5%), add 1 again, 2-propylene glycol 2～6g, dehydrated alcohol 1～3ml dissolve solution II;
D. solution II and solution I is mixed, after stirring, transfer to final volume 10ml with water for injection, mixing, embedding is in the 1ml ampoule respectively, and 100 ℃ of heating sterilization in 30 minutes makes paclitaxel vesicle injection.
Paclitaxel vesicle injection preparation method two comprises the steps:
E. prepare solution I:, add PEG to paclitaxel 50～500mg
4001～3g makes solution I;
F. prepare solution II: get soybean phospholipid 160～320mg, 1,2-propylene glycol 2-6g, Poloxamer188 (F68) 160～320mg, PVP
K15(or PVP
K30) 80～160mg, obtain solution II with ethanol 1～3ml dissolving;
G. solution II and solution I is mixed, after stirring, transfer to final volume 10ml with water for injection, mixing,
Embedding is asked small jar in the 1ml peace respectively, and 100 ℃ of heating sterilization in 30 minutes makes paclitaxel vesicle injection.
Paclitaxel vesicle injection preparation method three comprises the steps:
Get paclitaxel 50～500mg, soybean phospholipid 160～320mg, 1,2-propylene glycol 2～6g, Poloxamer188 (F68) 160～320mg, PEG
4001～3g, PVP
K15(or PVP
K30) 80～160mg, after ethanol 1～3ml dissolving, transfer to final volume 10ml with water for injection, mixing, embedding is in the 1ml ampoule respectively, and 100 ℃ of heating sterilization in 30 minutes makes paclitaxel vesicle injection.
The invention will be further described below by embodiment.It should be understood that the described preparation method of the embodiment of the invention is only used for illustrating the present invention, rather than limitation of the present invention, the simple modifications to preparation method of the present invention under design prerequisite of the present invention all belongs to the scope of protection of present invention.Except as otherwise noted, the percent among the present invention is percetage by weight.
By orthogonal design principle (factor and level see Table 1):
Table 1: orthogonal design factor and level
Embodiment 1. paclitaxel vesicle (Vesicle) injection preparation method I
1). solution I preparation: get paclitaxel 200mg, add PEG
4001g makes solution I;
2). the preparation of soybean phospholipid film: get SPC160mg, Poloxamer188 (F68) 160mg, PVP
K15(or PVP
K30) 80mg, add ethanol 100ml, be heated to 50 ℃ of dissolvings after, rotary evaporation reclaims ethanol, drain the SPC film, weigh.
3). solution II preparation: in the SPC film, add the injection water (for SPC film weight 5%), behind the aquation certain hour, add 1 again, 2-propylene glycol 2g, dehydrated alcohol 1.0ml, dissolving, mixing gets solution II;
4). solution II and solution I are mixed, after stirring, transfer to final volume 10ml with water for injection, mixing, embedding is in the 1ml ampoule respectively, and 100 ℃ of heating sterilization in 30 minutes makes paclitaxel vesicle injection;
5). the vesicle injection dilutes with 0.5% glucose, and (NICOMP380 USA) detected vesicle size, 6 hours intracellular vesicle sizes almost constant (less than 200nm) with laser particle diameter instrument every one hour.
Embodiment 2: paclitaxel vesicle injection preparation method II
1). preparation solution I: get paclitaxel 200mg, add PEG
4002g makes solution I;
2). preparation soybean phospholipid film: claim SPC160mg, Poloxamer188 (F68) 160mg, PVP
K15(or PVP
K30) 80mg, add ethanol 100ml, be heated to 50 ℃ of dissolvings after, rotary evaporation reclaims ethanol, drain the SPC film, weigh;
3). the preparation solution II: in the SPC film, add the injection water (for SPC film weight 5%), behind the aquation certain hour, add 1 again, 2-propylene glycol 4g, dehydrated alcohol 2.0ml, the dissolving, mixing gets solution II;
4). solution II and solution I is mixed, after stirring, transfer to final volume 10ml with water for injection, mixing, embedding is in the 1ml ampoule respectively, and 100 ℃ of heating sterilization in 30 minutes makes paclitaxel vesicle injection;
5). this vesicle injection dilutes with 0.5% glucose, and (NICOMP380 USA) detected vesicle size, 6 hours intracellular vesicle sizes almost constant (less than 200nm) with laser particle diameter instrument every one hour.
Embodiment 3: paclitaxel vesicle injection preparation method III
1). preparation solution I: get paclitaxel 200mg, add PEG
4003g makes solution I;
2). preparation soybean phospholipid film: get SPC160mg, Poloxamer188 (F68) 160mg, 80mg PVP
K15(or PVP
K30), add ethanol 100ml, be heated to 50 ℃ of dissolvings after, rotary evaporation reclaims ethanol, drain the SPC film, weigh;
3). the preparation solution II: in the SPC film, add the injection water (for SPC film weight 5%), behind the aquation certain hour, add 1 again, 2-propylene glycol 6g, dehydrated alcohol 3.0ml, the dissolving, mixing gets solution II; 4). solution II and solution I is mixed, after stirring, transfer to final volume 10ml with water for injection, mixing, embedding is in the 1ml ampoule respectively, and 100 ℃ of heating sterilization in 30 minutes makes paclitaxel vesicle injection;
5). this vesicle injection dilutes with 0.5% glucose, and (NICOMP380 USA) detected vesicle size, 6 hours intracellular vesicle sizes almost constant (less than 200nm) with laser particle diameter instrument every one hour.
Embodiment 4: paclitaxel vesicle injection preparation method IV
1). solution I preparation: get paclitaxel 200mg, add PEG
4002g makes solution I;
2). preparation soybean phospholipid film: get SPC 240mg, Poloxamer188 (F68) 240mg, PVP
K15(or PVP
K30) 120mg, add ethanol 100ml, be heated to 50 ℃ of dissolvings after, rotary evaporation reclaims ethanol, drain the SPC film, weigh;
3). the preparation solution II: in the SPC film, add the injection water (for SPC film weight 5%), behind the aquation certain hour, add 1 again, 2-propylene glycol 2g, dehydrated alcohol 3.0ml, the dissolving, mixing gets solution II;
4). solution II and solution I is mixed, after stirring, transfer to final volume 10ml with water for injection, mixing, embedding is in the 1ml ampoule respectively, and 100 ℃ of 30 minutes heat sterilizations make paclitaxel vesicle injection;
5). this vesicle injection dilutes with 0.5% glucose, and (NICOMP380 USA) detected vesicle size, 6 hours intracellular vesicle sizes almost constant (less than 200nm) with laser particle diameter instrument every one hour.
Embodiment 5: paclitaxel vesicle injection preparation method V
1). preparation solution I: get paclitaxel 200mg, add PEG
4003g makes solution I;
2). preparation soybean phospholipid film: get SPC 240mg, Poloxamer188 (F68) 240mg, PVP
K15(or PVP
K30) 120mg, add ethanol 100ml, be heated to 50 ℃ of dissolvings after, rotary evaporation reclaims ethanol, drain the SPC film, weigh;
3). the preparation solution II: in the SPC film, add the injection water (for SPC film weight 5%), behind the aquation certain hour, add 1 again, 2-propylene glycol 4g, dehydrated alcohol 1.0ml, the dissolving, mixing gets solution II;
4). solution II and solution I is mixed, after stirring, transfer to final volume 10ml with water for injection, mixing, embedding is in the 1ml ampoule respectively, and 100 ℃ of heating sterilization in 30 minutes makes paclitaxel vesicle injection;
5). the vesicle injection dilutes with 0.5% glucose, and (NICOMP380 USA) detected vesicle size, 6 hours intracellular vesicle sizes almost constant (less than 200nm) with laser particle diameter instrument every one hour.
Embodiment 6: paclitaxel vesicle injection preparation method VI
1). preparation solution I: get paclitaxel 200mg, add PEG
4001g makes solution I;
2). preparation soybean phospholipid film: get SPC 240mg, Poloxamer188 (F68) 240mg, PVP
K15(or PVP
K30) 120mg, add ethanol 100ml, be heated to 50 ℃ of dissolvings after, rotary evaporation reclaims ethanol, drain the SPC film, weigh;
3). the preparation solution II: it is an amount of to add the injection water in the SPC film, behind the aquation certain hour, adds 1 again, 2-propylene glycol 6g, dehydrated alcohol 2.0ml, dissolving, mixing gets solution II;
4). solution II and solution I is mixed, after stirring, transfer to final volume 10ml with water for injection, mixing, embedding is in the 1ml ampoule respectively, and 100 ℃ of heating sterilization in 30 minutes makes paclitaxel vesicle injection;
5). this vesicle injection dilutes with 0.5% glucose, and (NICOMP380 USA) detected vesicle size, 6 hours intracellular vesicle sizes almost constant (less than 200nm) with laser particle diameter instrument every one hour.
Embodiment 7: paclitaxel vesicle injection preparation method VII
1). preparation solution I: get paclitaxel 200mg, add PEG
4003g makes solution I;
2). preparation soybean phospholipid film: get SPC 320mg, Poloxamer188 (F68) 320mg, PVP
K15(or PVP
K30) 160mg, add ethanol 100ml, be heated to 50 ℃ of dissolvings after, rotary evaporation reclaims ethanol, drain the SPC film, weigh;
3). liquid II is held in preparation: in the SPC film, adds injection water (for SPC film weight 5%), behind the aquation certain hour, adds 1 again, 2-propylene glycol 2g, dehydrated alcohol 2.0ml, dissolving, mixing gets solution II;
4). solution II and solution I is mixed, after stirring, transfer to final volume 10ml with water for injection, mixing, embedding is in the 1ml ampoule respectively, and 100 ℃ of heating sterilization in 30 minutes makes paclitaxel vesicle injection;
5). the vesicle injection dilutes with 0.5% glucose, and (NICOMP380 USA) detected vesicle size, 6 hours intracellular vesicle sizes almost constant (less than 200nm) with laser particle diameter instrument every one hour.
Embodiment 8: paclitaxel vesicle injection preparation method VIII
1). preparation solution I: get paclitaxel 200mg, add PEG
4001g makes solution I;
2). preparation soybean phospholipid film: get SPC 320mg, Poloxamer188 (F68) 320mg, PVP
K15(or PVP
K30) 160mg, add ethanol 100ml, be heated to 50 ℃ of dissolvings after, rotary evaporation reclaims ethanol, drain the SPC film, weigh;
3). the preparation solution II: in the SPC film, add the injection water (for SPC film weight 5%), behind the aquation certain hour, add 1 again, 2-propylene glycol 4g, dehydrated alcohol 3.0ml, the dissolving, mixing gets solution II;
4). solution II and solution I is mixed, after stirring, transfer to final volume 10ml with water for injection, mixing, embedding is in the 1ml ampoule respectively, and 100 ℃ of heating sterilization in 30 minutes makes paclitaxel vesicle injection;
5). the vesicle injection dilutes with 0.5% glucose, and (NICOMP380 USA) detected vesicle size, 6 hours intracellular vesicle sizes almost constant (less than 200nm) with laser particle diameter instrument every one hour.
Embodiment 9: paclitaxel vesicle injection preparation method IX
1). preparation solution I: get paclitaxel 200mg, add PEG
4002g makes solution I;
2). preparation soybean phospholipid film: get SPC 320mg, Poloxamer188 (F68) 320mg, PVP
K15(or PVP
K30) 160mg, add ethanol 100ml, be heated to 50 ℃ of dissolvings after, rotary evaporation reclaims ethanol, drain the SPC film, weigh;
3). the preparation solution II: in the SPC film, add the injection water (for SPC film weight 5%), behind the aquation certain hour, add 1 again, 2-propylene glycol 6g, dehydrated alcohol 1.0ml, the dissolving, mixing gets solution II;
4). solution II and solution I is mixed, after stirring, transfer to final volume 10ml with water for injection, mixing, embedding is in the 1ml ampoule respectively, and 100 ℃ of 30 minutes heat sterilizations make paclitaxel vesicle injection;
5). the vesicle injection dilutes with 0.5% glucose, and (NICOMP380 USA) detected vesicle size, 6 hours intracellular vesicle sizes almost constant (less than 200nm) with laser particle diameter instrument every one hour.
Claims (2)
1. paclitaxel vesicle injection, it contains as the paclitaxel of active component and adjuvant, it is characterized in that having following composition and content:
The every ml injection of material content
Paclitaxel Paclitaxel 5mg～50mg
Soybean phospholipid SPC 16mg～32mg
Polyvidone-15 or polyvidone-30 8mg～16mg
Poloxamer-188 16mg～32mg
Polyethylene Glycol-400 100mg～300mg
1,2-propylene glycol 200mg～600mg
Ethanol 0.1ml～0.3ml
The water for injection surplus.
2. according to the preparation method of the paclitaxel vesicle injection of claim 1, comprise the steps:
A. prepare solution I: get paclitaxel 50～500mg, add 1～3g Polyethylene Glycol-400, make solution I;
B. the preparation of soybean phospholipid film: get soybean phospholipid 160～320mg, 160～320mg poloxamer-188,80～160mg polyvidone-15 or polyvidone-30, after ethanol 100ml dissolving, rotary evaporation reclaims ethanol, drain the soybean phospholipid film;
C. prepare solution II: claim the soybean phospholipid film 400～800mg, add injection water 20～40mg, after the mixing, add 1 again, 2-propylene glycol 2～6g, dehydrated alcohol 1～3ml dissolve solution II;
D. solution II and solution I is mixed, after stirring, transfer to final volume 10ml with water for injection, mixing, embedding is in the 1ml ampoule respectively, and 100 ℃ of heating sterilization in 30 minutes makes paclitaxel vesicle injection.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB031050484A CN1303994C (en) | 2003-03-03 | 2003-03-03 | Taxol vesicle injection and its prepn |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB031050484A CN1303994C (en) | 2003-03-03 | 2003-03-03 | Taxol vesicle injection and its prepn |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1526387A CN1526387A (en) | 2004-09-08 |
| CN1303994C true CN1303994C (en) | 2007-03-14 |
Family
ID=34282490
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB031050484A Expired - Lifetime CN1303994C (en) | 2003-03-03 | 2003-03-03 | Taxol vesicle injection and its prepn |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1303994C (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103385877A (en) * | 2013-08-02 | 2013-11-13 | 海南灵康制药有限公司 | Taxol and cimetidine pharmaceutical composition |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101843582B (en) * | 2010-05-18 | 2011-12-21 | 南京工业大学 | taxol nano suspension and preparation method thereof |
| CN115671110B (en) * | 2021-07-30 | 2024-05-10 | 上海云晟研新生物科技有限公司 | Pazopanib oral pharmaceutical composition, preparation method and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1267214A (en) * | 1997-06-27 | 2000-09-20 | 维沃Rx药物公司 | New formulations of medicaments and methods for their preparation and use |
| CN1293570A (en) * | 1999-01-08 | 2001-05-02 | 比奥纽默里克药物公司 | Pharmaceutical formulations of taxanes |
-
2003
- 2003-03-03 CN CNB031050484A patent/CN1303994C/en not_active Expired - Lifetime
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1267214A (en) * | 1997-06-27 | 2000-09-20 | 维沃Rx药物公司 | New formulations of medicaments and methods for their preparation and use |
| CN1293570A (en) * | 1999-01-08 | 2001-05-02 | 比奥纽默里克药物公司 | Pharmaceutical formulations of taxanes |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103385877A (en) * | 2013-08-02 | 2013-11-13 | 海南灵康制药有限公司 | Taxol and cimetidine pharmaceutical composition |
| CN103385877B (en) * | 2013-08-02 | 2014-04-16 | 海南灵康制药有限公司 | Taxol and cimetidine pharmaceutical composition |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1526387A (en) | 2004-09-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105056233B (en) | Multi-functional mesoporous silicon dioxide nano particle with near-infrared photo-thermal and internal fluorescence imaging characteristic and its preparation method and application | |
| CN1234416C (en) | Composition for sustained release of hydrophobic drug and preparation method thereof | |
| KR102203555B1 (en) | Use of polymeric excipients for lyophilization or freezing of particles | |
| ES2509490T3 (en) | Nanodispersion | |
| CN102580111B (en) | Quercetin hydroxypropyl beta-cyclodextrin clathrate liposome, and preparation method thereof and application thereof | |
| CN109771663B (en) | Preparation and application of acid-responsive anticancer nano-drug | |
| Chen et al. | Docetaxel loaded mPEG-PLA nanoparticles for sarcoma therapy: preparation, characterization, pharmacokinetics, and anti-tumor efficacy | |
| CN1840193A (en) | Nanomicelle preparation of anthracycline antitumor antibiotics entrapped in polyethylene glycol derivatized phospholipids | |
| TWI880897B (en) | Intratumor injection formulation | |
| CN102232933A (en) | Tumor-targeting albumin nano-lyophilized powder injection preparation and preparation method thereof | |
| CN1931156A (en) | Nanometer solid taxol lipoid particle and its prepn process | |
| CN103751107A (en) | Nano-particle containing docetaxel and vitamin E TPGS (d-alpha tocopheryl polyethylene glycol 1000 succinate) and preparation method thereof | |
| CN101028251A (en) | Camptothecine derivative phosphatide composite liposome nano-preparation and its making method | |
| CN101057831A (en) | Docetaxel liposome novel preparations and its preparation method | |
| CN1303994C (en) | Taxol vesicle injection and its prepn | |
| CN102166189B (en) | Targeted and fluorescence dual-functional slightly-soluble antitumor medicament nano structural lipid carrier | |
| KR101308746B1 (en) | Preparation of biocompatible polymeric drug delivery system with advanced tumor accumulation | |
| CN1927203A (en) | Nano micelle preparation of Catharanthus roseus alkaloids antineoplastic drugs with coating of phospholipid derived from polyethylene glycol | |
| CN107334745A (en) | Multifunctional nano pharmaceutical carrier and taxanes lipid nano particle and preparation method thereof | |
| JP2011529930A (en) | Injectable taxane pharmaceutical composition | |
| CN106265624A (en) | The treatment pharmaceutical composition of breast carcinoma, drug delivery system and preparation method thereof | |
| CN1931157A (en) | Polyene taxol liposome and its prepn process | |
| CN104840432A (en) | Taxane long-circulating nanoparticles and preparation method thereof | |
| CN101505727A (en) | Pharmaceutical composition for oral administration | |
| CN105963276A (en) | Epothilone B polymer nanoparticle preparation for treating tumors and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CX01 | Expiry of patent term |
Granted publication date: 20070314 |
|
| CX01 | Expiry of patent term |