CN102451157B - The Taxotere alkane submicron emulsion being intermediate carrier with steroid complex - Google Patents
The Taxotere alkane submicron emulsion being intermediate carrier with steroid complex Download PDFInfo
- Publication number
- CN102451157B CN102451157B CN201010529345.8A CN201010529345A CN102451157B CN 102451157 B CN102451157 B CN 102451157B CN 201010529345 A CN201010529345 A CN 201010529345A CN 102451157 B CN102451157 B CN 102451157B
- Authority
- CN
- China
- Prior art keywords
- taxotere
- alkane
- submicronized
- emulsion
- steroid
- 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.)
- Active
Links
Abstract
The invention discloses a kind of Taxotere alkane submicronized emulsion.Submicronized emulsion of the present invention comprises Docetaxel/steroid composite, oil for injection, water for injection, emulsifying agent, co-emulsifier and isotonic agent, and in described Docetaxel/steroid composite, Taxotere alkane and steroid mol ratio are 1: 0.25 ~ 40.The invention also discloses preparation method and the purposes of Taxotere alkane submicronized emulsion.Utilize complex to the improvement of medicine oil-soluble and sterilization stability, Docetaxel/steroid composite is dissolved in oil phase, preparation below mean diameter 400nm, pH are the oil-in-water submicron emulsion of 3.5-6, and stability improves, safer for treating malignant tumor.
Description
Technical field
The present invention relates to a kind of with steroid complex Taxotere alkane submicronized emulsion that is intermediate carrier and preparation method thereof, the invention still further relates to the purposes of this Taxotere alkane submicronized emulsion, belong to pharmaceutical preparations technology field.
Background technology
Taxotere alkyl compound, representative drugs is Docetaxel (docetaxel, Docetaxel, trade name docetaxel) there is important anti-tumor activity, be widely used in the treatment of ovarian cancer, breast carcinoma, nonsmall-cell lung cancer and gastric cancer etc. clinically.Because it is water-soluble hardly, Tween 80 and dehydrated alcohol is adopted to be the concentrated solution that aseptic filtration prepared by solvent for clinical Docetaxel normal injection agent system at present.Because tween easily causes severe allergic reaction, during this product clinical practice, apart from outside contraindication, everyone all must take oral glucocorticoid class in advance before accepting taxotere treatment, as dexamethasone, take before taxotere instils one day, every day 16mg (such as: every day 2 times, each 8mg), continue 3 days.
For Docetaxel injection Problems existing, more than two decades after Docetaxel listing comes, domestic and international pharmaceutics worker has carried out novel medicine-releasing system research widely, the technical scheme related to comprises cyclodextrin clathrate, liposome, polymer micelle, nanoparticle etc., but fail so far to make a breakthrough, commercial preparation is still the normal injection agent of Tween 80 solubilising.
Oil-in-water submicron emulsion is the lipotropy utilizing medicine, and medicine is dissolved in oil phase, take natural phospholipid as emulsifying agent, and the mean diameter obtained through high pressure homogenize emulsifying preparation is in the emulsion of below 600nm.Because medicine is present in interior oil phase, avoid contacting with water and air, insoluble drug is unfavorable for making liquid preparation defect because of the low and poor stability of dissolubility can be overcome.Compared with the technology such as liposome, nanoparticle or polymer micelle, submicron emulsion has more industrialized development advantage, can adopt terminal sterilization, can directly instil clinically, there will not be medicine to analyse to take out in instillation process, safety easy to use.Develop Docetaxel novel formulation using submicron emulsion as carrier and there is good prospect.
Docetaxel (especially midchain oil) dissolubility in oil is higher, be conducive to the preparation of oil-in-water submicronized emulsion, but study discovery further, the oil solution of Docetaxel or the oil-in-water submicron emulsion of Docetaxel all can not resistance to pressure sterilizings, sterilizing rear impurity obviously raises, and limits the terminal sterilization process of submicron emulsion transfusion.Someone once repaid pilot production and gets aseptic filtration mode and prepare submicron emulsion transfusion or freeze-dried emulsion, but for large capacity transfusion, aseptic filtration exists potential safety hazard, cannot be used for clinical treatment.
For improving the sterilization stability of medicine dissolubility and oil solution in oil phase, breaking through the key technology of restriction Docetaxel submicronized emulsion research, the application is studied Docetaxel/lipid complex, to the preparation by lipid complex, medicine and matrix material is made to form complex by intermolecular interaction, improve the dissolubility of medicine in oil or the sterilization stability of oil solution, the research for submicron emulsion preparation provides good intermediate carrier.
Present inventor has carried out following exploratory study: with cholesterol, soybean lecithin (S75), Ovum Gallus domesticus Flavus lecithin (E80), DMPC, DMPG, SPC-3, DSPG for matrix material, rotary evaporation is adopted to prepare Docetaxel lipid complex, with the dissolubility of complex in miscella (soybean oil mixes by 1: 1 equal-volume with midchain oil) for index, investigate the formation of lipid complex to Docetaxel oil-soluble and oil solution improved stability effect.Exploratory study result shows, no matter be natural phospholipid or synthetic phospholipid, the phosphatide complexes of preparation all makes the dissolubility of medicine in oil there occurs reduction in various degree, but also the impurity level after the sterilizing of medicine oil solution is obviously grown tall, and stability declines; And be the complex that matrix material is formed with cholesterol, have certain increasing action to medicine oil-soluble, more meaningfully, the sterilization stability of Docetaxel in oil solution is significantly improved, the impurity after sterilizing is starkly lower than the oil solution of Docetaxel.
Therefore, with steroid lipid complex for intermediate carrier preparation can the Docetaxel submicronized emulsion of terminal sterilization, there is novelty and technical feasibility.
Summary of the invention
An object of the present invention is to provide a kind of Docetaxel submicronized emulsion, it comprises Docetaxel/steroid composite, oil for injection, water for injection, emulsifying agent, co-emulsifier and isotonic agent; Described steroid lipid material is at least one in dissociation sterin, steroid derivatives or steroid ester.Described dissociation sterin is selected from cholesterol, 7-hydrocholesterol (also known as 7-DHC), lanosterol, sitosterol, brassicasterol, mycosterol, Concha Ostreae sterin, stigmasterol, Sitosterolum alcohol and ergosterol, be preferably cholesterol, 7-hydrocholesterol and ergosterol, be more preferably cholesterol; Described steroid derivatives is selected from cholic acid, deoxycholic acid and chenodeoxy cholic acid; Described steroid ester is selected from medium chain fatty acid ester (in carbochain carbon atom 6 ~ 12) and the long-chain fatty acid ester (in carbochain carbon atom more than 12) of steroid, preferred medium chain unsaturated fatty acid ester and long-chain unsaturated ester, more preferably long-chain unsaturated ester.Preferred long-chain unsaturated ester is cholesterol linoleate fat, cholesterol linolenic acid fat, cholesterol palmitate fat, cholesterol acid ester, cholesterol ester stearic acid and cholesterol myristinate, preferred cholesterol acid ester.
The emulsion droplet mean diameter of submicronized emulsion of the present invention at below 400nm, preferred below 300nm; The usage ratio of oil phase is 5% ~ 35% (ml/ml) of described submicronized emulsion total amount, preferably 10% ~ 30% (ml/ml); In Docetaxel, drug loading is 0.25mg/ml ~ 5mg/ml, preferred 0.25mg/ml ~ 2mg/ml.
In the present invention, described Docetaxel/steroid composite can be 1 or 2 preparations as follows,
Method 1 comprises step:
A. Taxotere alkane and steroid are mixed in proportion, add appropriate organic solvent dissolution, optionally add antioxidative stabilizer;
B. stir under suitable temperature conditions, remove organic solvent by rotary evaporation or spraying dry, vacuum drying and get final product;
Method 2 comprises step:
A. get a certain proportion of Taxotere alkane and steroid, add appropriate different organic solvent dissolution respectively, mixed, optionally add antioxidative stabilizer;
B. stir under suitable temperature conditions, remove organic solvent by rotary evaporation or spraying dry, vacuum drying and get final product.
In above-mentioned Docetaxel/steroid composite or its preparation method, the mol ratio of Taxotere alkane and steroid is 1: 0.25 ~ 40, preferably 1: 0.5 ~ 20, more preferably 1: 1 ~ 10.
In the preparation method of above-mentioned Docetaxel/steroid composite, described organic solvent can be selected from dichloromethane, ethanol, methanol, benzyl alcohol, acetone, ethyl acetate, oxolane, the tert-butyl alcohol one or more; Preferably, can be selected from ethanol, acetone, ethyl acetate and oxolane one or more." in right amount " in " appropriate organic solvent " refer to those skilled in the art conveniently technology can determine the amount of the mixture dissolving Docetaxel and steroid, specifically, Docetaxel and steroid complex concentration in the solution calculate with Docetaxel, control at 0.5 ~ 16mg/ml or higher, preferably 1.0 ~ 8.0mg/ml; " suitable temperature conditions " means and controls at 10 DEG C-70 DEG C, preferred 35-55 DEG C, such as 25 DEG C, 35 DEG C, 45 DEG C, 55 DEG C or 70 DEG C.The time of stirring reaction and vacuum drying time can by those skilled in the art conveniently technology determine, the time of such as stirring reaction can be 0.5-3.0 hour, such as 0.5 hour, 1.0 hours, 1.5 hours or 2.0 hours, the vacuum drying time can be 8 hours-48 hours, such as 8 hours, 12 hours, 16 hours or 24 hours.Described antioxidative stabilizer can be selected from least one in sodium sulfite, sodium pyrosulfite, injection Vitamin B_6 DTA and salt, vitamin E and derivant thereof, the consumption of antioxidative stabilizer be this area preparing the consumption usually adopted in lipid complex, be generally no more than 1% (weight) of complex total amount.
In the present invention, described oil for injection is selected from a kind of or their mixture in long-chain oil and midchain oil.The described one of long-chain grease separation in long-chain fatty acid, long-chain fatty acid ester and long-chain fatty alcohol, specifically can be selected from soybean oil, Oleum Ricini, linoleic acid, Semen Maydis oil, olive oil, Oleum Arachidis hypogaeae semen, Oleum Gossypii semen, oleic acid, glyceryl monostearate, glyceryl monooleate, hexadecanol; Described midchain oil is selected from the one in medium-chain fatty acid and medium chain fatty acid ester.Preferred long-chain oil is long-chain fatty acid ester, is in particular injection soybean oil; Preferred midchain oil is medium chain length fatty acid triglyceride.
In the present invention, described emulsifying agent is non-ionic surface active agent or natural surfactant.Non-ionic surface active agent is selected from least one in fatty glyceride, polyoxyethylene aliphatic alcohol ether class, polyoxyethylene sorbitan fatty acid ester, sorbitol and sorbitan fatty acid ester, polyoxyethylene fatty acid ester class, vitamin e derivative class and polyoxy olefin copolymer; Described natural surfactant is selected from least one in Ovum Gallus domesticus Flavus lecithin, fabaceous lecithin, cholesterol and Cholic acids, sodium alginate and chitosan.Preferred emulsifying agent is natural surfactant, and most preferred emulsifying agent is natural Ovum Gallus domesticus Flavus lecithin and soybean lecithin.The content of emulsifying agent in submicronized emulsion of the present invention is the 0.5%-5% (g/ml) of submicronized emulsion total composition, is preferably 1.0%-4.0% (g/ml), is most preferably 1.0%-2.0% (g/ml).
In the present invention, described co-emulsifier is selected from Polyethylene Glycol (PEG) class and poloxamer class.The content of co-emulsifier is the 0%-5% (g/ml) of submicronized emulsion total amount of the present invention, is preferably 0.5%-3% (g/ml), is most preferably 1.0%-2.0% (g/ml).
In the present invention, the osmotic pressure regulator (isotonic agent) of Taxotere alkane submicron emulsion be selected from glycerol, xylitol, sorbitol (sugar) alcohol and mannitol one or more, preferably glycerine and glucose, more preferably glycerol.Glycerol content is the 1.0-3.0% (g/ml) of Docetaxel submicronized emulsion total amount of the present invention, is preferably 1.5-2.5% (g/ml).
In the present invention, described Taxotere alkane submicronized emulsion also can add stabilizing agent, is selected from the one of oleic acid, enuatrol and PEG apoplexy due to endogenous wind, and preferred stabilizing agent is oleic acid and PEG, is more preferably oleic acid.The content of oleic acid is the 0.05-0.5% (g/ml) of Docetaxel submicronized emulsion total amount of the present invention, is preferably 0.1-0.2% (g/ml).
Taxotere alkane submicronized emulsion of the present invention, also can comprise antioxidant, can be selected from vitamin E or vitamin-e ester derivant, preferred vitamin E.
In the present invention, described " a kind of or its mixture " or " at least one " refer to can for the one in selected species, or the mixture of two kinds, or more kinds of mixture.
Another object of the present invention is a kind of preparation method providing Taxotere alkane submicronized emulsion of the present invention, and it comprises the steps:
get water for injection, add emulsifying agent, co-emulsifier and isotonic agent, put dispersion in tissue mashing machine or cutter and make homogeneous aqueous phase, be heated to 40-80 DEG C, insulation;
separately get Docetaxel/steroid composite, be optionally dissolved in together with stabilizing agent in the oil for injection being preheated to 40-80 DEG C, put dispersion in tissue mashing machine or cutter and make homogeneous oil phase;
under agitation, aqueous phase is slowly added in oil phase, 10000-20000 turns/and min shears 5-10min, makes the even colostrum of formation, to be transferred to rapidly in high pressure homogenizer emulsifying to size controlling at below 400nm, preferred below 300nm, collect whole emulsion, with hydrochloric acid joint pH to 3.5-6.0, preferred 4.0-5.0, and add water appropriate (to full dose), to obtain final product.
The present invention also provides the another kind of preparation method of Taxotere alkane submicronized emulsion, and it comprises the steps:
get water for injection, add co-emulsifier and isotonic agent, stir and make aqueous phase, be heated to 40-80 DEG C, insulation;
separately get Docetaxel/steroid composite, emulsifying agent and/or stabilizing agent, be dissolved in the oil for injection being preheated to 40-80 DEG C, put dispersion in tissue mashing machine or cutter and make homogeneous oil phase;
under agitation, aqueous phase is slowly added in oil phase, 10000-20000 turns/and min shears 5-10min, makes the even colostrum of formation, be transferred to rapidly emulsifying in high pressure homogenizer, size controlling is at below 400nm, and preferred 100-300nm, collects whole emulsion, with salt acid for adjusting pH to 3.5-6.0, preferred 4.0-5.0, and add water appropriate (to full dose), to obtain final product.
In the preparation process in accordance with the present invention, in high pressure homogenizer, emulsifying also can adopt other emulsification method to realize, if can emulsifying even, and reach described particle diameter; Temperature 40-80 DEG C can be such as 40 DEG C, 50 DEG C, 60 DEG C, 70 DEG C or 80 DEG C etc.
In the preparation process in accordance with the present invention, regulating the concentration of the hydrochloric acid of pH this area routine can adopt the concentration of hydrochloric acid regulating pH, can be such as 0.1mol/L, or 0.01mol/L; The wherein consumption of water for injection, oil for injection, the ratio of the oil phase of those skilled in the art given by the present invention can be determined completely; " add water appropriate (to full dose) " refers to that except the consumption of the water except adopting when preparing aqueous phase, those skilled in the art add water to reach the consumption of the water of the drug loading met given by the present invention according to routine techniques.
The present invention also provides a kind of preparation, and it comprises Taxotere alkane submicronized emulsion of the present invention, and said preparation can be any operable dosage form clinically, comprises the form of infusion solution or dry emulsion.Infusion solution is wherein prepared by the following method: after Docetaxel submicronized emulsion of the present invention fill, through flowing steam sterilization or the process of pressure sterilizing aseptic processing, to obtain final product; Dry emulsion is wherein prepared by the following method: in Taxotere alkane submicronized emulsion of the present invention, add appropriate proppant, after aseptic filtration process, adopts freeze drying process to make dry emulsion.Preferred proppant is mannitol, the mannitol of such as 5% (w/v).
The present invention also provides Taxotere alkane submicronized emulsion of the present invention preparing the application in cancer therapy drug, and described cancer is solid tumor, comprises ovarian cancer, breast carcinoma, cervical cancer, nonsmall-cell lung cancer, head cancer or neck cancer, esophageal carcinoma, renal carcinoma, hepatocarcinoma and gastric cancer.
In the present invention, if do not pointed out especially, Science and Technology term used herein and title all have understands the identical meaning with one skilled in the art's routine of the present invention; Further, if do not pointed out especially, wherein adopted material and content or ratio, device, instrument, preparation condition etc. are all well-known to those skilled in the art or it can be learnt according to description of the invention.
To illustrate below with reference to accompanying drawings and embodiment elaborates the present invention further, but to it will be appreciated by those skilled in the art that but the present invention is not limited to the preparation method of these embodiments and use.And those skilled in the art can carry out carrying out equivalent replacement, combination, improvement to it or modifying to the present invention according to description of the invention, but these all will comprise within the scope of the invention.
Accompanying drawing explanation
Accompanying drawing 1 (1-A, 1-B): (1-A: initial, stores 3 months for 1-B:4 DEG C the HPLC collection of illustrative plates of the reference Taxotere ethanol submicron emulsion study on the stability under test example 1; Wherein, 2.5 minutes is blank submicron emulsion solvent peak in the past, and the peak of 8.3 ~ 8.4 minutes is Docetaxel, and the chromatographic peak of 2.9,3.3,6.4,7.3,9.8,11.6,15.8 and 17.3 minutes is impurity)
Accompanying drawing 2 (2-A, 2-B): (2-A: initial, stores 3 months for 2-B:4 DEG C the HPLC collection of illustrative plates of the Docetaxel under test example 1/cholesterin complex submicron emulsion study on the stability; Wherein, 2.5 minutes is blank submicron emulsion solvent peak in the past, and the peak of 8.3 ~ 8.4 minutes is Docetaxel, and the chromatographic peak of 2.9,3.3,6.4,7.3,9.8,11.6,15.8 and 17.3 minutes is impurity)
Detailed description of the invention
Embodiment 1 Docetaxel/steroid composite
According to the art of this patent claimed range, according to the form below complex ingredient proportion prepares 2 groups of Docetaxel/cholesterin complexes (mol ratio is 1: 2 and 1: 5), 2 groups of Docetaxel/7-hydrocholesterol complex (mol ratio is 1: 2 and 1: 5), 2 groups of Docetaxel/cholesterol oleate ester complexes (mol ratio is 1: 2 and 1: 5), for the preparation of follow-up submicron emulsion provides intermediate carrier.
Table 1: the composition of Docetaxel/steroid composite and preparation result
Preparation method: get Docetaxel and steroid lipid material in proportion, be together placed in triangular flask, adds acetone 2000ml and is dissolved, stir 1 hour under 40 DEG C of temperature conditions, move in Rotary Evaporators, rotary evaporation removes solvent, through dry 24 hours of 40 DEG C of reduced vacuum and get final product.
Embodiment 2: the Taxotere ethanol submicron emulsion taking Docetaxel/steroid composite as intermediate carrier
Complex 1 ~ the complex 6 appropriate (being equivalent to Docetaxel 100mg) of Example 1 preparation, forms by following prescription 1 ~ prescription 4, prepares 24 groups of submicron emulsion respectively.
[prescription composition]
Component prescription 1 prescription 2 prescription 3 prescription 4
Complex 1 ~ 6 is appropriate
*in right amount
*in right amount
*in right amount
*
Ovum Gallus domesticus Flavus lecithin 2g2.4g3g3g
Poloxamer (188) 1g2g4g6g
Glycerol 5g5g5g5g
Soybean oil 40ml40ml50ml50ml
Water for injection adds to 200ml200ml200ml200ml
Total amount 200ml200ml200ml200ml
*refer in right amount and be equivalent to Docetaxel 100mg, the sample weighting amount of complex then adjusts according to the part by weight of medicine and steroid.
[preparation method]
get water for injection and be about 135ml, add Ovum Gallus domesticus Flavus lecithin, poloxamer (188) and glycerol by recipe quantity, put in tissue mashing machine and disperse, make homogeneous aqueous phase, be heated to 40 DEG C, insulation;
measure soybean oil by recipe quantity, be preheated to 40 DEG C, take Docetaxel cholesterin complex 1 prepared by embodiment 1, be dissolved in the soybean oil of preheating, put dispersion in tissue mashing machine and make homogeneous oil phase;
under agitation, aqueous phase is slowly added in oil phase, shears 5min with 10000 turns/min, make the even colostrum of formation, be transferred to rapidly in high pressure homogenizer, homogenizing 6 times, collect whole emulsion, with 0.1mol/L salt acid for adjusting pH to 4.0 ± 0.5, and add water to 200ml, shake up, subpackage, 115 DEG C of sterilizings 30 minutes, to obtain final product, mean diameter is at 215 ~ 223nm, and Docetaxel drug loading is 0.5mg/ml.
Embodiment 3: the Taxotere ethanol submicron emulsion taking Docetaxel/steroid composite as intermediate carrier
Complex 1 ~ complex 6 appropriate (being equivalent to Docetaxel 100mg) prepared by Example 1, forms by following prescription 5 ~ prescription 8, prepares 24 groups of submicron emulsion.
[prescription composition]
Component prescription 5 prescription 6 prescription 7 prescription 8
Complex 1 ~ 6 is appropriate
*in right amount
*in right amount
*in right amount
*
Ovum Gallus domesticus Flavus lecithin 2g2.4g3g3g
Poloxamer (188) 2.4g4g4g6g
Glycerol 5g5g5g5g
Midchain oil 40ml40ml50ml50ml
Water for injection adds to 200ml200ml200ml200ml
Total amount 200ml200ml200ml200ml
*refer in right amount and be equivalent to Docetaxel 100mg, the sample weighting amount of complex then adjusts according to the part by weight of medicine and steroid.
[preparation method]
get water for injection and be about 130-140ml, add poloxamer (188) and glycerol by recipe quantity, put in tissue mashing machine and disperse, make homogeneous aqueous phase, be heated to 80 DEG C, insulation;
measure soybean oil by recipe quantity, be preheated to 80 DEG C, take complex 2 and Ovum Gallus domesticus Flavus lecithin by recipe quantity, add in the soybean oil of preheating, put the oil phase that dispersing and dissolving in tissue mashing machine makes homogeneous transparent;
under agitation, aqueous phase is slowly added in oil phase, shears 10min with 20000 turns/min, make the even colostrum of formation, be transferred to rapidly in high pressure homogenizer, homogenizing 6 times, collects whole emulsion, with 0.1mol/L salt acid for adjusting pH to 4.5 ± 0.5, and add water to 200ml, shake up, subpackage, 115 DEG C of sterilizings 30 minutes, to obtain final product.Mean diameter is at 187 ~ 195nm, and drug loading, in Docetaxel, is 0.5mg/ml.
Embodiment 4: the Taxotere ethanol submicron emulsion being intermediate carrier with Taxotere alkane/steroid
Complex 1 ~ complex 6 appropriate (being equivalent to Docetaxel 150mg) prepared by Example 1, forms by following prescription 9 ~ prescription 12, prepares 24 groups of submicron emulsion.
[prescription composition]
Component prescription 9 prescription 10 prescription 11 prescription 12
Complex 1 ~ 6 is appropriate
*in right amount
*in right amount
*in right amount
*
Soybean phospholipid 2.4g2.4g2.4g3.0g
Poloxamer (188) 3g3g4g4g
Glycerol 5g5g5g5g
Oil mixture
*40ml40ml40ml50ml
Water for injection adds to 200ml200ml200ml200ml
Total amount 200ml200ml200ml200ml
*refer in right amount and be equivalent to Docetaxel 150mg, the sample weighting amount of complex then adjusts according to the part by weight of medicine and steroid.
*oil mixture is the mixture of soybean oil/midchain oil (volume ratio 1: 1).
[preparation method]
With embodiment 3.Mean diameter is at 133 ~ 145nm, and drug loading, in Docetaxel, is 0.75mg/ml.
Embodiment 5: the Taxotere ethanol submicron emulsion being intermediate carrier with Taxotere alkane/steroid
Complex 1,3 ~ 6 appropriate (being equivalent to Docetaxel 200mg) prepared by Example 1, forms by following prescription 13 ~ prescription 16, prepares 20 groups of submicron emulsion.
[prescription composition]
Component prescription 13 prescription 14 prescription 15 prescription 16
Complex 1,3 ~ 6 is appropriate
*in right amount
*in right amount
*in right amount
*
Soybean phospholipid 2.4g2.4g2.4g3.0g
Poloxamer (188) 3g3g4g4g
Glycerol 5g5g5g5g
Vitamin e1 0mg20mg30mg40mg
Oil mixture
*40ml40ml40ml50ml
Water for injection adds to 200ml200ml200ml200ml
Total amount 200ml200ml200ml200ml
*refer in right amount and be equivalent to Docetaxel 200mg, the sample weighting amount of complex then adjusts according to the part by weight of medicine and steroid.
*oil mixture is the mixture of soybean oil/midchain oil (volume ratio 1: 1).
[preparation method]
With embodiment 3, wherein vitamin E adds in oil phase.
Obtained submicron emulsion mean diameter is at 130 ~ 140nm, and drug loading, in Docetaxel, is 1.0mg/ml.
Embodiment 6: the Taxotere ethanol submicron emulsion being intermediate carrier with Taxotere alkane/steroid
The complex 2 of Example 1 preparation is appropriate respectively, forms, prepare 4 groups of submicron emulsion by following prescription 17 ~ prescription 20.
[prescription composition]
Component prescription 17 prescription 18 prescription 19 prescription 20
Complex 2 is appropriate
17*in right amount
18*in right amount
19*in right amount
20*
Soybean phospholipid 2.4g2.4g2.4g3.0g
Poloxamer (188) 3g3g3g3g
Glycerol 5g5g5g5g
Vitamin E 30mg40mg50mg60mg
Oil mixture
*40ml40ml40ml50ml
Water for injection adds to 200ml200ml200ml200ml
Total amount 200ml200ml200ml200ml
17*in right amount,
18*in right amount,
19*in right amount,
20*refer to that the amount that the sample weighting amount of complex is equivalent to Docetaxel is respectively 200mg, 300mg, 400mg and 600mg in right amount.
*oil mixture is the mixture of soybean oil/midchain oil (volume ratio 1: 1).
[preparation method]
With embodiment 3, wherein vitamin E adds in oil phase.
The submicron emulsion mean diameter of preparation is at 130 ~ 140nm, and drug loading, in Docetaxel, is respectively 1.0mg/ml, 1.5mg/ml, 2.0mg/ml, 3.0mg/ml.
Embodiment 7: the dry emulsion being intermediate carrier with Docetaxel cholesterin complex
The each 50ml of submicron emulsion of sterilized prepared by Example 5, adds 3% (w/v) mannitol and is stirred to dissolve, through 0.2 μm of filtering with microporous membrane, carry out lyophilization, obtain dry emulsion.
Test example 1 reference submicron emulsion compares with cholesterin complex submicron emulsion stability
The preparation of reference submicron emulsion
Get Docetaxel, form and preparation method by the prescription 17 of embodiment 6, prepare the reference submicronized emulsion that drug loading is the Docetaxel of 1.0mg/ml, for comparative study.Prescription is composed as follows:
Component recipe quantity
Docetaxel 200mg
Soybean phospholipid 2.4g
Poloxamer (188) 3g
Glycerol 5g
Vitamin E 30mg
Oil mixture
*40ml
Water for injection adds to 200ml
Total amount 200ml
The study on the stability of submicronized emulsion with compare
The reference submicronized emulsion of 4 groups of submicronized emulsions (Emulsion of prescription 17 ~ prescription 20) prepared by Example 6 and Docetaxel prepared by test example 1, store 3 months respectively under 4 DEG C of conditions, investigate the change of outward appearance, particle diameter, content and impurity according to following method.
Character: visual method, by the color describing submicronized emulsion in kind, whether recording surface has oil droplet or lamination.
Particle diameter: get submicronized emulsion, adopts MASTERSIZER2000 laser granulometry (MALVERN) to measure particle diameter.
Content and related substance: it is appropriate that precision measures Docetaxel submicronized emulsion, add dehydrated alcohol breakdown of emulsion and be diluted to the test solution of suitable concn.Precision measures test liquid 20 μ L injecting chromatograph, according to HPLC method, be chromatographic column with Kromasil-C18 (300mm × 4.6mm, 5 μm), acetonitrile-water (54: 46) is mobile phase, flow velocity 1.0mL/min, determined wavelength 230nm, column temperature is room temperature, measure in accordance with the law, record chromatogram, calculates Emulsion drug content according to peak area by external standard method, calculates impurity content by normalization method.
Measurement result: refer to following table.
Table 2 submicronized emulsion stability comparative result
With the submicronized emulsion that steroid complex of the present invention is prepared for intermediate carrier, no matter be physical stability or chemical stability, be all obviously better than the reference submicronized emulsion of Docetaxel.
Test example 2: Docetaxel submicronized emulsion sensitization is tested
Trial drug:
Test medicine solution: the submicronized emulsion that the prescription 17 of embodiment 6 is obtained;
Reference preparation solution: commercially available docetaxel injection (specification is 20mg:0.5mg), first dissolves with the solvent 1.5ml given as an addition before use, then to make containing Taxotere determining alcohol with normal saline dilution be the solution of 1.5mg/ml;
Positive control drug solns: the ovalbumin of 1.0%;
Blank emulsion solution: according to the prescription 14 of embodiment 6, do not add Docetaxel cholesterin complex, prepare blank emulsion;
Blank solvent: Tween 80 mixes by 1: 1 (v/v) with dehydrated alcohol, obtains (simulate the prescription of commercially available docetaxel injection, wherein do not add Docetaxel), faces used time normal saline dilution;
Experimental animal:
Cavia porcellus, body weight 300g ± 20g, male and female half and half.
Test method:
Get healthy guinea pig 30, body weight 300g ± 20g, be divided into 5 groups at random, often organize 6, male and female half and half.Before on-test, animal raises 1 week in advance to observe its active performance.Lumbar injection test medicine solution (submicronized emulsion group), reference preparation solution (reference preparation group), positive control solution (positive controls), blank emulsion (blank emulsion group) and blank solvent (blank solvent group) each 0.3ml next day of each group of Cavia porcellus, inject 3 times altogether, make its sensitization, wherein the Docetaxel dosage of test medicine group is 1.6mg/kg; 12d after last time administration, each treated animal is intravenous injection test medicine solution, reference preparation solution, positive control solution, blank emulsion and each 1.0ml of blank solvent respectively, excite, wherein the Docetaxel booster dose of test medicine group is 5mg/kg.Observe the reaction of each group of animal of Cavia porcellus after intravenous injection, the results are shown in following table.
Table 3: Taxotere ethanol submicron emulsion sensitivity test
Result shows, strong anaphylaxis all appears in commercially available docetaxel injection and blank solvent group thereof, and Docetaxel submicronized emulsion and blank submicronized emulsion group are all without obvious symptoms of allergic.
Claims (26)
1. a Taxotere alkane submicronized emulsion, it is characterized in that, it comprises Docetaxel/steroid complex, oil for injection, water for injection, emulsifying agent, co-emulsifier and isotonic agent, and in described Docetaxel/steroid complex, the mol ratio of Docetaxel and steroid is 1: 0.25 ~ 2.
2. Taxotere alkane submicronized emulsion according to claim 1, it is characterized in that, described steroid is at least one in dissociation sterin, steroid derivatives or steroid ester, and described steroid derivatives is selected from cholic acid, deoxycholic acid and chenodeoxy cholic acid.
3. Taxotere alkane submicronized emulsion according to claim 2, it is characterized in that, described dissociation sterin is selected from cholesterol, 7-hydrocholesterol, lanosterol, sitosterol, Semen Allii Tuberosi sterin, mycosterol, Concha Ostreae sterin, stigmasterol, Sitosterolum and ergosterol;
Described steroid ester is selected from the saturated or unsaturated fatty acid ester of saturated or unsaturated fatty acid ester or steroid the long-chain of medium chain of steroid, carbon atom in wherein said medium chain fatty acid ester in carbochain is 6-12, and the carbon atom in described long-chain fatty acid ester in carbochain is more than 12.
4. Taxotere alkane submicronized emulsion according to claim 3, described steroid ester is selected from medium chain unsaturated fatty acid ester and long-chain unsaturated ester.
5. Taxotere alkane submicronized emulsion according to claim 3, it is characterized in that, described steroid ester is cholesterol linoleate fat, cholesterol linolenic acid fat, cholesteryl palmitat, cholesterol ester stearic acid, cholesterol myristinate and cholesterol acid ester.
6. the Taxotere alkane submicronized emulsion according to any one of Claims 1 to 5, it is characterized in that, the emulsion droplet mean diameter of described submicronized emulsion is at below 400nm, the usage ratio of oil phase is 5% ~ 35% (ml/ml) of described submicronized emulsion total amount, in Docetaxel, drug loading is 0.25mg/ml ~ 5mg/ml.
7. Taxotere alkane submicronized emulsion according to claim 6, it is characterized in that, described emulsion droplet mean diameter is at below 300nm, and the usage ratio of described oil phase is 10% ~ 30% (ml/ml), in Docetaxel, drug loading is 0.25mg/ml ~ 2mg/ml.
8. the Taxotere alkane submicronized emulsion according to any one of Claims 1 to 5, is characterized in that, described oil for injection be selected from long-chain oil and midchain oil in one or its mixture; Described long-chain grease separation is from long-chain fatty acid, long-chain fatty acid ester and long-chain fatty alcohol; Described midchain oil is selected from medium-chain fatty acid, medium chain fatty acid ester and medium-chain fatty alcohol.
9. Taxotere alkane submicronized emulsion according to claim 8, is characterized in that, described oil for injection is long-chain fatty acid ester or medium chain length fatty acid triglyceride.
10. the Taxotere alkane submicronized emulsion according to any one of claim 1 to 5, is characterized in that, described emulsifying agent is non-ionic surface active agent or natural surfactant; Described non-ionic surface active agent is selected from least one in fatty glyceride, polyoxyethylene aliphatic alcohol ether class, polyoxyethylene sorbitan fatty acid ester, sorbitol and sorbitan fatty acid ester, polyoxyethylene fatty acid ester class, vitamin E and polyoxy olefin copolymer; Described natural surfactant is selected from least one in Ovum Gallus domesticus Flavus lecithin, fabaceous lecithin, cholesterol and Cholic acids, sodium alginate and chitosan.
11. Taxotere alkane submicronized emulsions according to claim 10, it is characterized in that, described natural surfactant is selected from Ovum Gallus domesticus Flavus lecithin and soybean phospholipid.
12. Taxotere alkane submicronized emulsions according to any one of Claims 1 to 5, it is characterized in that, the content of described emulsifying agent is the 0.5%-5% (g/ml) of described submicronized emulsion total amount.
13. Taxotere alkane submicronized emulsions according to claim 12, is characterized in that, the content of described emulsifying agent is the 1.0%-4.0% (g/ml) of described submicronized emulsion total amount.
14. Taxotere alkane submicronized emulsions according to claim 12, is characterized in that, the content of described emulsifying agent is the 1.0%-2.0% (g/ml) of described submicronized emulsion total amount.
15. Taxotere alkane submicronized emulsions according to any one of Claims 1 to 5, it is characterized in that, described co-emulsifier is selected from least one in Polyethylene Glycol (PEG) class and PLURONICS F87.
16. Taxotere alkane submicronized emulsions according to claim 15, is characterized in that, the content of described co-emulsifier is the 0%-5% (g/ml) of described submicronized emulsion total amount.
17. Taxotere alkane submicronized emulsions according to any one of Claims 1 to 5, is characterized in that, described isotonic agent is one or more in glycerol, xylitol, sorbitol and mannitol.
18. Taxotere alkane submicronized emulsions according to any one of Claims 1 to 5, it is characterized in that, it also comprises stabilizing agent, is selected from the one in oleic acid, enuatrol and PEG.
19. Taxotere alkane submicronized emulsions according to any one of Claims 1 to 5, it is characterized in that, it also comprises antioxidant, and antioxidant is vitamin E or vitamin-e ester.
The preparation method of 20. 1 kinds of Taxotere alkane submicronized emulsions any one of claim 1 to 19, is characterized in that, comprise the steps:
Get water for injection, add emulsifying agent, co-emulsifier and isotonic agent, put dispersion in tissue mashing machine or cutter and make homogeneous aqueous phase, be heated to 40-80 DEG C, insulation;
Another by Docetaxel and steroid, mix in described ratio, add appropriate organic solvent dissolution, stir under suitable temperature conditions, remove organic solvent, vacuum drying obtains complex, gets Docetaxel/steroid complex, optionally be dissolved in together with stabilizing agent in the oil for injection being preheated to 40-80 DEG C, put dispersion in tissue mashing machine or cutter and make homogeneous oil phase;
Under agitation, aqueous phase is slowly added in oil phase, 5-10min is sheared with 10000-20000 rev/min, make the even colostrum of formation, be transferred to rapidly emulsifying in high pressure homogenizer, size controlling is at below 400nm, collect whole emulsion, with salt acid for adjusting pH to 3.5-6.0, and it is appropriate to add water, and to obtain final product.
21. preparation methoies according to claim 20, is characterized in that, described size controlling is at below 300nm.
The preparation method of 22. 1 kinds of Taxotere alkane submicronized emulsions any one of claim 1 to 19, is characterized in that, adopts following steps:
Get water for injection, add co-emulsifier and isotonic agent, stir and make aqueous phase, be heated to 40-80 DEG C, insulation;
Another by Docetaxel and steroid, mix in described ratio, add appropriate organic solvent dissolution, stir under suitable temperature conditions, remove organic solvent, vacuum drying obtains complex, gets Docetaxel/steroid complex and emulsifying agent, be dissolved in the oil for injection being preheated to 40-80 DEG C, put dispersion in tissue mashing machine or cutter and make homogeneous oil phase;
Under agitation, be slowly added in oil phase by aqueous phase, high-speed stirred is sheared and is made the even colostrum of formation, be transferred to rapidly emulsifying in high pressure homogenizer, size controlling, at below 400nm, collects whole emulsion, with salt acid for adjusting pH to 3.5-6.0, and add water to appropriate, to obtain final product.
23. preparation methoies according to claim 22, is characterized in that, described size controlling is at 100-300nm.
24. 1 kinds of preparations, it comprises the Taxotere alkane submicronized emulsion any one of claim 1 to 19, and said preparation is the form of infusion solution or dry emulsion.
The preparation method of 25. preparations according to claim 24, it is characterized in that, infusion solution is wherein prepared by the following method: by the Taxotere alkane submicronized emulsion any one of claim 1 to 19 through logical steam sterilization or the process of pressure sterilizing aseptic processing, fill, to obtain final product; Dry emulsion is wherein prepared by the following method: in the Taxotere alkane submicronized emulsion any one of claim 1 to 19, add appropriate proppant, after aseptic filtration process, adopts freeze drying process to make dry emulsion.
The application in the medicine of preparation treatment ovarian cancer, breast carcinoma, nonsmall-cell lung cancer, head cancer or neck cancer, hepatocarcinoma and gastric cancer of the preparation of 26. Taxotere alkane submicronized emulsions according to any one of claim 1-19 or claim 24.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010529345.8A CN102451157B (en) | 2010-10-28 | 2010-10-28 | The Taxotere alkane submicron emulsion being intermediate carrier with steroid complex |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010529345.8A CN102451157B (en) | 2010-10-28 | 2010-10-28 | The Taxotere alkane submicron emulsion being intermediate carrier with steroid complex |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102451157A CN102451157A (en) | 2012-05-16 |
| CN102451157B true CN102451157B (en) | 2016-04-13 |
Family
ID=46035101
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201010529345.8A Active CN102451157B (en) | 2010-10-28 | 2010-10-28 | The Taxotere alkane submicron emulsion being intermediate carrier with steroid complex |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102451157B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103356641A (en) * | 2013-04-23 | 2013-10-23 | 福建省创欣生物科技有限公司 | Compound for inhibiting p-glycoprotein |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101396343A (en) * | 2007-09-26 | 2009-04-01 | 中国医学科学院药物研究所 | Paclitaxel submicron emulsion using lipid composite as middle carrier |
| CN101524329A (en) * | 2007-09-20 | 2009-09-09 | 中国医学科学院药物研究所 | Bicyclo-ethanol submicron emulsion and preparation method thereof |
-
2010
- 2010-10-28 CN CN201010529345.8A patent/CN102451157B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101524329A (en) * | 2007-09-20 | 2009-09-09 | 中国医学科学院药物研究所 | Bicyclo-ethanol submicron emulsion and preparation method thereof |
| CN101396343A (en) * | 2007-09-26 | 2009-04-01 | 中国医学科学院药物研究所 | Paclitaxel submicron emulsion using lipid composite as middle carrier |
| CN101396346A (en) * | 2007-09-26 | 2009-04-01 | 中国医学科学院药物研究所 | Paclitaxel lipid composite |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102451157A (en) | 2012-05-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102686217B (en) | Submicro emulsion of paclitaxel using steroid complex as intermediate carrier | |
| TWI290052B (en) | Emulsion vehicle for poorly soluble drugs | |
| CA1333993C (en) | Drug carriers | |
| CN103764127B (en) | The sustained release lipid preconcentrate of pharmacological active substance and the pharmaceutical composition containing it | |
| CN101909614B (en) | Nanodispersion | |
| CN104427976B (en) | Hydrophobic depot formulations of active ingredient and preparation method thereof | |
| CN103110579B (en) | Alprostadil injection | |
| CN101396346B (en) | Paclitaxel lipid composite | |
| CN102448441B (en) | Pharmaceutical solution of taxanes comprising ph regulator and preparation method thereof | |
| CN101366697A (en) | Novel nano-lipid carrier for injection embodying paclitaxel series substances and preparation method thereof | |
| WO2016177346A1 (en) | Cabazitaxel fat emulsion injection, and preparation method and use thereof | |
| WO2010127541A1 (en) | A nano-emulsion injection of vinca alkaloids and the preparation method thereof | |
| WO2022160971A1 (en) | Concentrate containing poorly soluble drug, and emulsion prepared therefrom | |
| CN102811706B (en) | Paclitaxel/steroidal Complex | |
| CN103381142A (en) | Ginsenoside Rh1 self-microemulsion composition, and preparation method and application thereof | |
| Shailendrakumar et al. | Improved oral pharmacokinetics of pentoxifylline with palm oil and capmul® mcm containing self-nano-emulsifying drug delivery system | |
| CN102451176B (en) | Docetaxel/steroid composite | |
| CN102552134B (en) | Fat emulsion containing vitamin K1 | |
| CN104997759B (en) | A kind of total toadpoison lactone solid lipid nano granule drug delivery system of injection and preparation method thereof | |
| CN105534904B (en) | Docetaxel for Injection composition and preparation method thereof | |
| CN102451157B (en) | The Taxotere alkane submicron emulsion being intermediate carrier with steroid complex | |
| CN104958267A (en) | Huperzine-a lipid micro-sphere preparation | |
| CN102038636B (en) | Taxane medicine solution containing chelating agent and preparation method thereof | |
| CN104524583B (en) | Artificial chyle carries drug composition and preparation method thereof and purposes | |
| CN105287376A (en) | Alprostadil injection 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 |