CN102451176A - Docetaxel/steroid composite - Google Patents
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- CN102451176A CN102451176A CN2010105293424A CN201010529342A CN102451176A CN 102451176 A CN102451176 A CN 102451176A CN 2010105293424 A CN2010105293424 A CN 2010105293424A CN 201010529342 A CN201010529342 A CN 201010529342A CN 102451176 A CN102451176 A CN 102451176A
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Abstract
The invention discloses a docetaxel/steroid composite. The docetaxel/steroid composite is prepared by compounding docetaxel with a steroid lipid material, wherein the molar rate of the docetaxel to the steroid is 1: (0.25-40). The invention also discloses a preparation method of the docetaxel/steroid composite and application of the docetaxel/steroid composite to preparation of a submicron emulsion, a dry emulsion, a self-microemulsion and a solid oral preparation. The docetaxel and the steroid are combined by intermolecular chemical bonds to form the composite, thus solubility in oil and sterilization stability are increased, and a favorable intermediate carrier is provided for preparation of a stable novel emulsion and an oral preparation with high bioavailability.
Description
Technical field
The present invention relates to a kind of how western taxane/steroid complex and preparation method thereof, the invention still further relates to the purposes of taxane/steroid complex, belong to the pharmaceutical preparations technology field.
Background technology
Many western bearing taxanes, representative drugs are that Docetaxel (is claimed Docetaxel again, docetaxel; Docetaxel; The trade name docetaxel), has 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, being used for clinical Docetaxel normal injection agent system employing Tween 80 and dehydrated alcohol at present is the concentrated solution that solvent prepares aseptic filtration.Because Tween 80 is prone to cause severe allergic reaction, except that contraindication was arranged, everyone is equal oral glucocorticoid class in advance before accepting the taxotere treatment; Like dexamethasone, before taxotere instiled one day, take, every day 16mg (for example: every day 2 times; Each 8mg), continue 3 days.
Problem to the existence of Docetaxel injection; More than two decades after the Docetaxel listing comes; The pharmaceutics worker has carried out novel widely medicine-releasing system research both at home and abroad; The technical scheme that relates to comprises cyclodextrin clathrate, liposome, polymer micelle, nanoparticle etc., but fails so far to make a breakthrough, and the commercial preparation still is the normal injection agent of Tween 80 solubilising.
The oil-in-water submicron emulsion is the lipotropy that utilizes medicine, and medicine is dissolved in oil phase, is emulsifying agent with the natural phospholipid, the emulsion of mean diameter below 600nm that obtains through high pressure homogenize emulsifying preparation.Because medicine is present in interior oil phase, avoids contacting with water and air, can overcomes insoluble drug and hang down the defective that is unfavorable for processing liquid preparation with poor stability because of dissolubility.With compared with techniques such as liposome, nanoparticle or polymer micelles, submicron emulsion has more the industrialized development advantage, can adopt terminal sterilization, can directly instil clinically, can in quiet process, not separate out medicine, safety easy to use.Has good prospect with submicron emulsion as carrier development Docetaxel novel formulation.
Docetaxel (especially midchain oil) dissolubility in oil is higher; Help the preparation of oil-in-water submicron emulsion; But further discover; The oil-in-water submicron emulsion of the oil solution of Docetaxel or Docetaxel all can not heat-resisting pressure be sterilized, and the sterilization rear impurity obviously raises, and has limited the terminal sterilization of submicron emulsion transfusion and has handled.Someone once repaid pilot production and gets the aseptic filtration mode and prepare submicron emulsion transfusion or freeze-dried emulsion, but for large capacity transfusion, there is potential safety hazard in aseptic filtration, can't be used for clinical treatment.
For the sterilization stability that improves medicine dissolubility and oil solution in oil phase, break through the key technology that limits the research of Docetaxel submicronized emulsion; The application studies Docetaxel/lipid complex; In the hope of preparation through lipid complex; Make medicine and matrix material form complex, improve the dissolubility of medicine in oil or the sterilization stability of oil solution, for the research of submicron emulsion preparation provides good intermediate carrier through intermolecular interaction.
The present inventor has carried out following exploratory study: with cholesterol, soybean lecithin (S75), Ovum Gallus domesticus Flavus lecithin (E80), DMPC, DMPG, SPC-3, DSPG is matrix material; Adopt the rotary evaporation legal system to be equipped with the Docetaxel lipid complex; With the dissolubility of complex in miscella (soybean oil mixes by 1: 1 equal-volume with midchain oil) is index, and the formation of investigating lipid complex is to Docetaxel oil-soluble and oil solution improved stability effect.Exploratory study is the result show; No matter be natural phospholipid or synthetic phospholipid; The phosphatide complexes of preparation all makes the dissolubility of medicine in oil that reduction has in various degree taken place, but also makes the impurity level after the sterilization of medicine oil solution obviously raise stability decreases; And be the complex that matrix material forms with the cholesterol, the medicine oil-soluble there is certain increase effect, more meaningfully, the sterilization stability of Docetaxel in oil solution obviously improved, the impurity after the sterilization is starkly lower than the oil solution of Docetaxel.
Therefore, through the preparation of how western taxane/steroid lipid complex, being expected to provides good intermediate carrier for the research of Docetaxel terminal sterilization submicronized emulsion.
Summary of the invention
One object of the present invention is to provide a kind of how western taxane/steroid complex, and it is composited by how western taxane and steroid.The mol ratio of many western taxanes and steroid is 1: 0.25～40, preferred 1: 0.5～20, more preferably 1: 1～10.
Of the present invention how western taxane/steroid complex is characterized in that, described how western taxane is any in Docetaxel or the Docetaxel derivant, preferred Docetaxel; Described steroid matrix material is at least a in dissociation sterin, steroid derivatives or the steroid ester.
Described dissociation sterin is selected from cholesterol, 7-hydrocholesterol (claiming the 7-dehydrocholesterol again), lanosterol, sitosterol, Semen Allii Tuberosi sterin, mycosterol, Concha Ostreae sterin, stigmasterol, Sitosterolum and ergosterol; Preferred cholesterol, 7-hydrocholesterol and ergosterol, more preferably cholesterol; Described steroid derivatives is selected from cholic acid, deoxycholic acid and chenodeoxy cholic acid; Described steroid ester is selected from the saturated or unsaturated fatty acid ester (carbon atom is 12～26 in the carbochain) of medium chain long-chain saturated or unsaturated fatty acid ester (carbon atom is 6～12 in the carbochain) or steroid of steroid; The preferred undersaturated fatty acid ester of medium chain and the undersaturated fatty acid ester of long-chain, more preferably long-chain unsaturated fatty acid ester.
Preferred long-chain unsaturated fatty acid ester is cholesterol linoleic acid fat, cholesterol linolenic acid fat, cholesterol palmitic acid lipid, cholesterol acid ester, cholesterol ester stearic acid and cholesterol myristinate, more preferably cholesterol acid ester and cholesterol cetylate.
Of the present invention how western taxane/steroid complex can also contain antioxidative stabilizer.
Said antioxidative stabilizer is selected from least a in sodium sulfite, sodium pyrosulfite, vitamin C, EDTA and salt thereof, vitamin E and the derivant thereof.
Another object of the present invention is to provide the method for preparing of of the present invention how western taxane/steroid complex, and said how western taxane/steroid complex can be according to following method 1 or 2 preparations.
A. with how western taxane and steroid proportional mixing, add an amount of organic solvent dissolution, randomly add antioxidative stabilizer;
B. under suitable temperature conditions, stir, remove organic solvent, vacuum drying promptly gets.
A. with how western taxane and steroid, add an amount of different organic solvent dissolution respectively,, randomly add antioxidative stabilizer its mixing;
B. under suitable temperature conditions, stir, remove organic solvent through rotary evaporation or spray drying, vacuum drying promptly gets.
In method for preparing of the present invention, said organic solvent can be selected from one or more in dichloromethane, ethanol, methanol, benzyl alcohol, acetone, ethyl acetate, oxolane, the tert-butyl alcohol; Preferably, can be selected from ethanol, acetone, ethyl acetate and the oxolane one or more.When selecting multiple organic solvent for use, it is meant the mixture of selected organic solvent.
In method for preparing of the present invention, the removal of organic solvent realizes through rotary evaporation or spray drying.
In method for preparing of the present invention; " proportional mixing " is meant according to the above-mentioned how western taxane that provides of the application and the mixed of steroid; The mol ratio of promptly how western taxane and steroid is 1: 0.25～40, preferred 1: 0.5～20, more preferably 1: 1～10; " in right amount " in " appropriate amount of organic " is meant that those skilled in the art can confirm to be used to dissolve the amount of the mixture of how western taxane and steroid according to routine techniques; Such as; Many western taxanes and the concentration of steroid complex in solution are calculated with Docetaxel; Can be 0.5～16mg/ml or higher, preferred 1.0～8.0mg/ml; " suitable temperature conditions " means that temperature can be at 25 ℃-70 ℃, preferred 35-55 ℃, and for example 25 ℃, 35 ℃, 45 ℃, 55 ℃ or 70 ℃.
In method for preparing of the present invention; The time of stirring reaction and vacuum drying time can be confirmed according to routine techniques by those skilled in the art; Time such as stirring reaction can be 0.5-3.0 hour; For example 0.5 hour, 1.0 hours, 1.5 hours or 2.0 hours, the vacuum drying time can be 8 hours to 48 hours, for example 8 hours, 12 hours, 16 hours or 24 hours.
In method for preparing of the present invention; Can consider to add an amount of antioxidative stabilizer; The antioxidative stabilizer consumption is the consumption that adopt in the preparation lipid complex usually this area, generally is no more than 1% (weight) of Docetaxel and cholesterol weight sum.
The present invention also provides the application of of the present invention how western taxane/steroid complex in preparation oil-in-water type submicronized emulsion, dry emulsion, self-microemulsion system or oral formulations.Wherein oil-in-water submicron emulsion preparation or dry emulsion prepare through of the present invention how western taxane/steroid complex is dissolved in oil phase; It can be used for the clinical treatment of tumor through drug administration by injection; The said preparation drug loading is high, good stability; And tween 80 not in the prescription, safety is superior to commercially available injection.The self-microemulsion system is through of the present invention how western taxane/steroid complex is dissolved in oil phase; Adding proper amount of surfactant (emulsifying agent), cosurfactant (co-emulsifier) prepare; It can be used for the clinical treatment of tumor through injection, mucosa or oral administration.Oral formulations; Particularly solid preparation is such as capsule or tablet etc.; Be through with of the present invention how western taxane/steroid complex; The pharmaceutical excipient that allows on the adding pharmaceutics prepares, but the clinical treatment of the tumor that its administered through oral is administered for has higher bioavailability.
The present invention also provides the application of of the present invention how western taxane/steroid complex in the preparation cancer therapy drug, and described cancer is selected from ovarian cancer, breast carcinoma, nonsmall-cell lung cancer, gastric cancer.
In the present invention, if do not point out especially, Science and Technology term used herein and title all have and the identical meaning of the conventional understanding of one skilled in the art of the present invention; And, if do not point out especially, material that is wherein adopted and content thereof or ratio, device, instrument, preparation condition etc. all well-known to those skilled in the art or its can learn according to description of the invention.
Further elaboration the present invention in detail of explanation and embodiment below with reference to accompanying drawings still it will be appreciated by those skilled in the art that but the present invention is not limited to the method for preparing of these embodiment and use.And those skilled in the art can carry out it is equal to replacement, combination, improvement or modification according to description of the invention to the present invention, but these all will comprise within the scope of the invention.
Description of drawings
Accompanying drawing 1 (1-A, 1-B): (1-A is for before sterilizing, after 1-B is sterilization for HPLC collection of illustrative plates before and after the Docetaxel oil solution sterilization of Test Example 1; Wherein, 2.5 minutes was the oil solvent peak in the past, and 8.7～8.8 minutes is the Docetaxel peak, was impurity peaks in 3.4,6.7,14.3 and 16.9 minutes)
Accompanying drawing 1 (2-A, 2-B): (2-A is for before sterilizing, after 2-B is sterilization for HPLC collection of illustrative plates before and after the Docetaxel oil solution sterilization of Test Example 1; Wherein, 2.5 minute be the oil solvent peak in the past, 8.1～8.2 minutes is the Docetaxel peak, is impurity peaks in 3.4,6.7 and 16.9 minutes)
The specific embodiment
Preparation embodiment
Get Docetaxel 5.0g, cholesterol 0.60g places Rotary Evaporators, adds acetone 600ml it is dissolved, and under 40 ℃ temperature, stirs 1 hour, moves in the Rotary Evaporators, and the rotary evaporation method is removed solvent, promptly gets in dry 12 hours through 40 ℃ of reduced vacuum.
Get Docetaxel 5.0g, cholesterol 1.20g places Rotary Evaporators, adds oxolane 2000ml it is dissolved; Under 25 ℃ temperature, stirred 1 hour; Move in the Rotary Evaporators, the rotary evaporation method is removed solvent, promptly gets in dry 12 hours through 25 ℃ of reduced vacuum.
Embodiment 3 Docetaxel cholesterol complex
Get Docetaxel 5.0g, cholesterol 2.40g places triangular flask, adds oxolane 3000ml it is dissolved; Under 45 ℃ of temperature conditions, stirred 1.5 hours; Move in the Rotary Evaporators, the rotary evaporation method is removed solvent, promptly gets in dry 16 hours through 45 ℃ of reduced vacuum.
Get Docetaxel 5.0g, cholesterol 11.98 places triangular flask, vitamin E 0.05g; Add acetone 1000ml it is dissolved, under 35 ℃ of temperature conditions, stirred 1 hour, move in the Rotary Evaporators; The rotary evaporation method is removed solvent, promptly gets in dry 10 hours through 35 ℃ of reduced vacuum.
Embodiment 5 Docetaxel cholesterol complex
Get Docetaxel 5.0g, cholesterol 23.95g places triangular flask, vitamin E 0.05g; Add acetone 3000ml it is dissolved, under 50 ℃ of temperature conditions, stirred 2 hours, move in the Rotary Evaporators; The rotary evaporation method is removed solvent, promptly gets in dry 15 hours through 50 ℃ of reduced vacuum.
Get Docetaxel 5.0g, cholesterol 47.91g places triangular flask, and the ethyl acetate that adds 5000ml is dissolved it; Under 55 ℃ of temperature conditions, stirred 1 hour; Move in the Rotary Evaporators, the rotary evaporation method is removed solvent, promptly gets in dry 15 hours through 40 ℃ of reduced vacuum.
Embodiment 7 Docetaxel cholesterol complex
Get Docetaxel 5.1g, cholesterol 97.71g places Rotary Evaporators; The dichloromethane that adds 3000ml dissolves it, under 60 ℃ of temperature conditions, stirs 2.5 hours, moves in the Rotary Evaporators; The rotary evaporation method is removed solvent, promptly gets in dry 15 hours through 55 ℃ of reduced vacuum.
Get Docetaxel 5.2g, 7-hydrocholesterol 0.25g, vitamin E 0.05g; Place Rotary Evaporators, the oxolane that adds 4000ml dissolves it, under 40 ℃ of temperature conditions, stirs 1 hour; Spray drying was removed solvent in 15 hours, promptly got in dry 15 hours through 55 ℃ of reduced vacuum.
Embodiment 9 Docetaxel cholesterol complex
Get Docetaxel 5.1g; 7-hydrocholesterol 0.49g places Rotary Evaporators, adds the ethanol of 3000ml and the mixture of the tert-butyl alcohol it is dissolved; Under 45 ℃ of temperature conditions, stirred 1 hour; Move in the Rotary Evaporators, the rotary evaporation method is removed solvent, promptly gets in dry 15 hours through 65 ℃ of reduced vacuum.
Get Docetaxel 5.0g; 7-hydrocholesterol 0.95g places Rotary Evaporators, adds the ethanol of 4200ml and the mixture of the tert-butyl alcohol it is dissolved; Under 45 ℃ of temperature conditions, stirred 1 hour; Move in the Rotary Evaporators, the rotary evaporation method is removed solvent, promptly gets in dry 15 hours through 65 ℃ of reduced vacuum.
Embodiment 11 Docetaxel cholesterol complex
Get Docetaxel 5.0g, 7-hydrocholesterol 4.76g places Rotary Evaporators; Add 3000ml acetone it is dissolved, under 45 ℃ of temperature conditions, stirred 1 hour, move in the Rotary Evaporators; The rotary evaporation method is removed solvent, promptly gets in dry 15 hours through 65 ℃ of reduced vacuum.
Get Docetaxel 5g, add 7-dehydrocholesterol 9.52g respectively, place Rotary Evaporators; The acetone that adds 500ml dissolves it, under 45 ℃ of temperature conditions, stirs 1 hour, moves in the Rotary Evaporators; The rotary evaporation method is removed solvent, promptly gets in dry 15 hours through 65 ℃ of reduced vacuum.
Embodiment 13 Docetaxels/7-dehydrocholesterol complex
Get Docetaxel 5g, add 7-dehydrocholesterol 19.01g respectively, place Rotary Evaporators; The acetone that adds 500ml dissolves it, under 45 ℃ of temperature conditions, stirs 1 hour, moves in the Rotary Evaporators; The rotary evaporation method is removed solvent, promptly gets in dry 15 hours through 65 ℃ of reduced vacuum.
Get Docetaxel 5g, add 7-dehydrocholesterol 38.10g respectively, place Rotary Evaporators; The acetone that adds 500ml dissolves it, under 45 ℃ of temperature conditions, stirs 1 hour, moves in the Rotary Evaporators; The rotary evaporation method is removed solvent, promptly gets in dry 15 hours through 65 ℃ of reduced vacuum.
Embodiment 15 Docetaxels/cholesterol acid ester complex
Get Docetaxel 5g, cholesterol acid ester 0.4g places Rotary Evaporators; The acetone that adds 500ml dissolves it, under 45 ℃ of temperature conditions, stirs 1 hour, moves in the Rotary Evaporators; The rotary evaporation method is removed solvent, promptly gets in dry 15 hours through 65 ℃ of reduced vacuum.
Get Docetaxel 5g, cholesterol acid ester 0.80g places Rotary Evaporators; The dichloromethane that adds 1000ml dissolves it, under 45 ℃ of temperature conditions, stirs 1 hour, moves in the Rotary Evaporators; The rotary evaporation method is removed solvent, promptly gets in dry 15 hours through 65 ℃ of reduced vacuum.
Embodiment 17 Docetaxels/cholesterol acid ester complex
Get Docetaxel 5g, cholesterol acid ester 1.61g places Rotary Evaporators; The oxolane that adds 1000ml dissolves it, under 45 ℃ of temperature conditions, stirs 1 hour, moves in the Rotary Evaporators; The rotary evaporation method is removed solvent, promptly gets in dry 15 hours through 65 ℃ of reduced vacuum.
Get Docetaxel 5g, cholesterol acid ester 8.04g places Rotary Evaporators; The acetone that adds 1000ml dissolves it, under 45 ℃ of temperature conditions, stirs 1 hour, moves in the Rotary Evaporators; The rotary evaporation method is removed solvent, promptly gets in dry 15 hours through 65 ℃ of reduced vacuum.
Embodiment 19 Docetaxels/cholesterol acid ester complex
Get Docetaxel 5g, cholesterol acid ester 16.10g places Rotary Evaporators; The ethanol ethyl ester that adds 1000ml dissolves it, under 45 ℃ of temperature conditions, stirs 1 hour, moves in the Rotary Evaporators; The rotary evaporation method is removed solvent, promptly gets in dry 15 hours through 65 ℃ of reduced vacuum.
Embodiment 20: with how western taxane/steroid complex is the submicronized emulsion of intermediate carrier
Get glycerol 12.5g and be dissolved in about 360ml water for injection, be heated to 40-60 ℃, add refining soybean lecithin 7.5g and poloxamer (188) 10g, put in the tissue mashing machine and handle, make into even water, remain under this temperature; Get the how western taxane/steroid complex an amount of (being equivalent to Docetaxel 250mg) among the embodiment 1 to embodiment 19 in addition respectively, add in the 125ml soybean oil, be heated to 40～60 ℃, process oil phase.Under stirring condition, water slowly is added to oil phase, stirs and make the even colostrum of formation.Colostrum is transferred to homogenizing several in the high pressure homogenizer rapidly, regulates pH to 4.0-6.0 with the hydrochloric acid of 0.1mol/L, and add water to 500ml, collect whole emulsions, sterilized 30 minutes, and promptly got the submicronized emulsion that drug loading is 0.5mg/ml for 115 ℃.Laser granulometry is measured, and mean diameter is 125nm～150nm.
Embodiment 21: with how western taxane/steroid complex is the submicronized emulsion of intermediate carrier
Get glycerol 12.5g and be dissolved in about 300ml water for injection, be heated to about 50 ℃, add refine yolk lecithin 7.5g and poloxamer (188) 15g, put in the tissue mashing machine and handle, make into even water, remain under this temperature; Other gets how western taxane/steroid complex an amount of (being equivalent to Docetaxel 250mg) of embodiment 1 to embodiment 19, adds in the 100ml midchain oil, is heated to about 50 ℃, processes oil phase.Under stirring condition, water slowly is added to oil phase, high-speed stirred makes and forms even colostrum.Colostrum is transferred to homogenizing several in the high pressure homogenizer rapidly, regulates pH to 4.0-6.0 with the hydrochloric acid of 0.1mol/L, and add water to 500ml, collect whole emulsions, sterilized 30 minutes, and promptly got the submicronized emulsion that drug loading is 0.5mg/ml for 115 ℃.Laser granulometry is measured, and mean diameter is 230nm～250nm.
Embodiment 22: with Docetaxel steroid complex is the submicronized emulsion of intermediate carrier
Get glycerol 12.5g and be dissolved in about 300ml water for injection, be heated to 55 ℃, add refining soybean lecithin 7.5g and poloxamer (188) 15g, put tissue mashing machine and handle, make into even water, remain under this temperature; Other gets the how western taxane/steroid complex an amount of (being equivalent to Docetaxel 600mg) among the embodiment 1 to embodiment 19, and vitamin E 60mg in the miscella of adding 120ml soybean oil/midchain oil (equal-volume mixing), is heated to 55 ℃, processes oil phase.Under stirring condition, water slowly is added to oil phase, high-speed stirred makes and forms even colostrum.Colostrum is transferred to homogenizing several in the high pressure homogenizer rapidly, regulates pH to 4.0-6.0 with the hydrochloric acid of 0.1mol/L, and add water to 600ml, collect whole emulsions, sterilized 30 minutes, and promptly got the submicronized emulsion that drug loading is 1.0mg/ml for 115 ℃.Laser granulometry is measured, and mean diameter is 125nm～132nm.
Embodiment 23: with Docetaxel steroid complex is the dry emulsion of intermediate carrier
Get the unpasteurized submicronized emulsion 100ml of embodiment 20～22 preparations, add the dissolving of 3% (W/V) mannitol,, carry out lyophilization, promptly get dry emulsion through filtering with microporous membrane.
Embodiment 24: be the self-microemulsion agent of intermediate carrier with Docetaxel steroid complex
Get how western taxane/steroid complex an amount of (being equivalent to Docetaxel 100mg) of embodiment 1～19 respectively; Add midchain oil 5ml, stir and make dissolving, add 1.6ml PEG400,0.5ml Tween 80; Stir, promptly get the self-microemulsion system of homogeneous transparent.
Get the above-mentioned self-microemulsion 5ml of system, add 5% glucose injection to 100ml, form microemulsion at once, particle diameter is less than 100nm.
Embodiment 25: with Docetaxel steroid complex is the capsule of intermediate carrier
Get how western taxane/steroid complex an amount of (being equivalent to Docetaxel 100mg) of embodiment 1～19 respectively, in No. 2 hard capsules of packing into, promptly get.
Embodiment 26: with Docetaxel steroid complex is the tablet of intermediate carrier
How western taxane/steroid complex of getting embodiment 1～19 respectively be an amount of, adds an amount of microcrystalline Cellulose and lactose, adds a small amount of magnesium stearate again, mixes mixing, and tabletting promptly gets.
Test Example
Test Example 1:
Steroid and consumption thereof to medicine in oil dissolubility improve effect
According to the form below complex composition feeds intake, and presses the method for preparing of embodiment 1, prepares 7 groups of cholesterol complex, 7 groups of 7-hydrocholesterol complex, 3 groups of cholic acid complex and 5 groups of cholesterol acid ester complex.It is an amount of to get each complex, adds miscella (soybean oil mixes with the midchain oil equal-volume), at 60 ℃ of condition down cuts preparation in 30 minutes supersaturated solution; Filter, get subsequent filtrate and add dehydrated alcohol and be settled to suitable concn, get 20 μ L and inject chromatograph of liquid; With Kromasil-C18 (250mm * 4.6mm, 5 μ m) is chromatographic column, and acetonitrile-water (54: 46) is a mobile phase; Flow velocity 1.0mL/min detects wavelength 230nm, measures in accordance with the law; Calculate the dissolubility of Docetaxel in miscella, and compare, investigate different steroid materials and different amounts the oil-soluble effect of improving of medicine with free Docetaxel.
Table 1 steroid kind and consumption thereof are to the result that influences of dissolubility in the Docetaxel oil
Comparing with Docetaxel, is that matrix material prepares complex with cholesterol, 7-hydrocholesterol, cholic acid or cholesterol acid ester, and Docetaxel dissolubility in oil is slightly increased.
The oil solution sterilization fore-and-aft stability of steroid complex is investigated
The oil solution of getting respectively in this Test Example table 1 is an amount of; The miscella (equal-volume mixing) that adds soybean oil/midchain oil; Be diluted to and contain the oil solution that Docetaxel concentration is 6.6mg/mL; The 30min that under 115 ℃ of conditions, sterilizes, the HPLC method is investigated the changes of contents of Docetaxel related substance before and after the sterilization, and the result is following:
Table 2: its related substances before and after the oil solution sterilization changes
Table 2 result shows that the oil solution of Docetaxel related substance after sterilization treatment increases to 3.1% by 0.2%, and the oil solution of complex sterilization back related substance does not all surpass 1.0%, and along with the increase of matrix material consumption, stability has the trend of raising.
Comprehensive above table 1 and table 2 result, show that the generation of Docetaxel and steroid matrix material is compound after, though, can significantly improve the sterilization stability of oil solution to the increase DeGrain of medicine dissolubility in oil.
Test Example 2: the study on the stability of how western taxane/steroid complex
7 groups of cholesterol complex, 7 groups of 7-hydrocholesterol complex, 3 groups of cholic acid complex and 5 groups of cholesterol acid ester complex of preparation are stored sampling regularly, investigation cosmetic variation under 25 ℃ of conditions down with 1 of Test Example.Add dehydrated alcohol and process the solution of suitable concn, measure 20 μ L and inject the HPLC appearance, with Kromasil-C18 (250mm * 4.6mm; 5 μ m) be chromatographic column, acetonitrile-water (54: 46) is mobile phase, flow velocity 1.0mL/min; Detect wavelength 230nm, measure content and impurity.The result shows that with the initial phase ratio, outward appearance, content and impurity have no significant change, steady quality.
The how western taxane of table 3/steroid complex long term storage stability
Claims (13)
1. western taxane/steroid complex more than a kind is characterized in that, is composited by how western taxane and steroid matrix material, and the mol ratio of how western taxane and steroid is 1: 0.25～40.
2. according to claim 1 how western taxane/steroid complex is characterized in that, the mol ratio of how western taxane and steroid is 1: 0.5～20.
3. according to claim 1 how western taxane/steroid complex is characterized in that, the mol ratio of how western taxane and steroid is 1: 1～10.
4. according to each described how western taxane/steroid complex among the claim 1-3, it is characterized in that,
Described how western taxane is any in Docetaxel or the Docetaxel derivant, preferred Docetaxel;
Described steroid matrix material is at least a in dissociation sterin, steroid derivatives or the steroid ester.
5. according to claim 4 how western taxane/steroid complex 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; Preferred cholesterol, 7-hydrocholesterol and ergosterol, more preferably cholesterol;
Described steroid derivatives is selected from cholic acid, deoxycholic acid and chenodeoxy cholic acid;
Described steroid ester is selected from the saturated or unsaturated fatty acids ester of medium chain long-chain saturated or unsaturated fatty acid ester or steroid of steroid; Carbon atom in the wherein said medium-chain fatty acid in the carbochain is 6-12; Carbon atom in the described LCFA in the carbochain is more than 12, preferred medium chain unsaturated fatty acid ester and long-chain unsaturated fatty acid ester.
6. according to claim 5 how western taxane/steroid complex; It is characterized in that; Described steroid ester is cholesterol linoleic acid fat, cholesterol linolenic acid fat, cholesterol cetylate, cholesterol ester stearic acid, cholesterol myristinate and cholesterol acid ester, preferred cholesterol acid ester and cholesterol cetylate.
7. according to each described how western taxane/steroid complex in the claim 1 to 6, it is characterized in that said complex also contains antioxidative stabilizer.
8. according to claim 7 how western taxane/steroid complex is characterized in that, said antioxidative stabilizer is selected from least a in sodium sulfite, sodium pyrosulfite, vitamin C, EDTA and salt thereof, vitamin E and the derivant thereof.
9. according to the method for preparing of each described how western taxane/steroid complex among the claim 1-8, it is characterized in that, comprise the steps:
A. with how western taxane and steroid matrix material proportional mixing, add an amount of organic solvent dissolution, randomly add antioxidative stabilizer;
B. under suitable temperature conditions, stir, remove organic solvent, vacuum drying promptly gets.
10. method for preparing according to claim 8 is characterized in that, at step a.) in, with getting how western taxane and steroid respectively, adopt different organic solvent dissolutions, mix afterwards.
11., it is characterized in that said organic solvent can be selected from one or more in dichloromethane, ethanol, methanol, benzyl alcohol, acetone, ethyl acetate, oxolane, the tert-butyl alcohol according to each described method for preparing among the claim 9-10.
12., it is characterized in that said organic solvent can be selected from one or more in ethanol, acetone, ethyl acetate and the oxolane according to each described method for preparing among the claim 10-11.
13. according to the application of each described how western taxane/steroid complex among the claim 1-7 in preparation oil-in-water type submicronized emulsion, dry emulsion, self-microemulsion system or oral formulations.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201010529342.4A CN102451176B (en) | 2010-10-28 | 2010-10-28 | Docetaxel/steroid composite |
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| CN201010529342.4A CN102451176B (en) | 2010-10-28 | 2010-10-28 | Docetaxel/steroid composite |
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| CN102451176B CN102451176B (en) | 2016-06-01 |
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| CN201010529342.4A Active CN102451176B (en) | 2010-10-28 | 2010-10-28 | Docetaxel/steroid composite |
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| CN103357013A (en) * | 2013-04-23 | 2013-10-23 | 福建省创欣生物科技有限公司 | Composition for enhancing bioavailability of taxane medicament |
| 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 |
| CN103462906A (en) * | 2013-08-27 | 2013-12-25 | 青岛东辉医药科技发展有限公司 | Injection docetaxel nanoparticle and preparation method thereof |
| WO2024076056A1 (en) * | 2022-10-05 | 2024-04-11 | 한국과학기술연구원 | Oral pharmaceutical composition containing taxane and preparation method therefor |
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| 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 |
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| CN103357013A (en) * | 2013-04-23 | 2013-10-23 | 福建省创欣生物科技有限公司 | Composition for enhancing bioavailability of taxane medicament |
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| WO2024076056A1 (en) * | 2022-10-05 | 2024-04-11 | 한국과학기술연구원 | Oral pharmaceutical composition containing taxane and preparation method therefor |
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