CN101081219A - Composition containing taxane genus compound, the method for preparing the same and the use thereof - Google Patents
Composition containing taxane genus compound, the method for preparing the same and the use thereof Download PDFInfo
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- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
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Abstract
The present invention discloses one kind of taxane medicine composition, which contains taxane compound in effective treating amount, surfactant, cosolvent and stabilizer. The cosolvent is glycerin, polyglycol and/or propylene glycol; and the stabilizer is sulfonic acid, sulfonate or sulfonate mixture. The taxane medicine composition may be prepared into injection or freeze dried powder for injection. The taxane medicine composition has raised solubility and stability of taxane compound. The present invention discloses also the preparation process and use of the taxane medicine composition.
Description
Technical field
The present invention relates to a kind of is the Pharmaceutical composition of active component and the preparation method and its usage of said composition with the bearing taxanes.
Background technology
Bearing taxanes is the anticancer compound that a class has the taxane-skeleton structure, its mechanism of action is the polymerization by the stimulating catheter element, promote the microtubule dimer to be assembled into microtubule, and cause microtubule to be stablized and the reorganization of inhibition microtubule net kinetics, finally make cell proliferation stop at stage mitostatic phase, thereby play the effect of cytotoxic agent.Using at present maximum in the bearing taxanes is exactly paclitaxel and Docetaxel (being docetaxel), has been widely used in the treatment of preinvasive cancer such as breast carcinoma, ovarian cancer, nonsmall-cell lung cancer (NSCLC), small cell lung cancer (SCLC), incidence squamous cell carcinoma and malignant melanoma and metastatic carcinoma.Yet because bearing taxanes, for example paclitaxel and docetaxel dissolubility in water is low, therefore has certain difficulty when being prepared into preparation.For example, at present the paclitaxel injection (trade name taxol) of listing is that the 30mg paclitaxel is dissolved in the solvent of 5ml Cremophor EL (CremophorEL*) and ethanol (Ethanol) [1: 1] and makes, because Cremophor EL (CremophorEL*) can cause severe anaphylactic reaction, therefore clearly indicate in the description of paclitaxel injection: ", and before the injection paclitaxel, gave intravenous injection cimetidine (300mg) or ranitidine (50mg) in 30-60 minute in order to prevent severe anaphylactic reaction; all patients that accept paclitaxel should carry out prophylactic in advance; can adopt dexamethasone 20mg oral; gave in 12 and 6 hours before with paclitaxel usually; diphenhydramine (or its similar medicine) 50mg 30 to 60 minutes quiet notes before paclitaxel.", make very inconvenience in this clinical practice of said preparation; The docetaxel injection (trade name docetaxel) of same listing, the Tween 80 (TWEEN 80 or Polysorbate 80) of high concentration (nearly 100%) is contained in its preparation (concentrated solution) lining, and every milliliter of concentrated solution contains the Tween 80 of 40mg Docetaxel and 1040mg.This concentrated solution is furnished with special solvent 13% ethanol, can inject after with 13% ethanol concentrated solution being diluted, and clinical use is inconvenience very.
For solving the solubility of bearing taxanes, existing many pieces of bibliographical informations be prepared as preparations such as Emulsion and microemulsion, cyclodextrin clathrate, liposome, nanoparticle, yet above preparation exists shortcomings such as complicated process of preparation, cost height, poor stability.Therefore, need a kind of simple to operate, dissolubility improves, good stability can reduce clinical anaphylactoid taxanes preparation simultaneously again.
Summary of the invention
The present inventor is surprised to find that, bearing taxanes is added surfactant, cosolvent after, add stabilizing agent more simultaneously, can obtain Pharmaceutical composition stable, good aqueous solubility.The particularly adding of stabilizing agent can obviously improve the dissolubility of bearing taxanes in water on the one hand again, can strengthen the stability of bearing taxanes solution on the other hand significantly.Described bearing taxanes is the chemical compound with taxane-skeleton structure, is preferably paclitaxel and docetaxel, most preferably is paclitaxel; Surfactant is selected from non-ionic surface active agent, for example can be tween, span etc. or their mixture; Cosolvent is selected from polyhydric alcohol, for example can be Polyethylene Glycol, glycerol, propylene glycol or their mixture; Stabilizing agent is selected from the mixture of sulfonic acid or its salt or different sulfonate.Sulfonic acid among the present invention has RSO
3The H formula, wherein R has the replacement of 1 to 10 carbon atom or non-substituted straight chain or branched alkyl, cycloalkyl, phenyl, phenylalkyl, preferred straight or branched alkyl, phenyl, phenylalkyl.Wherein, substituted radical can be selected from hydroxyl, halogen, amido etc.Sulfonic acid can be single sulfonic acid, also can be the sulfonic acid of disulfonic acid or two above sulfonate radicals of tool.Preferred sulfonic acid is methanesulfonic acid, ethyl sulfonic acid, propane sulfonic acid, 1,4-fourth disulfonic acid, benzene methanesulfonic acid, benzenesulfonic acid etc.; Sulfonate can be selected from the sodium salt, potassium salt, ammonium salt, magnesium salt, calcium salt, zinc salt of sulfonic acid etc., and preferred sulfonate is sodium sulfonate, potassium sulfonate; Particularly preferred sulfonate is methanesulfonic sodium, methanesulfonic acid potassium, ethyl sulfonic acid sodium, ethyl sulfonic acid potassium, propane sulfonic acid sodium, propane sulfonic acid potassium, 1,4-sodium butanedisulfonic acid, 1,4-fourth disulfonic acid potassium or their mixture.
The invention provides a kind of pharmaceutical composition that contains bearing taxanes, comprise bearing taxanes, surfactant, cosolvent and the stabilizing agent for the treatment of effective dose.
In pharmaceutical composition of the present invention, surfactant is a non-ionic surface active agent, preferred Tweens surfactant, particularly tween 20, one or more in Tween-40, Tween-60 and the tween 80, most preferably tween 80.
In pharmaceutical composition of the present invention, cosolvent is selected from polyhydric alcohol, one or more in preferred Polyethylene Glycol, propylene glycol, the glycerol, and the mean molecule quantity of Polyethylene Glycol wherein is 200～10000, preferred PEG200, PEG400, PEG800, most preferably PEG400.
In pharmaceutical composition of the present invention, stabilizing agent is selected from the mixture of sulfonic acid or its salt or different sulfonate.Sulfonic acid among the present invention has RSO
3The H formula, wherein R has the replacement of 1 to 10 carbon atom or non-substituted straight chain or branched alkyl, cycloalkyl, phenyl, phenylalkyl, preferred straight or branched alkyl, phenyl, phenylalkyl.Wherein, substituted radical can be selected from hydroxyl, halogen, amido etc.Sulfonic acid can be single sulfonic acid, also can be the sulfonic acid of disulfonic acid or two above sulfonate radicals of tool.Preferred sulfonic acid is methanesulfonic acid, ethyl sulfonic acid, propane sulfonic acid, 1,4-fourth disulfonic acid, benzene methanesulfonic acid, benzenesulfonic acid etc.; Sulfonate can be selected from the sodium salt, potassium salt, ammonium salt, magnesium salt, calcium salt, zinc salt of sulfonic acid etc., and preferred sulfonate is sodium sulfonate, potassium sulfonate; Particularly preferred sulfonate is methanesulfonic sodium, methanesulfonic acid potassium, ethyl sulfonic acid sodium, ethyl sulfonic acid potassium, propane sulfonic acid sodium, propane sulfonic acid potassium, 1,4-sodium butanedisulfonic acid, 1,4-fourth disulfonic acid potassium or their mixture.
Weight ratio in the pharmaceutical composition of the present invention between bearing taxanes and Tweens surfactant, cosolvent and the stabilizing agent is 1: 10-150: 2-100: 0.1-100, preferred 1: 30-90: 5-50: 0.3-50, preferred especially 1: 40-80: 10-40: 0.5-30, most preferably 1: 50-70: 10-30: 1-30.
Pharmaceutical composition of the present invention can be the dosage form of injection or injection freeze-dried powder.The concentration of bearing taxanes is 0.1mg～80mg/ml in injection of the present invention or in the solution before the freeze-dried powder lyophilization, be preferably 1mg～50mg/ml, the concentration of cosolvent is 5mg～500mg/ml, be preferably 30mg～200mg/ml, surfactant concentrations is 20mg～500mg/ml, be preferably 30mg～300mg/ml, the concentration of stabilizing agent is 0.2mg～400mg/ml, is preferably 1mg～200mg/ml.
Pharmaceutical composition of the present invention can also comprise other the conventional adjuvant that is used for injection or injection freeze-dried powder.These conventional adjuvant include but not limited to the lyophilization excipient, antiseptic, stabilizing agent, pH regulator agent, isotonic agent.Wherein can be selected from but to be not limited to be in mannitol, lactose, glucose, sorbitol, sodium chloride, gelatin hydrolysate, dextran, sucrose, glycine, the polyvinylpyrrolidone etc. one or more to excipient; Be preferably mannitol or glucose.Antiseptic can be selected from but be not limited to is in phenol, cresol, three tert-butyl alcohols, benzyl alcohol, the nipalgin one or more.Stabilizing agent can be selected from but be not limited in sodium thiosulfate, thiourea, vitamin C, butylated hydroxyarisol, dibutyl phenol, propyl gallate, tocopherol, methionine, cysteine hydrochloride, acetylcysteine, N-acetyl-DL-methionine, ascorbyl palmitate, ethylenediaminetetraacetic acid, the disodiumedetate one or more.The PH regulator includes but not limited to hydrochloric acid, citric acid, tartaric acid, phosphoric acid, Metaphosphoric acid, poly-Metaphosphoric acid, carbonic acid, sodium hydroxide, potassium hydroxide, sodium citrate, potassium citrate, sodium bicarbonate, potassium bicarbonate, amine carbonate, sodium hydrogen phosphate, dipotassium hydrogen phosphate, ethanolamine, diethanolamine, triethanolamine, 1, and 2-is one or more in diamidogen, sodium carbonate, potassium sodium tartrate, potassium metaphosphate, Kurrol's salt, the Polymeric sodium metaphosphate..
According to the situation of concrete active component, those skilled in the art can adjust the pH value of compositions.Specific to taxone compositions of the present invention, its pH value should be below 8, be preferably pH in the scope of 3-5, the PH regulator includes but not limited to one or more in hydrochloric acid, citric acid, lactic acid, tartaric acid, phosphoric acid, Metaphosphoric acid, the poly-Metaphosphoric acid, is preferably citric acid, lactic acid.
In pharmaceutical composition of the present invention, the consumption of bearing taxanes has no particular limits, and can be normally used any dosage in injection." treatment effective dose " is meant that taxone reaches the common consumption of therapeutic effect, and the doctor can make suitable adjustment according to patient's the state of an illness and otherwise situation.Usually, the content of bearing taxanes is 0.1-80mg/ml in the compositions of the present invention.
The Pharmaceutical composition of bearing taxanes of the present invention can be clear and bright injectable aqueous solution form, or is the form of injection freeze-dried powder.Can use water for injection, 5% or 10% glucose solution or the direct dissolved freeze-dried powder pin of 0.9% sodium chloride solution, obtain clear and bright injection.
The injection of taxone of the present invention or injection freeze-dried powder have following characteristics:
Do not need special solvent, be convenient to clinical use, zest is little, simultaneously owing to do not contain Cremophor EL (CremophorEL*), avoids or has greatly reduced anaphylaxis in the clinical use.
This injectable powder is drying solid block or powder, can prevent the influence of bearing taxanes factor such as oxidation, hydrolysis in solution, increases the stability in the goods storage process.
Because of this injectable powder exists with solid state, be convenient to transportation.
This preparation of injection is simple, convenient quality control, and product stability is good, is convenient to suitability for industrialized production.
The lowest total of the melting point height of content among the present invention, pre-freeze gets final product under-40 ℃ temperature, and outward appearance is better.This injectable powder contained humidity can reach below 1%, generally is controlled at 5% and gets final product with interior.
According to " Chinese Pharmacopoeia version (two ones) in 2005 " appendix IX B method, with the turbidity standard of solution and the equivalent of preparation place respectively paired than turbid with glass tubing, after turbidity standard prepares 5 minutes, vertical with placing under the umbrella canopy lamp in the darkroom, illumination is 1000Lx, observe, compare from horizontal direction, the solution of preparation should be clarified, and is not deeper than turbidity standard No. 1.
The injection of taxone of the present invention or injection freeze-dried powder are suitable for intramuscular injection, intravenous injection.
On the other hand, the invention provides a kind of method of improving the bearing taxanes dissolubility, comprise the step that bearing taxanes and cosolvent, surfactant and stabilizing agent are mixed, stir.Surfactant is selected from non-ionic surface active agent; Cosolvent is selected from polyhydric alcohol, for example can be Polyethylene Glycol, glycerol, propylene glycol or their mixture; Stabilizing agent is selected from sulfate, sulphite, pyrosulfite or two or more mixture among them.This method also can further comprise the step that above mixture is prepared into injection, specifically be included in and add aqueous vehicles in the said mixture, for example, distilled water, water for injection, Osmitrol or contain the aqueous solution of other any adjuvant, mix the back and add the active carbon stirring, after taking off charcoal through 0.8 μ m filter membrane coarse filtration, reuse 0.22 μ m filter membrane degerming, packing.The concentration of bearing taxanes is 0.1mg～80mg/ml in the described compositions, and the concentration of cosolvent is 5mg～500mg/ml, and surfactant concentrations is 20mg～500mg/ml, and the concentration of stabilizing agent is 0.2mg～400mg/ml.This method can also further comprise the step of above-mentioned injection lyophilization being made freeze-dried powder more in addition, the conventional freeze drying technology of freeze drying injection in the medicament field is adopted in wherein lyophilization, and those skilled in the art instruct not the needs creative work promptly can finish according to the technology in prior art and the textbook.
In the method for the invention, surfactant is a non-ionic surface active agent, preferred Tweens surfactant, particularly tween 20, one or more in Tween-40, Tween-60 and the tween 80, most preferably tween 80.
In the method for the invention, cosolvent is selected from polyhydric alcohol, one or more in preferred Polyethylene Glycol, propylene glycol, the glycerol, and the mean molecule quantity of Polyethylene Glycol wherein is 200～10000, preferred PEG200, PEG400, PEG800, most preferably PEG400.
In the method for the invention, stabilizing agent is selected from the mixture of sulfonic acid or its salt or different sulfonate.Sulfonic acid among the present invention has RSO
3The H formula, wherein R has the replacement of 1 to 10 carbon atom or non-substituted straight chain or branched alkyl, cycloalkyl, phenyl, phenylalkyl, preferred straight or branched alkyl, phenyl, phenylalkyl.Wherein, substituted radical can be selected from hydroxyl, halogen, amido etc.Sulfonic acid can be single sulfonic acid, also can be the sulfonic acid of disulfonic acid or two above sulfonate radicals of tool.Preferred sulfonic acid is methanesulfonic acid, ethyl sulfonic acid, propane sulfonic acid, 1,4-fourth disulfonic acid, benzene methanesulfonic acid, benzenesulfonic acid etc.; Sulfonate can be selected from the sodium salt, potassium salt, ammonium salt, magnesium salt, calcium salt, zinc salt of sulfonic acid etc., and preferred sulfonate is sodium sulfonate, potassium sulfonate; Particularly preferred sulfonate is methanesulfonic sodium, methanesulfonic acid potassium, ethyl sulfonic acid sodium, ethyl sulfonic acid potassium, propane sulfonic acid sodium, propane sulfonic acid potassium, 1,4-sodium butanedisulfonic acid, 1,4-fourth disulfonic acid potassium or their mixture.
One preferred embodiment in, the weight ratio of bearing taxanes and surfactant, cosolvent and stabilizing agent is 1: 10-150: 2-100: 0.1-100, preferred 1: 30-90: 5-50: 0.3-50, preferred especially 1: 40-80: 10-40: 0.5-30, most preferably 1: 50-70: 10-30: 1-30.
One preferred embodiment in, taxane compounds is docetaxel and paclitaxel, wherein most preferably is paclitaxel.
The 3rd aspect of the present invention is the purposes that paclitaxel of the present invention or docetaxel compositions is used for the treatment of proliferative disease, especially for cancer, as the treatment of breast carcinoma, nonsmall-cell lung cancer, ovarian cancer, AIDS dependency kaposi's sarcoma, cancer of pancreas, colorectal cancer, melanoma, incidence cancer, lymphoma, cerebroma, gastric cancer etc.
Various improvement of the present invention and variation it will be apparent to those skilled in the art that, and without prejudice to the spirit and scope of the present invention.Below concrete preferred implementation the present invention has been described, should not be limited to following specific embodiments but should understand claimed the present invention.For the person of ordinary skill in the field, be that the various improvement of significantly implementing mode of the present invention are all covered by the present invention.
The specific embodiment
Embodiment 1
Docetaxel 20mg
Macrogol 200 200mg
Tween 80 750mg
Methanesulfonic sodium 50mg
Mannitol 400mg
Water for injection is to 6ml
Docetaxel and Macrogol 200, Tween 80, methanesulfonic sodium are mixed, stir, add Osmitrol, mix, transferring pH with citric acid soln is 4, and solution adds 0.1% active carbon and stirred 20 minutes.After solution took off charcoal through 0.8 μ m filter membrane coarse filtration, reuse 0.22 μ m filter membrane degerming divided to be filled in the cillin bottle.According to " Chinese Pharmacopoeia version (two ones) in 2005 " appendix IX B method, with the turbidity standard of solution and the equivalent of preparation place respectively paired than turbid with glass tubing, after turbidity standard prepares 5 minutes, vertical with placing under the umbrella canopy lamp in the darkroom, illumination is 1000Lx, observe, compare from horizontal direction, the solution clarification of preparation is not deeper than turbidity standard No. 1.Room temperature was placed 8 hours, and solution is still clarified.
Embodiment 2
Paclitaxel 30mg
Macrogol 200 500mg
Tween 80 1500mg
Methanesulfonic acid potassium 120mg
Mannitol 900mg
Water for injection is to 9ml
Paclitaxel and Macrogol 200, Tween 80, methanesulfonic acid potassium are mixed, stir, add Osmitrol, mix, transferring pH with lactic acid solution is 4, and solution adds 0.1% active carbon and stirred 20 minutes.After solution took off charcoal through 0.8 μ m filter membrane coarse filtration, reuse 0.22 μ m filter membrane degerming divided to be filled in the cillin bottle.According to " Chinese Pharmacopoeia version (two ones) in 2005 " appendix IX B method, with the turbidity standard of solution and the equivalent of preparation place respectively paired than turbid with glass tubing, after turbidity standard prepares 5 minutes, vertical with placing under the umbrella canopy lamp in the darkroom, illumination is 1000Lx, observe, compare from horizontal direction, the solution clarification of preparation is not deeper than turbidity standard No. 1.Room temperature was placed 6 hours, and solution is still clarified.
Embodiment 3:
Paclitaxel 30mg
PEG400 500mg
Tween 80 1800mg
Ethyl sulfonic acid potassium 300mg
Mannitol 800mg
Water for injection is to 10ml
Method by embodiment 1 prepares paclitaxel injection, according to " Chinese Pharmacopoeia version (two ones) in 2005 " appendix IX B method, with the turbidity standard of solution and the equivalent of preparation place respectively paired than turbid with glass tubing, after turbidity standard prepares 5 minutes, vertical in the darkroom illumination is 1000Lx with placing under the umbrella canopy lamp, observes, compares from horizontal direction, the solution clarification of preparation is not deeper than turbidity standard No. 1.Room temperature was placed 8 hours, and solution is still clarified.
Embodiment 4
Paclitaxel 30mg
Glycerol 150mg
PEG400 150mg
Tween 80 750mg
Ethyl sulfonic acid sodium 900mg
Mannitol 400mg
Water for injection is to 6ml
Method by embodiment 1 prepares paclitaxel injection, according to " Chinese Pharmacopoeia version (two ones) in 2005 " appendix IX B method, with the turbidity standard of solution and the equivalent of preparation place respectively paired than turbid with glass tubing, after turbidity standard prepares 5 minutes, vertical in the darkroom illumination is 1000Lx with placing under the umbrella canopy lamp, observes, compares from horizontal direction, the solution clarification of preparation is not deeper than turbidity standard No. 1.Room temperature was placed 4 hours, and solution is still clarified.
Embodiment 5
Paclitaxel 30mg
Glycerol 300mg
Tween 80 1800mg
1,4-fourth disulfonic acid potassium 300mg
Mannitol 300mg
Water for injection is to 6ml
Method by embodiment 1 prepares paclitaxel injection, according to " Chinese Pharmacopoeia version (two ones) in 2005 " appendix IX B method, with the turbidity standard of solution and the equivalent of preparation place respectively paired than turbid with glass tubing, after turbidity standard prepares 5 minutes, vertical in the darkroom illumination is 1000Lx with placing under the umbrella canopy lamp, observes, compares from horizontal direction, the solution clarification of preparation is not deeper than turbidity standard No. 1.Room temperature was placed 8 hours, and solution is still clarified.
Embodiment 6
Paclitaxel 30mg
PEG400 600mg
Tween 80 1500mg
1,4-sodium butanedisulfonic acid 120mg
Mannitol 600mg
Water for injection is to 6ml
Method by embodiment 1 prepares paclitaxel injection, according to " Chinese Pharmacopoeia version (two ones) in 2005 " appendix IX B method, with the turbidity standard of solution and the equivalent of preparation place respectively paired than turbid with glass tubing, after turbidity standard prepares 5 minutes, vertical in the darkroom illumination is 1000Lx with placing under the umbrella canopy lamp, observes, compares from horizontal direction, the solution clarification of preparation is not deeper than turbidity standard No. 1.Room temperature was placed 8 hours, and solution is still clarified.
Embodiment 7
Paclitaxel 30mg
Glycerol 900mg
Tween 80 900mg
Propane sulfonic acid potassium 150mg
Mannitol 500mg
Water for injection is to 7ml
Method by embodiment 1 prepares paclitaxel injection, according to " Chinese Pharmacopoeia version (two ones) in 2005 " appendix IX B method, with the turbidity standard of solution and the equivalent of preparation place respectively paired than turbid with glass tubing, after turbidity standard prepares 5 minutes, vertical in the darkroom illumination is 1000Lx with placing under the umbrella canopy lamp, observes, compares from horizontal direction, the solution clarification of preparation is not deeper than turbidity standard No. 1.Room temperature was placed 8 hours, and solution is still clarified.
Embodiment 8
Paclitaxel 30mg
Glycerol 500mg
PEG400 400mg
Tween 80 1200mg
Propane sulfonic acid sodium 750mg
Mannitol 600mg
Water for injection is to 6ml
Method by embodiment 1 prepares paclitaxel injection, according to " Chinese Pharmacopoeia version (two ones) in 2005 " appendix IX B method, with the turbidity standard of solution and the equivalent of preparation place respectively paired than turbid with glass tubing, after turbidity standard prepares 5 minutes, vertical in the darkroom illumination is 1000Lx with placing under the umbrella canopy lamp, observes, compares from horizontal direction, the solution clarification of preparation is not deeper than turbidity standard No. 1.Room temperature was placed 6 hours, and solution is still clarified.
Embodiment 9
Paclitaxel 30mg
Glycerol 900mg
Tween 20 1800mg
1,4 sodium butanedisulfonic acid 900mg
Mannitol 400mg
Water for injection is to 10ml
Method by embodiment 1 prepares paclitaxel injection, according to " Chinese Pharmacopoeia version (two ones) in 2005 " appendix IX B method, with the turbidity standard of solution and the equivalent of preparation place respectively paired than turbid with glass tubing, after turbidity standard prepares 5 minutes, vertical in the darkroom illumination is 1000Lx with placing under the umbrella canopy lamp, observes, compares from horizontal direction, the solution clarification of preparation is not deeper than turbidity standard No. 1.Room temperature was placed 8 hours, and solution is still clarified.
Embodiment 10
Paclitaxel 30mg
Glycerol 900mg
Tween-40 750mg
1,4-fourth disulfonic acid potassium 150mg
Mannitol 400mg
Water for injection is to 6ml
Method by embodiment 1 prepares paclitaxel injection, according to " Chinese Pharmacopoeia version (two ones) in 2005 " appendix IX B method, with the turbidity standard of solution and the equivalent of preparation place respectively paired than turbid with glass tubing, after turbidity standard prepares 5 minutes, vertical in the darkroom illumination is 1000Lx with placing under the umbrella canopy lamp, observes, compares from horizontal direction, the solution clarification of preparation is not deeper than turbidity standard No. 1.Room temperature was placed 8 hours, and solution is still clarified.
Embodiment 11
Paclitaxel 30mg
PEG400 1500mg
Tween-60 750mg
Benzene potassium sodium sulfonate 600mg
Mannitol 400mg
Water for injection is to 5ml
Method by embodiment 1 prepares paclitaxel injection, according to " Chinese Pharmacopoeia version (two ones) in 2005 " appendix IX B method, with the turbidity standard of solution and the equivalent of preparation place respectively paired than turbid with glass tubing, after turbidity standard prepares 5 minutes, vertical in the darkroom illumination is 1000Lx with placing under the umbrella canopy lamp, observes, compares from horizontal direction, the solution clarification of preparation is not deeper than turbidity standard No. 1.Room temperature was placed 6 hours, and solution is still clarified.
Embodiment 12
Docetaxel 20mg
PEG400 200mg
Tween 80 1200mg
Benzene potassium potassium sulfonate 50mg
Mannitol 500mg
Water for injection is to 6ml
Method by embodiment 1 prepares docetaxel injection, according to " Chinese Pharmacopoeia version (two ones) in 2005 " appendix IX B method, with the turbidity standard of solution and the equivalent of preparation place respectively paired than turbid with glass tubing, after turbidity standard prepares 5 minutes, vertical in the darkroom illumination is 1000Lx with placing under the umbrella canopy lamp, observes, compares from horizontal direction, the solution clarification of preparation is not deeper than turbidity standard No. 1.Room temperature was placed 8 hours, and solution is still clarified.
The solution that embodiment 1,2,4-12 are made carries out lyophilization by following:
Pre-freeze: products temperature drops to-45 ℃, is incubated and promptly can carries out sublimation drying after 3 hours;
Sublimation drying: the sublimation drying temperature is controlled at below-12 ℃;
Dry again: the drying stage maximum temperature is controlled at 35 ℃ again, and loss on drying should be up to specification;
Behind dry the end, the intrinsic pressure plug of case, outlet lock aluminium lid, the qualified back of product inspection packing is promptly.
Lyophilisation product adds the dissolving of 3～15ml water for injection again, according to " Chinese Pharmacopoeia version (two ones) in 2005 " appendix IX B method, with the turbidity standard of solution and the equivalent of preparation place respectively paired than turbid with glass tubing, after turbidity standard prepares 5 minutes, vertical in the darkroom illumination is 1000Lx with placing under the umbrella canopy lamp, observes, compares from horizontal direction, the solution clarification of preparation is not deeper than turbidity standard No. 1.The solution room temperature was placed more than 8 hours, still kept clear state.
Reference examples 1
Paclitaxel 30mg
PEG400 300mg
Tween 80 1400mg
Mannitol 400mg
Water for injection is to 4ml
Paclitaxel and PEG400, Tween 80 are mixed, stir, add Osmitrol, mix, solution adds 0.1% active carbon and stirred 20 minutes.After solution took off charcoal through 0.8 μ m filter membrane coarse filtration, reuse 0.22 μ m filter membrane degerming divided to be filled in the cillin bottle.Part room temperature is placed, and another part carries out lyophilization.The sample that room temperature is placed is after 1 hour, and solution becomes gets muddy.Freeze drying example redissolves with water for injection, solution muddiness after 1 hour.
Reference examples 2
Paclitaxel 30mg
Glycerol 150mg
PEG400 250mg
Tween 80 1500mg
Mannitol 100mg
Water for injection is to 6ml
Paclitaxel and PEG400, glycerol, Tween 80 are mixed, stir, add Osmitrol, mix, solution adds 0.1% active carbon and stirred 20 minutes.After solution took off charcoal through 0.8 μ m filter membrane coarse filtration, reuse 0.22 μ m filter membrane degerming divided to be filled in the cillin bottle.Part room temperature is placed, and another part carries out lyophilization.The sample that room temperature is placed is after 1 hour, and solution becomes gets muddy.Freeze drying example redissolves with water for injection, solution muddiness after 1 hour.
Reference examples 3
Paclitaxel 30mg
Glycerol 600mg
Tween 80 1200mg
Mannitol 100mg
Water for injection is to 6ml
Paclitaxel and glycerol, Tween 80 are mixed, stir, add Osmitrol, mix, solution adds 0.1% active carbon and stirred 20 minutes.After solution took off charcoal through 0.8 μ m filter membrane coarse filtration, reuse 0.22 μ m filter membrane degerming divided to be filled in the cillin bottle.Part room temperature is placed, and another part carries out lyophilization.The sample that room temperature is placed is after 1 hour, and solution becomes gets muddy.Freeze drying example redissolves with water for injection, solution muddiness after 1 hour.
This shows that the combination that adds tween, cosolvent, stabilizing agent can obviously improve the clarity of bearing taxanes solution, and increases its stability, satisfies the needs of clinical use.
Embodiment 21
Stability experiment under the acceleration environment
In addition, the lyophilized products that makes according to the method for embodiment 1-12 has the required characteristic of freeze-dried composition of the present invention.Each sample was deposited 6 months under the accelerated tests condition, measured the variation of indexs such as content, related substance, the results are shown in Table 1.
Table 1 accelerated tests result
| Embodiment | Outward appearance | Content (%) | Catabolite (%) | PH value |
| 1 | The white cake | 98.2 | 0.65 | 4.5 |
| 2 | The white cake | 98.3 | 0.32 | 4.6 |
| 3 | The white cake | 97.2 | 0.92 | 4.3 |
| 4 | The white cake | 98.9 | 0.44 | 4.1 |
| 5 | The white cake | 97.5 | 0.85 | 4.0 |
| 6 | The white cake | 98.7 | 0.41 | 4.2 |
| 7 | The white cake | 99.7 | 0.12 | 4.0 |
| 8 | The white cake | 96.9 | 0.88 | 4.3 |
| 9 | The white cake | 97.1 | 0.69 | 4.3 |
| 10 | The white cake | 99.5 | 0.72 | 4.4 |
| 11 | The white cake | 99.2 | 0.28 | 4.5 |
| 12 | The white cake | 97.8 | 0.45 | 4.3 |
6 months measurement results of accelerated test show that the obtained freeze-drying goods are stable, and effect duration is measurable to 2 years.
Embodiment 22 zest researchs
To carry out the zest of animal blood vessels according to the lyophilized products that embodiment 1,2,4-12 method make.Method is to get 6 of health, ear edge not damaged rabbit, is divided into two groups at random by body weight, i.e. Docetaxel for Injection or injection paclitaxel test group and sodium chloride injection matched group.Intend with dosage with clinical adult and serve as according to design rabbit dosage, slowly inject administration that matched group gives the isometric(al) sodium chloride injection, gives 5 days continuously from rabbit left side auricular vein.Result of the test shows, compare with the sodium chloride injection group, intravenous injection gives Docetaxel for Injection or injection paclitaxel, reach the last administration during the administration after 24 hours, blood vessel and surrounding tissue redness are not seen in perusal, the visible rabbit ear vein clear in structure of tissue slice inspection, indivedual vasodilation are obvious, the tube wall thickness is even, and inwall is level and smooth, the Guan Zhouwu inflammatory exudate.Show under the experiment condition that Docetaxel for Injection or injection paclitaxel do not have the obvious stimulation effect to the rabbit auricular vein.
Claims (33)
1. the pharmaceutical composition of a taxanes comprises taxane compounds, surfactant, cosolvent and the stabilizing agent for the treatment of effective dose, and cosolvent wherein is selected from polyhydric alcohol, and stabilizing agent is selected from the mixture of sulfonic acid or its salt or different sulfonate.
2. according to the pharmaceutical composition of claim 1, wherein said surfactant is selected from nonionic surfactant.
3. according to the pharmaceutical composition of claim 1, it is Polyethylene Glycol, glycerol, propylene glycol or their mixture that wherein said polyhydric alcohol is selected from.
4. according to the pharmaceutical composition of claim 2, wherein said nonionic surfactant is a tween.
5. according to the pharmaceutical composition of claim 4, wherein said tween is selected from tween 20, one or more in Tween-40, Tween-60 and the tween 80.
6. according to the pharmaceutical composition of claim 5, wherein said Tweens surfactant is a tween 80.
7. according to the pharmaceutical composition of claim 3, wherein said polyhydric alcohol is a glycerol.
8. according to the pharmaceutical composition of claim 3, wherein said polyhydric alcohol is a Polyethylene Glycol.
9. according to the pharmaceutical composition of claim 3, wherein said polyhydric alcohol is a propylene glycol
10. pharmaceutical composition according to Claim 8, Polyethylene Glycol wherein is selected from Macrogol 200, PEG400, Polyethylene Glycol 800 or its mixture.
11. according to the pharmaceutical composition of claim 10, Polyethylene Glycol wherein is a PEG400.
12. according to the pharmaceutical composition of claim 1, wherein said sulfonic acid has RSO
3The H formula, wherein R has the replacement of 1 to 10 carbon atom or non-substituted straight chain or branched alkyl, cycloalkyl, phenyl, phenylalkyl, and substituted radical is selected from hydroxyl, halogen, amido.
13. according to the pharmaceutical composition of claim 12, wherein said sulfonic acid is methanesulfonic acid, ethyl sulfonic acid, propane sulfonic acid, 1,4-fourth disulfonic acid, benzene methanesulfonic acid, benzenesulfonic acid or their mixture.
14. according to the pharmaceutical composition of claim 1, wherein said sulfonate is sodium salt, potassium salt, ammonium salt, magnesium salt, calcium salt, zinc salt or their mixture of sulfonic acid.
15. according to the pharmaceutical composition of claim 1, wherein said sulfonate is sodium salt, potassium salt or its mixture of sulfonic acid.
16. according to the pharmaceutical composition of claim 15, wherein said sulfonate is methanesulfonic sodium, methanesulfonic acid potassium, ethyl sulfonic acid sodium, ethyl sulfonic acid potassium, propane sulfonic acid sodium, propane sulfonic acid potassium, 1,4-sodium butanedisulfonic acid, 1,4-fourth disulfonic acid potassium or their mixture.
17. according to the pharmaceutical composition of claim 1, wherein the weight ratio between taxane compounds, surfactant, cosolvent and the stabilizing agent is 1: 10-150: 2-100: 0.1-100.
18. according to the pharmaceutical composition of claim 1, wherein the weight ratio between taxane compounds, surfactant, cosolvent and the stabilizing agent is 1: 30-90: 5-50: 0.3-50.
19. according to the pharmaceutical composition of claim 1, wherein the weight ratio between taxane compounds, surfactant, cosolvent and the stabilizing agent is 1: 40-80: 10-40: 0.5-30.
20. according to the pharmaceutical composition of claim 1, wherein the weight ratio between taxane compounds, surfactant, cosolvent and the stabilizing agent is 1: 50-70: 10-30: 1-30.
21. according to the pharmaceutical composition of claim 1, the dosage form of wherein said pharmaceutical composition is injection or injection freeze-dried powder.
22., also can further add other pharmaceutically acceptable injection adjuvant in the compositions according to the pharmaceutical composition of any one claim among the claim 1-21.
23. according to the pharmaceutical composition of claim 22, wherein in described injection or in the solution before the freeze-dried powder lyophilization, the concentration of described cosolvent is 5mg～500mg/ml.
24. according to the pharmaceutical composition of claim 22, wherein in described injection or in the solution before the freeze-dried powder lyophilization, described surfactant concentrations is 20mg～500mg/ml.
25. according to the pharmaceutical composition of claim 22, wherein in described injection or in the solution before the freeze-dried powder lyophilization, the concentration of described cosolvent is 0.2mg～400mg/ml.
26. according to the pharmaceutical composition in above each claim, taxane compounds wherein is selected from paclitaxel or docetaxel.
27. according to the pharmaceutical composition of claim 26, taxane compounds is a paclitaxel.
28. the purposes in the medicine of the described pharmaceutical composition of above each claim in preparation treatment proliferative disease.
29. according to the purposes of claim 28, wherein said proliferative disease is a cancer.
30. according to the purposes of claim 29, wherein said cancer is selected from the preinvasive cancer and the metastatic carcinoma of breast carcinoma, nonsmall-cell lung cancer (NSCLC), small cell lung cancer (SCLC), ovarian cancer, AIDS dependency kaposi's sarcoma, cancer of pancreas, colorectal cancer, melanoma, incidence cancer, lymphoma, cerebroma, gastric cancer.
31. the described preparation of drug combination method of arbitrary claim in the claim 1～27 comprises bearing taxanes is mixed the step that stirs with cosolvent, surfactant, stabilizing agent.
32. according to the preparation method of claim 31, also further comprise the adding solvent, add the step of active carbon, filtration, degerming.
33., also further comprise the step of described injection lyophilization being made freeze-dried powder according to the preparation method of claim 32.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2007101186243A CN101081219B (en) | 2007-07-10 | 2007-07-10 | Composition containing taxane genus compound, the method for preparing the same and the use thereof |
| PCT/CN2008/001298 WO2009006799A1 (en) | 2007-07-10 | 2008-07-10 | A pharmaceutical compositon comprising taxanes, the preparation and use thereof |
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| CN2007101186243A CN101081219B (en) | 2007-07-10 | 2007-07-10 | Composition containing taxane genus compound, the method for preparing the same and the use thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009006799A1 (en) * | 2007-07-10 | 2009-01-15 | Beijing Century Biocom Pharmaceutical Technology Co., Ltd. | A pharmaceutical compositon comprising taxanes, the preparation and use thereof |
| CN104507467A (en) * | 2012-07-19 | 2015-04-08 | 富士胶片株式会社 | Liquid composition containing taxane-based active ingredient, process for producing same, and liquid medicinal preparation |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2002360816A1 (en) * | 2001-12-28 | 2003-07-24 | Ivax Research, Inc. | Taxane based compositions and methods of use |
| CN1868459A (en) * | 2006-06-19 | 2006-11-29 | 云南省玉溪望子隆生物制药有限公司 | Docetaxel freeze-dried powder-injection, and its prepn. method |
| CN101081219B (en) * | 2007-07-10 | 2010-12-22 | 北京世纪博康医药科技有限公司 | Composition containing taxane genus compound, the method for preparing the same and the use thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009006799A1 (en) * | 2007-07-10 | 2009-01-15 | Beijing Century Biocom Pharmaceutical Technology Co., Ltd. | A pharmaceutical compositon comprising taxanes, the preparation and use thereof |
| CN104507467A (en) * | 2012-07-19 | 2015-04-08 | 富士胶片株式会社 | Liquid composition containing taxane-based active ingredient, process for producing same, and liquid medicinal preparation |
| CN104507467B (en) * | 2012-07-19 | 2019-04-26 | 富士胶片株式会社 | Liquid composition, its manufacturing method and the liquid preparation of the active constituent of methane series containing Japanese yew |
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| CN101081219B (en) | 2010-12-22 |
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