CN107496352A - A kind of Docetaxel pharmaceutical composition and preparation method thereof - Google Patents
A kind of Docetaxel pharmaceutical composition and preparation method thereof Download PDFInfo
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- CN107496352A CN107496352A CN201710951391.9A CN201710951391A CN107496352A CN 107496352 A CN107496352 A CN 107496352A CN 201710951391 A CN201710951391 A CN 201710951391A CN 107496352 A CN107496352 A CN 107496352A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
Abstract
The present invention is for problem present in Docetaxel injection clinical practice, study and provide a kind of new Docetaxel pharmaceutical composition and preparation method thereof, the Docetaxel pharmaceutical composition of the present invention does not contain ethanol, and employ new nonionic surfactant Solutol HS15 and substitute easily generation haemolysis and anaphylactoid tween, it is lower that toxicity compared with prior art can be made by preparation technology simple and easy to operate, there is good compatibility stability and uniformity with transfusion liquid, the higher Docetaxol injection of product storage stability, it is adapted to industrialized production and clinical safety to use.
Description
Technical field
The present invention relates to pharmaceutical technology field, and in particular to a kind of Docetaxel pharmaceutical composition and preparation method thereof.
Background technology
Docetaxel (alias docetaxel, Docetaxel) is a kind of semi-synthetic antineoplastic, is taxanes
One of cancer therapy drug.Docetaxel is semi-synthetic obtained being the inactive precursor extracted since European yew tree needle,
There are two changes in its chemical constitution, compared with taxol (Paclitaxel) one is on the C-10 positions of cephalomannie ring
Acetyl group is replaced with carboxyl, the second is C-13 side chains change.The difference of chemical constitution causes Docetaxel and taxol
It is active different, its CDCC is 1.3-12 times of taxol.Docetaxel (docetaxel) structural formula is as follows：
Docetaxel belongs to microtubule depolymerization inhibitor, acts on micro-pipe/microtubuli system, promotes micro-pipe dimer dress
Micro-pipe is made into, while prevents polymerisation process and makes microtubule stabilization, blocks the cell generation G2/M phases, so as to suppress cancer cell
Mitosis and propagation, this mechanism of action cause it that there is less serious side reaction compared with taxol.Clinic is ground
Study carefully and show, Docetaxel has good active anticancer to various tumor diseases, for treatment breast cancer, non-small cell lung
Cancer, film gland cancer, soft tissue sarcoma, head and neck cancer, stomach cancer, oophoroma and prostate cancer etc. have the effect of fine.
In the 1980s, it is successful by French scholar Potiere and Rhone-Poulenc Rorer companies joint development,
The treatment of metastatic breast cancer is approved for earliest.November nineteen ninety-five, the docetaxel injection of Sai Nuofei productions
(Taxotere) ratify to list in the multiple countries in Europe through European Union first, indication is metastatic breast cancer；It is in May, 1996, more
Xi Tasai parenteral solutions (Taxotere) are ratified to list in the U.S. through FDA, for treatment of metastatic breast cancer；It is in June, 1997, more western
He matches parenteral solution, and ((Taxotere) lists in Japan, then carries out the clinical research of Several Kinds of Malignancy in multiple countries and obtains
Approval listing, in Discussion on Chinese Listed, product isThe indication granted in the whole world mainly includes at present：Mammary gland
Cancer, non-small cell lung cancer, prostate cancer, stomach cancer, incidence cancer, oophoroma, the cancer of the esophagus and carcinoma of endometrium etc..
Clinical practice mainly has freeze-dried powder and water needle injection at present.Earliest by the exploitation listing of match Norfin, Inc of France
Product be two dress injections, including (13% ethanol is water-soluble for the parenteral solution of 1 docetaxel containing main ingredient and 1 added solvent
Liquid), added solvent need to be used to be used after being diluted to docetaxel injection during Clinical practice.To simplify preparation, the said firm
Single bottle dress parenteral solution (One-vial Taxotere) is developed again, and docetaxel is dissolved in Tween-80 and absolute ethyl alcohol
(mass ratio 1:27:20), but above two parenteral solution due to triggering adverse reaction again and again containing ethanol during Clinical practice,
Then, the third generation product of docetaxel is had listed respectively in Japan in 2015 and the U.S. --- without ethanol docetaxel injection
(single branch dress), do not include ethanol in the new product prescription, but use Tween-80 (Tween-80) as solubilizer, but
The adverse reactions such as haemolysis and allergy when tween clinically uses be present.
Patent document CN101062028A discloses a kind of pharmaceutical composition of taxanes, the purple comprising therapeutically effective amount
China fir hydride compounds, surfactant, cosolvent and stabilizer, wherein cosolvent are in glycerine or polyethylene glycol, propane diols
One or more, stabilizer are selected from sulfate, sulphite, pyrosulfite or two or more mixing among them
Thing.Said composition uses tween as surfactant, the problem of not solving on the medicine Clinical practice.
Patent document CN101330912A discloses a kind of pharmaceutical composition of docetaxel, comprising therapeutic dose it is more west he
One or more in match, Tweens surfactant and cosolvent, wherein cosolvent selection glycerine or polyethylene glycol.The group
Although compound improves the solubility of docetaxel, still having used tween, not solving the medicine clinic makes as surfactant
With the problem of.
Patent document CN101485652A discloses a kind of pharmaceutical composition of taxanes, the purple comprising therapeutically effective amount
China fir hydride compounds, surfactant, cosolvent and stabilizer, wherein cosolvent are selected from polyethylene glycol, propane diols, glycerine or second
One or more mixtures in glycol, stabilizer are selected from hydrochloride, carbonate, phosphate nitrate or its mixture.Should
Composition can improve the solubility and stability of taxane compounds, still use Tween 80 as surfactant, not
Solve the problems, such as on the medicine Clinical practice.
Patent document CN104507467A provides a kind of fluid composition, and it contains (a) and is selected from docetaxel and its derivative
Japanese yew methane series active component, (b) at least one kind of glycol and (c) in thing are selected from polysorbate, polyoxyethylene glycol ester and polyoxy
At least one kind of surfactant component in ethylene castor oil derivative, and the body of (b) glycol and (c) surfactant component
Product is than the total content for 45/55~55/45 scope, (b) glycol and (c) surfactant component relative to fluid composition
Cumulative volume is more than 95v/v%.The fluid composition still uses surface active agent tween 80.
Due to Docetaxel bulk drug poorly water-soluble, it is equal that an ejection preparation either generation or three generation products is listed at present
Tween-80 be with the addition of as solubilizer.The addition of these solubilizer tends to cause haemolysis and severe allergic reaction.To reduce
Anaphylactoid incidence and severity, clinic need to give steroids and other histamine blocking drugs in advance, but this forerunner gives
There is also adverse reaction for prescription formula.Because adverse reaction limits the application of the medicine clinically, therefore, research a new generation gives
Pharmaceutically dosage form and the dissolubility for improving yew alkanes medicine, further improve bioavilability, it is very necessary to reduce its toxicity
's.
For raising taxol stability, toxic side effect, raising Drug bioavailability are reduced, in recent years many new polyenoid
Administering paclitaxel system formulation makes great progress, and the delivery system that people more pay close attention to includes liposome, cyclodextrin bag
Compound, water-soluble prodrug, micella and nano liposomes etc..Some defects be present in various delivery systems, such as:The particle diameter of microballoon is too
Greatly, mucous membrane can not be passed through or through body circulation directly drug delivery to target tissue, is not suitable for injecting drug use.Liposome has certain
Targeting, but structure is not sufficiently stable, and carrying drug ratio is relatively low.With the prodrug of macromolecular support, large biological molecule has to swollen
The characteristic of knurl position aggregation, and the feature of pharmaceutical in vivo dynamics can be improved, reduce toxicity, but connection medicine and macromolecular at present
Bridge formation group be not easy to find, and joint efficiency is relatively low.In addition, these new delivery system capability of industrialization are low, at present only
Rest on laboratory stage.
The content of the invention
In view of technical problem present in prior art, it is an object of the invention to provide a kind of Docetaxel drug regimen
Thing and preparation method thereof, the toxic side effect of Docetaxel existing product can be reduced, stability is good, has good with transfusion solution
Good compatibility stability, operating procedure is easy, is adapted to industrialized production.
Docetaxel pharmaceutical composition provided by the invention, it is characterised in that composed of the following components：Polyenoid Japanese yew
Alcohol, the dihydroxystearic acid of polyethylene glycol-ten ester, polyethylene glycol 400 and citric acid.Wherein in addition to active component Docetaxel,
The dihydroxystearic acid of polyethylene glycol-ten ester and polyethylene glycol 400 are cosolvent, and citric acid is stabilizer.
Preferably, the Docetaxel pharmaceutical composition, it is characterised in that be made up of each component of following mass parts：
The preferred scope is obtained by many experiments, and if not in the range of, described pharmaceutical composition toxicity is slightly higher, and defeated
The compatibility stability of liquor is slightly worse.
Most preferably, the Docetaxel pharmaceutical composition, it is characterised in that be made up of each component of following mass parts：
When described pharmaceutical composition is above-mentioned mass parts, obtain optimal with transfusion solution compatibility stability and minimum poison
Property.
Combined by the ratio of above-mentioned each component, not only avoid the use of ethanol and Tween-80, while improve this hair
Bright pharmaceutical composition and transfusion solution compatibility stability, reduce toxicity, are advantageous to the application of pharmaceutical composition clinically, mitigate
The pain of patient.
Prior art polyethylene glycol on the books can be used in the injection of Docetaxel being used to promote the molten of active medicine
Solution, including polyethylene glycol 200, Liquid Macrogol, polyethylene glycol 400, Macrogol 600, polyethylene glycol-800 etc., inventor are real
It is best for the products obtained therefrom stability for preparing Docetaxol injection to issue after examination and approval existing polyethylene glycol 400.The present invention uses poly-
Ethylene glycol 400, it is commercially available prod, such as PEG400 (Nanjing Weir medicine company limited company) can be enumerated, PEG400 (makes pottery in the U.S.
Family name company).
Above-mentioned Docetaxel pharmaceutical composition is colorless transparent viscous liquid, and stability is good, can by filtration sterilization,
Packing process is further prepared into the intravenous fluid for Clinical practice, and wherein filtration sterilization can be pressurizeed using 0.22 μm of filter membrane
Filter.The pharmaceutical composition of the present invention can be used as the treatment of cancer, and application method is drip-feed, and the cancer species for the treatment of include breast
Gland cancer, non-small cell lung cancer, stomach cancer, incidence cancer, oophoroma, cancer of the esophagus, carcinoma of endometrium, prostate cancer etc..
The present invention also provides a kind of method for preparing described Docetaxel pharmaceutical composition, comprises the following steps：1)
The dihydroxystearic acid ester of polyethylene glycol-ten is heated to 45~60 DEG C, citric acid is added, is slowly added to polyethylene glycol 400, obtains
Mixed solution, it is stirred until homogeneous；2) Docetaxel is slowly added in above-mentioned mixed solution, 45~60 DEG C of following edgeds stir
Mix, dissolving is until solution is clarified.
The model Solutol HS 15 for the dihydroxystearic acid ester of polyethylene glycol-ten that the present invention uses, by German BASF
Company, it is solid-state to produce under normal temperature, and it is liquid to be heated to more than 30 DEG C, when inventor is to preparing Docetaxel pharmaceutical composition
Heating-up temperature is investigated, use mass fraction for 1 part of Docetaxel, 26 parts of the dihydroxystearic acid of polyethylene glycol-ten ester,
The prescription of 0.1 part of 27 parts of polyethylene glycol 400 and citric acid, investigate active medicine under different temperatures and dissolve situation and to activity
The influence of medicine long-time stability, the fluid composition obtained by different heating temperature are filled into cillin bottle using same method
In, carrying out accelerated stability test, (experiment condition is accelerated test case, temperature：40℃±2℃；Humidity：75% ± 5%), tie
Fruit is as follows：
From the result of upper table, temperature is higher, and the dissolving of Docetaxel is faster.More than 65 DEG C dissolve Docetaxel
Although have a small amount of medicine precipitation, solution turned cloudy quickly but after being down to room temperature.In addition, just prepared under each heating-up temperature
Decoction, total impurities content no significant difference, but during accelerated stability test, the always miscellaneous growth of 60 DEG C of decoctions prepared
Comparatively fast.50 DEG C are heated the decoction impurity no significant difference prepared with 30~45 DEG C.Therefore, in heating process, the present invention
It is preferred that 50 DEG C, on the premise of active component stability is taken into account, the speed of dissolving is faster.
As stirring means, known method can be used, is such as started using magnetic stirring apparatus, Three-One Motor
Machine drive-type agitator is stirred.
The present invention is studied and provided a kind of new more for problem present in Docetaxel injection clinical practice
Alkene taxol drug composition and preparation method thereof, Docetaxel pharmaceutical composition of the invention does not contain ethanol, and uses
New nonionic surfactant polyethylene glycol-ten dihydroxystearic acid ester, which substitutes, easily to be produced haemolysis and anaphylactoid tells
Temperature, can by preparation technology simple and easy to operate be made compared with prior art toxicity it is lower, with transfusion liquid have well match somebody with somebody
5 stability and the higher Docetaxol injection of uniformity, product storage stability, it is adapted to industrialized production and clinical pacifies
It is complete to use.
With reference to the embodiment of embodiment, the present invention will be further described.
Embodiment
Embodiment 1~7
The composition of embodiment 1~7 see the table below：
The preparation method of embodiment 1~7 is：1) the dihydroxystearic acid ester of polyethylene glycol-ten of prescription dosage is taken to be heated to
50 DEG C, citric acid is added, the polyethylene glycol 400 of recipe quantity is slowly added to, obtains mixed solution；2) it is the polyenoid of above-mentioned dosage is purple
China fir alcohol is slowly added in above-mentioned mixed solution, stirring while adding at 50 DEG C, and dissolving is until solution is clarified.
The preparation of the polyene taxol lipid preparation of comparative example 1
Composition：
Preparation method：Phosphatide and propane diols are weighed, 50 DEG C of heating water baths, obtains solution A.Weigh Docetaxel, poly- second
The dihydroxystearic acid of glycol-ten ester, glycerine, citric acid, absolute ethyl alcohol, normal-temperature dissolution, obtain solution B.By solution A and solution B
Mixing, is stirred at room temperature, is well mixed, and filters, obtains polyene taxol liposome preparation, leads to nitrogen protection, is sealed.Will be upper
The polyene taxol liposome preparation for stating step preparation is diluted with the water for injection of 20 times of volumes, obtains polyenic taxusol nano system
Agent.
Docetaxel pharmaceutical composition of comparative example 2 (using cetomacrogol 1000) and preparation method thereof
Composition：
Preparation method：1) take the dihydroxystearic acid ester of polyethylene glycol-ten of above-mentioned dosage to be heated to 50 DEG C, add lemon
Acid, the cetomacrogol 1000 of above-mentioned dosage is slowly added to, obtains mixed solution；2) Docetaxel of above-mentioned dosage is slowly added
Enter in above-mentioned mixed solution, stirring while adding at 50 DEG C, dissolving is until solution is clarified.
Docetaxel pharmaceutical composition of comparative example 3 (using Liquid Macrogol) and preparation method thereof
Composition：
Preparation method：1) take the dihydroxystearic acid ester of polyethylene glycol-ten of above-mentioned dosage to be heated to 50 DEG C, add lemon
Acid, the Liquid Macrogol of above-mentioned dosage is slowly added to, obtains mixed solution；2) Docetaxel of above-mentioned dosage is slowly added
Enter in above-mentioned mixed solution, stirring while adding at 50 DEG C, dissolving is until solution is clarified.
The Docetaxel medicine that comparative example 4 is prepared by composition of the commercialized product without ethanol docetaxel injection
Compositions and preparation method thereof
Composition：
Preparation method：1) polyoxyethylene sorbitan monoleate of above-mentioned dosage is taken to 50 DEG C, is added citric acid, is slowly added to above-mentioned dosage
Polyethylene glycol 400, obtain mixed solution；2) Docetaxel of above-mentioned dosage is slowly added in above-mentioned mixed solution, 50 DEG C
Under it is stirring while adding, dissolving until solution clarify.
The acute toxicity test of embodiment 8
Healthy Kunming mouse (18-22g) 240, male and female half and half, mouse is randomly divided into 12 experimental groups, every group 20
Only, embodiment 1~7, composition made from comparative example 1~4 and the commercialized product list branch for matching Norfin, Inc are given respectively
Dress docetaxel injection (Lot number is bF257A).
Experimental group 1 (20 mouse)：Docetaxel pharmaceutical composition prepared by embodiment 1, dosage is injected intraperitoneally
For 10mg/Kg.
Experimental group 2 (20 mouse)：Docetaxel pharmaceutical composition prepared by embodiment 2, dosage is injected intraperitoneally
For 10mg/Kg.
Experimental group 3 (20 mouse)：Docetaxel pharmaceutical composition prepared by embodiment 3, dosage is injected intraperitoneally
For 10mg/Kg.
Experimental group 4 (20 mouse)：Docetaxel pharmaceutical composition prepared by embodiment 4, dosage is injected intraperitoneally
For 10mg/Kg.
Experimental group 5 (20 mouse)：Docetaxel pharmaceutical composition prepared by embodiment 5, dosage is injected intraperitoneally
For 10mg/Kg.
Experimental group 6 (20 mouse)：Docetaxel pharmaceutical composition prepared by embodiment 6, dosage is injected intraperitoneally
For 10mg/Kg.
Experimental group 7 (20 mouse)：Docetaxel pharmaceutical composition prepared by embodiment 7, dosage is injected intraperitoneally
For 10mg/Kg.
Control group 1 (20 mouse)：Docetaxel pharmaceutical composition prepared by comparative example 1 is injected intraperitoneally, administration
Dosage is 10mg/Kg.
Control group 2 (20 mouse)：Docetaxel pharmaceutical composition prepared by comparative example 2 is injected intraperitoneally, administration
Dosage is 10mg/Kg.
Control group 3 (20 mouse)：Docetaxel pharmaceutical composition prepared by comparative example 3 is injected intraperitoneally, administration
Dosage is 10mg/Kg.
Control group 4 (20 mouse)：Docetaxel pharmaceutical composition prepared by comparative example 4 is injected intraperitoneally, administration
Dosage is 10mg/Kg.
Control group 5 (20 mouse)：Docetaxel injection commercially available prod, dosage 10mg/Kg is injected intraperitoneally.
The toxic reaction symptom of experimental group and control group mice after observation administration.
After 10mg/Kg dosage is administered, there is death within 1 day after the administration of the mouse of control group 5, mouse death rate is after one week
60%；There is death after being administered 2 days in the mouse of control group 1, and the death rate of mouse is 55% after one week, 1 after the administration of the mouse of control group 2
There is death in it, and mouse death rate is 68% after one week, dead, dead mouse after one week occurs within 1 day after the administration of the mouse of control group 3
Rate is 56%；There is death within 2 days after the administration of the mouse of control group 4, mouse death rate is 50% after one week；Seven groups of mouse of the present invention
Toxic reaction, experimental group 1, experimental group 2, experimental group 3, experimental group 4, experimental group 5, experimental group 6 and the mouse of experimental group 7 are respectively
Dead mouse is begun with 1 day, the 4th day, the 4th day, the 3rd day, the 3rd day, the 2nd day, the 2nd day, the death rate of mouse after being administered one week
Respectively 65%, 48%, 36%, 30%, 40%, 45%, 50%, other group of toxic reaction result is obvious in addition to experimental group 1
Less than control group.
Above test result indicates that, with the commercialized product that grinds of original and in the prior art compared with improved formulations product, this hair
Without using Tween 80, show toxicity significantly reduces bright Docetaxel product, and there is higher Clinical practice to be worth.
Embodiment 9 and the compatibility stability of transfusion solution are investigated
By embodiment 1~7, the drug combination preparation of the gained of comparative example 1~4 and commercially available single branch dress docetaxel note
Penetrate liquid product (Lot number is bF257A) it is dissolved in 0.9% physiological saline and (obtains 1~experimental group of experimental group 7, right successively
According to the sample of group 1~control group 5) so that Docetaxel concentration about 0.32mg/mL, placed under the conditions of cool place, evaluation 0~
The interior compatibility stabilities with transfusion solution of 24h, if having generation precipitation.
| Group | Compatibility stability | Group | Compatibility stability |
| Experimental group 1 | Medicine separates out | Control group 1 | 4h is stable |
| Experimental group 2 | 12h is stable | Control group 2 | 4h is stable |
| Experimental group 3 | 24h is stable | Control group 3 | 8h is stable |
| Experimental group 4 | 24h is stable | Control group 4 | 24h is stable |
| Experimental group 5 | 24h is stable | Control group 5 (commercially available prod) | 8h is stable |
| Experimental group 6 | 12h is stable | ||
| Experimental group 7 | 10h is stable |
From the result of upper table, Docetaxel drug combination preparation of the invention is starting to mix with transfusion solution
Afterwards, when the mass fraction of the dihydroxystearic acid ester of polyethylene glycol-ten is no less than 10 times relative to active medicine, under the conditions of shady and cool
It can keep more than 10h stable, otherwise solution is down to room temperature and medicine precipitation phenomenon then occurs；When the dihydroxy of polyethylene glycol-ten
When the mass fraction of the mass fraction of stearate is no more than 50 times relative to active medicine, with that can be kept after transfusion solution compatibility
12 hours stable；When the mass fraction of the dihydroxystearic acid ester of polyethylene glycol-ten relative to active medicine at 15~35 times when
24h can be kept stable under the conditions of cool place, showing transfusion solution has the compatibility stability of highly significant, hence it is evident that higher than commercially available
The docetaxel injection of single branch dress.Illustrate that the feelings of Tween 80 are being not used in the Docetaxel drug combination preparation of the present invention
Condition has been issued to the third generation product with docetaxel --- without (the control of the identical prescription of ethanol docetaxel injection (single branch dress)
Organize 4) identical compatibility stability.And the compatibility stability of Docetaxel Liposomal formulation is poor, by prescription of the present invention
Polyethylene glycol replaces with cetomacrogol 1000 (control group 2) and Liquid Macrogol (control group 3) also substantially not as the present invention makes
The Docetaxel composite preparation prepared with polyethylene glycol 400 is stable.
The accelerated stability test of embodiment 10
Fluid composition made from embodiment 1~7, comparative example 1~4 is filled into cillin bottle using same method
In, with commercially available prod list branch dress docetaxel injection product (Lot number is bF257A) together, carry out acceleration for stabilization
Property experiment (experiment condition is Acceleration study case, temperature：40℃±2℃；Humidity：75% ± 5%).
Commented with the main decomposition thing impurity 7- tables docetaxel of docetaxel, 10- oxygen docetaxel and total miscellaneous content
The stability of liquid preparation after valency accelerated stability test.Using each embodiment of high effective liquid chromatography for measuring and comparative example
The concentration of docetaxel after the just preparation of gained fluid composition and accelerated test, calculate the peak of two main decomposition things and total impurities
As a result area see the table below with respect to the peak area ratio of docetaxel：
From the result of upper table, Docetaxel drug combination preparation is when acceleration environment is placed, main decomposition thing
7- tables docetaxel, 10- oxygen docetaxel and total impurities can increase, Docetaxel drug combination preparation provided by the invention
The preferable Docetaxel drug combination preparation of stability can be prepared in the case of without using Tween-80.
Claims (7)
- A kind of 1. Docetaxel pharmaceutical composition, by Docetaxel, the dihydroxystearic acid of polyethylene glycol-ten ester, poly- second two Alcohol 400 and citric acid composition.
- 2. pharmaceutical composition according to claim 1, it is characterised in that described pharmaceutical composition includes following mass parts Each component：
- 3. pharmaceutical composition according to claim 1, it is characterised in that described pharmaceutical composition includes following mass parts Each component：
- 4. pharmaceutical composition according to claim 1, it is characterised in that the dihydroxystearic acid of polyethylene glycol-ten ester Model Solutol HS 15.
- 5. pharmaceutical composition according to claim 1, it is characterised in that described pharmaceutical composition can be used further Injection is made in 0.22 μm of filter membrane pressure filtration sterilizing, packing.
- 6. the preparation method of Docetaxel pharmaceutical composition, comprises the following steps described in a kind of claim 1：1) the dihydroxystearic acid ester of polyethylene glycol-ten is heated to 45~60 DEG C, adds citric acid, be then slowly added into poly- second two Alcohol 400, obtains mixed solution；2) Docetaxel is slowly added in above-mentioned mixed solution, stirring while adding at 45~60 DEG C, dissolving is until solution is clear Clearly.
- 7. the preparation method of pharmaceutical composition according to claim 6, it is characterised in that heating-up temperature is 50 in step 1) DEG C, the temperature that Docetaxel adds mixed solution dissolving in step 2) is 50 DEG C.
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