CN106852911A - A kind of Cabazitaxel albumin composition of stabilization and preparation method thereof - Google Patents
A kind of Cabazitaxel albumin composition of stabilization and preparation method thereof Download PDFInfo
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Abstract
The invention provides a kind of aseptic freeze-dried composition of the Cabazitaxel of stabilization and preparation method.By the screening to preparation prescription and preparation technology; the characteristics of present invention has outstanding stability, security using the Cabazitaxel albumin composition that the albumin solution of low concentration is prepared; and without using the big organic solvent of toxicity such as water-insoluble chloroform/dichloromethane in preparation process; freeze drying protectant and protein stabiliser need not be added in step of freeze drying; reduce medicine production cost, it is ensured that the security of clinical application.
Description
Technical field
The present invention relates to field of pharmaceutical preparations.It is more particularly related to a kind of Cabazitaxel albumin of stabilization
Aseptic freeze-dried composition and preparation method thereof.
Background technology
Prostate cancer is the most common malignant tumour of male reproductive system, and morbidity increases with the age, and its incidence of disease has bright
Aobvious regional disparity, European and American areas is higher, and the Asia incidence of disease is relatively low.The morbidity and mortality of prostate cancer are only second to lung
Cancer, occupies the second of cancer mortality.In most of cases, prostate cancer slower development in older male,
Asia, its incidence of disease is less than western countries, but is in recent years rapid ascendant trend.
ACS counts, and prostate cancer has accounted for a quarter that cases of cancer is newly made a definite diagnosis in the U.S. every year, 2010
The prostate cancer sufferer about 220,000 that year makes a definite diagnosis, has more than 32,000 patient and dies from the disease.In Europe, annual death figure is
27,000, but global prostate cancer death toll is digital considerably beyond this.Because the age of onset of prostate cancer is generally later,
Thus patients show aging trend.The market prospects of prostate cancer medicine are very wide.Market survey company
Decision Resources are, it is expected that the market value of prostate cancer medicine rises to from nearly 4,000,000,000 dollars of 2009
5,700,000,000 dollars in 2014；8,700,000,000 dollars will further be increased within 2019.
At present, the conventional drug therapy of prostate cancer has following several：
(1) anti-androgen therapy：Antiandrogen preparation acts predominantly on blocking of the androgen to prostatic cell recipient,
Cancer cell is set to receive androgenic message without continued growth, antiandrogen medicine has：Flutamide piece, Kang Shi get
(Bicalutamide piece) etc..
(2) chemotherapy：Endocrine therapy and the irreplaceable effect of radiotherapy can be often played as auxiliary therapy.
The most sensitive chemotherapeutics of prostate cancer is Cyclophosphamide Compound Tablet, and other chemotherapeutics also have cis-platinum (PDD), 5 FU 5 fluorouracil
(5-FU), adriamycin (ADM), mitomycin (MMC), EMP (EMP), taxanes etc..
(3) treatment by Chinese herbs：According to different pulse-phase Coryza Treated by Syndrome Differentiation, there is certain therapeutic effect.
(4) immunization therapy：Immune in recent years rather noticeable with the relation of tumour, immune drug is by improving body
Immunity, improves resistance against diseases to suppress the growth of tumour cell, while it can also protect cell function, reduces endocrine agents
Infringement with cancer therapy drug to body.That clinically applies at present has Kaiyinyisheng (recombinant human interferon alpha 2 b parenteral solution), Xin Ji
Your (injection RhIL-2 (125Ala)) etc..
(5) Bisphosphonates treatment：It is mainly used in prostate cancer with osseous metastasis patient, carries out targeted therapy etc..
Cabazitaxel (cabazitaxel) is a kind of antineoplastic, belongs to taxanes, the precursor extracted by Chinese yew
It is semi-synthetic to prepare.
Cabazitaxel molecular formula is C45H57NO14, white crystals are water insoluble, dissolve in ethanol, chemistry it is entitled (2R,
3S)-3- t-butoxycarbonyl aminos-α of PLA-4-α of acetyl group-2-- 1 β of benzoyl-5 β, 20- epoxy-hydroxyl
Base -7 β, 10 β-α -ester of dimethoxy -9- oxygen -11- Japanese yews alkene -13, its structural formula are as follows：
On June 17th, 2010, FDA (Food and Drug Adminstration) (FDA) have approved Cabazitaxel to be used to control as second-line therapy
Treat prostate cancer.Cabazitaxel belongs to anti-micro-pipe class medicine in antitumor mechanism, mainly by with free tubulin binding,
Promote tubulin polymerization into micro-pipe, while preventing the micro-pipe for having assembled from disintegrating, form the non-functional micro-pipe of stabilization, and then
Suppress the mitosis of cell and intermitotic tumour cell function.Cabazitaxel has extraordinary curative effect to prostate cancer,
Can be combined with metacortandracin, treatment is previously with the patients with prostate cancer of the metastatic hormone refractory containing Docetaxel therapeutic scheme.
In physics and chemistry in nature, Cabazitaxel is as other yew alkanes medicines, with excessively poor water solubility, about 6 μ g/
ml.During Clinical practice Cabazitaxel parenteral solution, Tween-80 must be dissolved in, then noted with ethanol, glucose or normal saline dilution
Penetrate, not only can bring inconvenience to clinical practice, can also cause a series of safety because of the introducing of the auxiliary materials such as Tween-80
Problem.
The content of the invention
On the one hand, the invention provides a kind of aseptic freeze-dried composition of albumin medicine of safe and stable Cabazitaxel.
Composition of the invention is the nano particle of Cabazitaxel or derivatives thereof such as solvate and albumin composition
System.
In aforementioned pharmaceutical compositions, Cabazitaxel or derivatives thereof is 1 with albumin mass ratio：2~30, pH are 6.0
~7.5, average grain diameter is not more than 200nm, freeze after composition zeta current potentials in -2~-9mv, wherein, in freeze-drying process, nothing
Freeze drying protectant and protein stabiliser need to be added.
As it is of the invention preferably, Cabazitaxel or derivatives thereof and albumin mass ratio are 1:10~20, more preferably
1:12~17；
As of the invention preferred, the aseptic freeze-dried pharmaceutical composition that Cabazitaxel or derivatives thereof is constituted with albumin
In, pH is 6.5-7.0；
As it is of the invention preferably, in the pharmaceutical composition that Cabazitaxel or derivatives thereof constitute with albumin, it is lyophilized after
Composition zeta current potentials in -5~-8mv, wherein, the redissolution solvent is included such as physiological saline.
As it is of the invention preferably, the albumin is with sulfydryl or disulfide bond, preferably human serum albumins.
On the other hand, the present invention provides a kind of preparation side of the aseptic freeze-dried composition of Cabazitaxel and albumin
Method, comprises the following steps：
1) Cabazitaxel or derivatives thereof such as solvate is dissolved in organic solvent, forms organic phase；It is described organic
Solvent is selected from alcohols solvent, and the concentration of Cabazitaxel or derivatives thereof is 10~45mg/ml in organic phase；
2) albumin is scattered in aqueous medium, forms water phase；In the water phase, the concentration of albumin is 3-
20mg/ml；
3) by step 1) organic phase and step 2) water mix, high speed shear, homogeneous, prepare the average grain of particle
Footpath is not more than the suspension of 200nm；Wherein, homogeneous can be by the way of for example mixture be transferred in high pressure homogenizer；
4) by step 3) gained suspension be concentrated by ultrafiltration, obtain the albumin composition of Cabazitaxel；
5) by step 4) in gained composition carry out filtration sterilization, then directly freezed dry, be obtained Cabazitaxel and
The aseptic freeze-dried composition of albumin.
In above-mentioned preparation method, step 5) refrigerating process need not add freeze drying protectant and protein stabiliser, wherein,
The freeze drying protectant includes but is not limited to trehalose, sucrose, maltose, lactose, mannitol；Wherein, the protein stabiliser
One or more including but not limited in trehalose, sucrose, Sodium Caprylate, amino acid (such as acetyltryptophan, glycine etc.).
As it is of the invention preferably, step 1) described in alcohols solvent be selected from methyl alcohol, ethanol, ethylene glycol, isopropanol, more
Preferably ethanol；
As it is of the invention preferably, step 2) in albumin concentration be 3-15mg/ml；
As it is of the invention preferably, step 4) in be concentrated by ultrafiltration to 2~20 times；
As it is of the invention preferably, step 3) and 4) in the concentration of Cabazitaxel or derivatives thereof be 0.1~6mg/ml；It is excellent
Select 0.4~4mg/ml；
As it is of the invention preferably, step 3) in the rotating speed cutting of 7000~15000rpm；
As it is of the invention preferably, step 3) in carried out under the pressure of 30000~40000psi it is high-pressure homogeneous；
As it is of the invention preferably, step 3) in homogenizing step repeat 5~6 circulation.
On the other hand, the present invention also provides a kind of Cabazitaxel prepared using above-mentioned preparation method and albumin
Aseptic freeze-dried composition.
The Cabazitaxel albumin freeze-dried composition that preparation method of the present invention is prepared, good stability for example exists
It is electric using Cabazitaxel changes of contents or change of size or zeta of the composition in certain period of time is determined in the present invention
Position changes to assess the stability of composition, it turned out that, the freeze-dried composition that preparation method of the present invention is obtained, in these areas
Stability is all higher than 72 hours.
On the other hand, the present invention also provides a kind of preparation, aseptic freeze-dried group comprising above-mentioned Cabazitaxel and albumin
Compound and pharmaceutically acceptable carrier and/auxiliary material.
As of the invention preferred, sterilized water, salt are included for pharmaceutically acceptable carrier of the invention and/or auxiliary material
Water, glucose, oil (such as corn oil；Peanut oil, sesame oil and the like), acid, low-grade alkane alcohol (glycol；PAG).
As of the invention preferred, anti-corrosion is may also include for pharmaceutically acceptable carrier of the invention and/or auxiliary material
Agent, wetting agent, emulsifying agent, penetration enhancer and the like.
As it is of the invention preferably, preparation of the invention can also include antimicrobial (such as chelating agent, including but do not limit
In EDTA, edetate (ester), citrate (ester), pentetate (ester), trometamol, sorbate (ester), ascorbic acid
Salt (ester), its derivative or its mixture；Such as non-chelating agent, including but not limited to sulphite (ester), benzoic acid, benzylalcohol, chlorine
Any one or more in butanol and p-hydroxybenzoate), sugared (such as sucrose), reconstruct accelerator, negative electrical charge component (example
Such as bile salt, bile acid, glycocholic acid, cholic acid, chenodesoxycholic acid, taurocholate, glycochenodeoxycholate, ox sulphur goose deoxidation courage
Acid, lithocholic acid, ursodesoxycholic acid, dehydrocholic acid, phosphatide).
Preferably preparation of the present invention can be prepared using aseptic preparation, end-filtration or ray sterilizing as of the invention,
Gained preparation preserves or is prepared to lyophilized formulations using solution, it is further preferred that preparation of the present invention is intravenous injection
Preparation.
The aseptic freeze-dried composition or preparation of another further aspect, Cabazitaxel of the invention and albumin can be used to treat cancer
Disease, including but not limited to prostate cancer, colon cancer, SCCHN, breast cancer, head and neck cancer, cancer of pancreas, carcinoma of urinary bladder,
One or more in embryonal-cell lipoma, lung cancer, sdenocarcinoma of stomach, the cancer of the esophagus and oophoroma.
The dosage of freeze-dried composition of the invention or preparation can be with specific medication and the tool of treated cancer
Body type and change.The dosage is enough to produce desired beneficial effect.Composition can be formulated for single dose and apply or many
Relatively heavy amount is applied.
Freeze-dried composition of the invention or preparation can be applied by any approach well known by persons skilled in the art, including
In intramuscular, intravenous, intradermal, focus, intraperitoneal injection or any other suitable approach.Using can be local, surface
Or whole body, depending on therapentic part.Most suitable approach in the case of any giving depends on many factors, such as disease
Property, the process of disease, the seriousness of disease etc..Preferably, pharmaceutical composition of the invention or pharmaceutical preparation are by quiet
Arteries and veins inner injecting and administering.
Freeze-dried composition of the invention or preparation can also be applied together with the second reactive compound/second therapeutic agent.This
The freeze-dried composition or pharmaceutical preparation of invention can simultaneously, in succession or parallel be applied with the second reactive compound/second therapeutic agent.
When applying respectively, freeze-dried composition of the invention or preparation and the second reactive compound or second therapeutic agent can be with different
Medicine frequency or interval are applied.
Can be used for the second reactive compound of the invention/second therapeutic agent can include but is not limited to anthracene nucleus medicament (such as
Epirubicin), nucleoside compound (such as gemcitabine).
In order to solve the dissolubility defect of Cabazitaxel, prior art is mostly using the side of human serum albumins nanometer formulation
Formula.The preparation method of the albumin nano preparation generally selected is the technology based on disulfide formation method, i.e., first that medicine is molten
Yu Yushui not miscible organic solvent obtains oil phase, and albumin is dissolved in into aqueous medium obtains water phase, then again by oil phase with
Water mixes homogenizing, prepares nanoparticle.But the method must use the water-insoluble organic solvents ability such as chloroform, dichloromethane
Ensure to obtain uniform suspension during preparation, so as to guarantee to prepare trickle nano particle, but these have
Not only there is machine solvent larger toxicity to be unsuitable for largely being applied to human body for a long time, also result in albumin denaturation, destroy albumen
The stability of nano particle preparations.
Patent CN102458112A and patent CN103393632A disclose taxone albumin nanoparticle group
Compound, largely the big organic solvent of toxicity such as chloroform/dichloromethane has been used in preparation.Patent CN103393632A is saying
Being particularly pointed out in bright book need to control dichloromethane/chloroform content in more than 90% (v/v), and can ensure to prepare can be aseptic
The nano particle of filtering, and illustrate to be less than 200nm and the particle that can be sterile filtered to obtain diameter, organic phase is contained within one
Plant the organic solvent not miscible with water to be very important, or even dichloromethane is directly used also in embodiment as organic
Phase；And patent CN1515244A then explicitly points out what is only prepared in the case of low-down ethanol component (less than 3%, V/V)
Particle can be sterile filtered.
Additionally, prior art has used the albumin of high concentration for the kappa albumin nano preparation stablized.Specially
Sharp CN103393632A points out albumin concentration of aqueous solution for 5-25% (w/v), and scope preferably, that is, exists in 10%-20% (w/v)
Concentration range is 50-250mg/ml, in patent CN103393632A it is mentioned that protein played in nano particle dispersion,
The effect of stabilization particulate, enzyme protein dosage cannot prepare the albumin nanoparticle of stabilization more at least.Due to high concentration
The human serum albumins adverse reaction such as allergy, body fluid can be caused to be detained, and in the collection of albumin, blood collection, storage etc.
Process there may be pollution, can also cause that the security of blood product has hidden danger.Therefore, a large amount of of albumin use not only not
Beneficial to clinical safety, can also increase production cost.The aseptic freeze-dried composition of Cabazitaxel of the present invention and albumin and preparation side
Method has the beneficial effect that：
1st, the composition of Cabazitaxel of the present invention and albumin, without using surfactants such as Tween-80s.It is of the invention
Adjustment that pharmaceutical composition passes through prescription and technological parameter, it is to avoid the surfactant such as addition Tween-80, it is also possible to be prepared into
To the composition of stabilization, the severe allergic defect that surface-active is brought is overcome.
2nd, the composition of Cabazitaxel of the present invention and albumin in preparation process using only alcohol organic solvent, it is to avoid make
With organic solvents such as dichloromethane/chloroforms, overcome that must to add toxicity in the prior art big and the unmixing solvent of water lack
Fall into.
3rd, the composition of Cabazitaxel of the present invention and albumin reduces the concentration of albumin, it is ensured that clinical application
Security, reduce production cost.
4th, the composition of Cabazitaxel of the present invention and albumin has the average grain diameter and outstanding stabilization less than 200nm
Property.
5th, the composition of Cabazitaxel of the invention and albumin is when lyophilized formulations are prepared, it is not necessary to add frozen-dried protective
Agent and protein stabiliser, it is also possible to prepare qualified lyophilized formulations.
Brief description of the drawings
Fig. 1 shows the grain size distribution of the Cabazitaxel albumin nanoparticle of embodiment 1.
Fig. 2 shows the grain size distribution of the Cabazitaxel albumin nanoparticle of embodiment 2.
Fig. 3 shows the grain size distribution of the Cabazitaxel albumin nanoparticle of embodiment 3.
Fig. 4 shows the grain size distribution of the Cabazitaxel albumin nanoparticle of embodiment 4.
Fig. 5 shows the grain size distribution of the Cabazitaxel albumin nanoparticle of embodiment 5.
Fig. 6 shows the grain size distribution of the Cabazitaxel albumin nanoparticle of embodiment 6.
Fig. 7 shows the grain size distribution of the Cabazitaxel albumin nanoparticle of embodiment 7.
Fig. 8 shows the zeta potential diagrams of the Cabazitaxel albumin nanoparticle of embodiment 1.
Specific embodiment
Below in conjunction with embodiment, the present invention is further elaborated, but these embodiments do not constitute any limit to the present invention
System.
Rev/min rpm in the present invention is the unit of rotating speed, i.e.,；The unit of psi pressure, i.e., pound/square inch.
Cabazitaxel derivative in the present invention includes but is not limited to compound of the structure similar to Cabazitaxel, or
Same total with the pharmaceutically-acceptable salts of Cabazitaxel, Cabazitaxel department analog or Cabazitaxel or its analog
Compound in chemical classes, can also include the pharmaceutically acceptable salt of above-claimed cpd.
The measure of average grain diameter of the invention：Take the dispersion of the solution such as testing sample plus water for injection or 0.9% sodium chloride equal
It is even, sample stock solution is obtained, take sample stock solution in right amount, translucent (or 5-30 times of dilute with water) is diluted with water to, use nanometer
Particle size analyzer (Zetasizer Nano ZS, Malvern Instr Ltd.) carries out the measure of average grain diameter.
The measure of Zeta potential of the invention：Take testing sample plus water for injection or 0.9% sodium chloride solution be uniformly dispersed,
The measure of Zeta potential is carried out using nano particle size instrument (Zetasizer Nano ZS, Malvern Instr Ltd.).
Embodiment 1
The Cabazitaxel of 300mg is dissolved in the ethanol of 30ml, organic phase is formed, by the 400ml human serum albumin aqueous solution
(15mg/ml) mixes water with organic as water phase, is placed in high-speed shearing machine and turns with after the rotating speed cutting of 10000rpm
Enter in high pressure homogenizer, homogeneous is carried out under the pressure of 35000psi, 5 circulations prepare suspension, the average grain of its particle
Footpath is 119.8nm, and pH is 6.7, and suspension is passed through 0.22 μm of aseptic filter filtration sterilization, and directly freezed dries 60h,
Freeze-dried composition is obtained, by the composition after the completion of freeze-drying, using physiological saline as medium is redissolved, zeta current potentials is measured
It is -5.7mv, grain size analysis is carried out using Malvern particle size analyzer, the average grain diameter for measuring is 120.3nm, after room temperature is placed,
Detected through high performance liquid chromatography (HPLC), find Cabazitaxel content without significant change, stability is more than 72 hours.
Embodiment 2
The Cabazitaxel of 300mg is dissolved in the ethanol of 15ml, organic phase is formed, by the 500ml human serum albumin aqueous solution
(6mg/ml) mixes water with organic as water phase, is placed in high-speed shearing machine to be transferred to after the rotating speed cutting of 7000rpm
In high pressure homogenizer, homogeneous is carried out under the pressure of 30000psi, 5 circulations prepare suspension, its mean particle size
It is 134.4nm, pH is 6.5, suspension is passed through 0.22 μm of aseptic filter filtration sterilization, directly freezed dries 60h, obtains
To freeze-dried composition, by the composition after the completion of freeze-drying, using physiological saline as medium is redissolved, measure zeta current potentials for-
3.4mv, grain size analysis is carried out using Malvern particle size analyzer, and the average grain diameter for measuring is 135.4nm, after room temperature is placed, warp
HPLC detects that find Cabazitaxel content without significant change, stability is more than 72 hours.
Embodiment 3
The Cabazitaxel of 300mg is dissolved in the ethanol of 10ml, organic phase is formed, by the 180ml human serum albumin aqueous solution
(20mg/ml) mixes water with organic as water phase, is placed in high-speed shearing machine and turns with after the rotating speed cutting of 15000rpm
Enter in high pressure homogenizer, homogeneous is carried out under the pressure of 40000psi, 6 circulations prepare suspension, the average grain of its particle
Footpath is 164.4nm, and pH is 7.0, and suspension is passed through 0.22 μm of aseptic filter filtration sterilization, and directly freezed dries 60h,
Freeze-dried composition is obtained, by the composition after the completion of freeze-drying, using physiological saline as medium is redissolved, zeta current potentials is measured
It is -7.5mv, grain size analysis is carried out using Malvern particle size analyzer, the average grain diameter for measuring is 165.7nm, after room temperature is placed,
Detected through HPLC, find Cabazitaxel content without significant change, stability is more than 72 hours.
Embodiment 4
The Cabazitaxel of 300mg is dissolved in the ethanol of 6.7ml, organic phase is formed, 1700ml human serum albumins is water-soluble
Liquid (3mg/ml) mixes water with organic as water phase, after being placed in high-speed shearing machine with the rotating speed cutting of 12000rpm
It is transferred in high pressure homogenizer, homogeneous is carried out under the pressure of 30000psi, 6 circulations prepares suspension, and its particle is average
Particle diameter is 184.1nm, and pH is 7.5, and suspension is passed through 0.22 μm of aseptic filter filtration sterilization, and directly freezed dries 60h i.e.
Can, freeze-dried composition is obtained, by the composition after the completion of freeze-drying, using physiological saline as medium is redissolved, measure zeta electricity
Position is -4.6mv, and grain size analysis is carried out using Malvern particle size analyzer, and the average grain diameter for measuring is 185.1nm, and room temperature is placed
Afterwards, detected through HPLC, find Cabazitaxel content without significant change, stability is more than 72 hours.
Embodiment 5
The Cabazitaxel of 300mg is dissolved in the ethanol of 15ml, organic phase is formed, by the 1125ml human serum albumin aqueous solution
(4mg/ml) mixes water with organic as water phase, is placed in high-speed shearing machine to be transferred to after the rotating speed cutting of 7000rpm
In high pressure homogenizer, homogeneous is carried out under the pressure of 40000psi, 6 circulations prepare suspension, its mean particle size
It is 162.1nm, pH is 6.2, suspension is passed through 0.22 μm of aseptic filter filtration sterilization, directly freezed dries 60h, obtains
To freeze-dried composition, by the composition after the completion of freeze-drying, using physiological saline as medium is redissolved, measure zeta current potentials for-
2.8mv, grain size analysis is carried out using Malvern particle size analyzer, and the average grain diameter for measuring is 163.6nm, after room temperature is placed, warp
HPLC detects that find Cabazitaxel content without significant change, stability is more than 72 hours.
Embodiment 6
The Cabazitaxel of 300mg is dissolved in the ethylene glycol of 15ml, organic phase is formed, 150ml human serum albumins is water-soluble
Liquid (3mg/ml) mixes water with organic as water phase, is placed in high-speed shearing machine and turns with after the rotating speed cutting of 7000rpm
Enter in high pressure homogenizer, homogeneous is carried out under the pressure of 40000psi, 5 circulations prepare suspension, the average grain of its particle
Footpath is 143.5nm, and pH is 6.1, and suspension is passed through 0.22 μm of aseptic filter filtration sterilization, and directly freezed dries 60h,
Freeze-dried composition is obtained, by the composition after the completion of freeze-drying, using physiological saline as medium is redissolved, zeta current potentials is measured
It is -8.3mv, grain size analysis is carried out using Malvern particle size analyzer, the average grain diameter for measuring is 143.6nm, after room temperature is placed,
Detected through HPLC, find Cabazitaxel content without significant change, stability is more than 72 hours.
Embodiment 7
The Cabazitaxel of 300mg is dissolved in the methyl alcohol of 10ml, organic phase is formed, by the 75ml human serum albumin aqueous solution
(10mg/ml) mixes water with organic as water phase, is placed in high-speed shearing machine and turns with after the rotating speed cutting of 10000rpm
Enter in high pressure homogenizer, homogeneous is carried out under the pressure of 40000psi, 5 circulations prepare suspension, the average grain of its particle
Footpath is 168.7nm, and pH is 6.8, and suspension is passed through 0.22 μm of aseptic filter filtration sterilization, and directly freezed dries 60h,
Freeze-dried composition is obtained, by the composition after the completion of freeze-drying, using physiological saline as medium is redissolved, zeta current potentials is measured
It is -6.1mv, grain size analysis is carried out using Malvern particle size analyzer, the average grain diameter for measuring is 169.0nm, after room temperature is placed,
Detected through HPLC, find Cabazitaxel content without significant change, stability is more than 72 hours.
Test example 1
By compositions of the embodiment 1-7 after lyophilized, after being redissolved with physiological saline, its is determined in different time points respectively average
Particle diameter and Zeta potential, as a result such as following table
From above-mentioned data, Cabazitaxel preparation stability of the present invention is excellent, after being redissolved with physiological saline in 72 hours
Particle diameter and Zeta potential are measured without substantially change.
Test example 2
According to the preparation method of embodiment 3, the lyophilized combination of Cabazitaxel albumin is prepared using different organic solvents
Thing, after being redissolved with physiological saline, determines its particle diameter in different time points respectively, investigates different organic solvents white for Cabazitaxel
The influence of the average grain diameter and stability of protein nano preparation, as a result such as following table：
From above-mentioned data, using " ethyl acetate ", " dichloromethane ", " acetone ", " ethanol/chloroform ", " ethanol/bis-
The Cabazitaxel albumin freeze-dried composition that the organic solvents such as chloromethanes " are prepared, its particle size stability is less than 72 hours.
Test example 3
According to the preparation method of embodiment 1, the lyophilized group of Cabazitaxel albumin is prepared using different albumin concentrations
Compound, after being redissolved with physiological saline, determines its particle diameter in different time points respectively, investigates different albumin concentrations to Cabazitaxel
The influence of the average grain diameter and stability of albumin nano preparation, as a result such as following table：
From above-mentioned data, during using preparation method of the invention, when albumin concentration is too small, will be unable to form nanometer
Grain, and albumin concentration it is excessive when, the particle size stability to the freeze-dried composition for preparing brings considerable influence.
Test example 4
Freeze-dried composition prepared by Example 1-7, the main ingredient Cabazitaxel after HPLC is investigated and placed different time
The situation of change of content and impurity
From above-mentioned data, Cabazitaxel preparation stability of the present invention is excellent, and drug content and impurity content are small 72
Shi Zhongwu significant changes.
Test example 5
Investigate the property influence of add/not add freeze drying protectant and protein stabiliser on the present composition
Dispersion suspension is prepared according to the preparation method homogeneous of embodiment 1, by above-mentioned dispersion suspension filtration sterilization
Afterwards plus 5% mass volumn concentration mannitol (W:V) directly freeze 60 hours, physiological saline redissolve after, measure kappa he
Match average diameter of particles is 121.5nm, and Zeta potential is -5.7mv, and drug content is 99.5%, impurity 0.08%；
The freeze-dried composition that 60h is obtained is dried according to the preparation method directly freezed of embodiment 1, using physiological saline as again
Molten medium, measures Cabazitaxel mean particle size for 120.3nm, and zeta current potentials are -5.7mv, and drug content is 99.9%, miscellaneous
Matter 0.07%.
Be can be seen that from this test example data：The present composition in step of freeze drying, with addition freeze drying protectant and egg
White stabilizer is compared, and the property without freeze drying protectant and the composition of protein stabiliser is basically unchanged.Therefore of the present invention group
Compound need not add freeze drying protectant and protein stabiliser in step of freeze drying, reduce medicine production cost, it is ensured that clinical
The security of medication.
Test example 6
Investigate influence of the composition without freeze drying protectant/stabilizer to property beyond the present invention
300mg Cabazitaxels are dissolved in the absolute ethyl alcohol of the chloroform of 1.35ml and 0.15ml, it is organic to be added to
To in the human serum albumin aqueous solution of 28.5ml (9.47%, w/v), mixture is in slow-speed of revolution condition down cut 3 minutes shapes of homogenate
Into thick emulsion, it is transferred in high-pressure homogenate device, 7 circulations of homogenate under 3,000~30,000psi pressure conditions.The liquid for obtaining
It is transferred in rotary evaporator, (10-15KPa) evaporation of being depressurized under the conditions of 40 DEG C removes organic solvent in 30 minutes.The dispersion for obtaining
Suspension is translucent, and by dispersion suspension by 0.22 μm of nuclepore membrane filter, Cabazitaxel average diameter of particles is
153nm。
It is lyophilized：
A, by above-mentioned dispersion suspension directly freezed dry 48 hours, physiological saline redissolve after, measure Cabazitaxel particle
Average diameter is 155nm, and zata current potentials are -21.4mv, and drug content is 90.4%, impurity 8.4%；
B, by above-mentioned dispersion suspension directly freeze 60 hours, physiological saline redissolve after, measure Cabazitaxel particle average
A diameter of 152nm, zata current potential are -18.7mv, and drug content is 88.7%, impurity 11.2%；
The Cabazitaxel albumin composition beyond the present invention is can be seen that from this test example data, it is lyophilized being not used
In the case of protective agent or stabilizer, the product for obtaining directly is freezed, drug content and impurity content are substantially inferior to the present invention.
The all documents referred in the present invention are all incorporated as reference in this application, and each document is individually recited
As reference.Moreover, it should be understood that after the above of the invention has been read, those skilled in the art can be to this hair
Bright to make various changes or modifications, these equivalent forms equally fall within the application claims limited range.
Claims (10)
1. the aseptic freeze-dried composition of a kind of Cabazitaxel and albumin, it is characterised in that：The composition is by Cabazitaxel
Or derivatives thereof the nanoparticle system for freezing that is constituted with albumin, Cabazitaxel or derivatives thereof is with albumin mass ratio
1:2~30, pH are 6.0~7.5, and average grain diameter is not more than 200nm, and zeta current potentials are -2~-9mv, wherein, in freeze-drying process,
Freeze drying protectant and protein stabiliser need not be added；
Wherein, the albumin preferably carries sulfydryl or disulfide bond, further preferred human serum albumins.
2. the aseptic freeze-dried composition of Cabazitaxel according to claim 1 and albumin, it is characterised in that：Cabazitaxel
Or derivatives thereof with albumin mass ratio be 1:10~20, more preferably 1:12~17；PH is 6.5~7.0；Zeta current potentials are -5
~-8mv.
3. Cabazitaxel described in a kind of claim 1 and the preparation method of the aseptic freeze-dried composition of albumin, its feature exist
In preparation process is as follows：
1) Cabazitaxel or derivatives thereof is dissolved in organic solvent, forms organic phase；The organic solvent is selected from alcohols solvent,
The concentration of Cabazitaxel or derivatives thereof is 10~45mg/ml in organic phase；
2) albumin is scattered in aqueous medium, forms water phase；In the water phase, the concentration of albumin is 3-20mg/
ml；
3) by step 1) organic phase and step 2) water mix, high speed shear, homogeneous, prepare mean particle size not
Suspension more than 200nm；
4) by step 3) gained suspension be concentrated by ultrafiltration, obtain the albumin composition of Cabazitaxel；
5) by step 4) in gained composition carry out filtration sterilization, then directly freezed dry, be obtained Cabazitaxel and white egg
White aseptic freeze-dried composition.
4. the preparation method of the aseptic freeze-dried composition of Cabazitaxel according to claim 3 and albumin, its feature exists
In：Step 1) described in alcohols solvent be selected from methyl alcohol, ethanol, ethylene glycol, isopropanol, more preferably ethanol.
5. Cabazitaxel according to claim 3 or 4 and the preparation method of the aseptic freeze-dried composition of albumin, its feature
It is：Step 2) in albumin concentration be 3-15mg/ml；Step 3) and step 4) in the concentration of Cabazitaxel or derivatives thereof be
0.1~6mg/ml, it is preferred that the concentration of Cabazitaxel or derivatives thereof is 0.4~4mg/ml；Step 4) in be concentrated by ultrafiltration to 2
~20 times.
6. Cabazitaxel according to any one of claim 3 to 5 and the preparation side of the aseptic freeze-dried composition of albumin
Method, it is characterised in that：High speed shear speed is 7000~15000rpm；Homogenization pressure is 30000~40000psi；Homogenizing step
Repeat 5~6 circulations.
7. a kind of preparation, the aseptic freeze-dried composition comprising Cabazitaxel according to claim 1 and 2 and albumin and
Pharmaceutically acceptable carrier and/auxiliary material.
8. a kind of preparation, the Cabazitaxel and the nothing of albumin prepared comprising the method according to any one of claim 3 to 6
Bacterium freeze-dried composition and pharmaceutically acceptable carrier and/auxiliary material.
9. the preparation according to claim 7 or 8, it is characterised in that the preparation can using aseptic preparation, end-filtration or
Prepared by ray sterilizing, gained preparation preserves or be prepared to lyophilized formulations using solution, it is preferred that the preparation is intravenous injection
Preparation.
10. described in Cabazitaxel described in claim 1 or 2 and the aseptic freeze-dried composition of albumin or claim 8 or 9
Purposes of the preparation in the medicine for treating cancer is prepared, it is thin that the cancer is selected from prostate cancer, colon cancer, incidence squamous
Born of the same parents' cancer, breast cancer, head and neck cancer, cancer of pancreas, carcinoma of urinary bladder, embryonal-cell lipoma, lung cancer, sdenocarcinoma of stomach, the cancer of the esophagus and oophoroma.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111135296A (en) * | 2018-11-02 | 2020-05-12 | 四川大学 | Albumin-bound indocyanine green anti-tumor photo-thermal preparation and preparation method thereof |
| US11413265B2 (en) | 2018-04-20 | 2022-08-16 | Zhuhai Beihai Biotech Co., Ltd. | Formulations and compositions of Cabazitaxel |
| US11510895B2 (en) | 2016-01-15 | 2022-11-29 | Zhuhai Beihai Biotech Co., Ltd. | Compositions and formulations including cabazitaxel and human serum albumin |
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| CN103393632A (en) * | 2013-07-26 | 2013-11-20 | 齐鲁制药有限公司 | Cabazitaxel drug composition and preparation method thereof |
| CN104224750A (en) * | 2014-09-17 | 2014-12-24 | 四川大学 | Cabazitaxel albumin nanoparticle preparation for injection and preparation method thereof |
| WO2015018380A2 (en) * | 2014-07-03 | 2015-02-12 | Cspc Zhongqi Pharmaceutical Technology(Shijiazhuang)Co., Ltd. | Therapeutic nanoparticles and the preparation methods thereof |
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| CN103393632A (en) * | 2013-07-26 | 2013-11-20 | 齐鲁制药有限公司 | Cabazitaxel drug composition and preparation method thereof |
| WO2015018380A2 (en) * | 2014-07-03 | 2015-02-12 | Cspc Zhongqi Pharmaceutical Technology(Shijiazhuang)Co., Ltd. | Therapeutic nanoparticles and the preparation methods thereof |
| CN104224750A (en) * | 2014-09-17 | 2014-12-24 | 四川大学 | Cabazitaxel albumin nanoparticle preparation for injection and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US11510895B2 (en) | 2016-01-15 | 2022-11-29 | Zhuhai Beihai Biotech Co., Ltd. | Compositions and formulations including cabazitaxel and human serum albumin |
| US11413265B2 (en) | 2018-04-20 | 2022-08-16 | Zhuhai Beihai Biotech Co., Ltd. | Formulations and compositions of Cabazitaxel |
| CN117205305A (en) * | 2018-04-20 | 2023-12-12 | 珠海贝海生物技术有限公司 | Formulations and compositions of cabazitaxel |
| CN117205305B (en) * | 2018-04-20 | 2024-04-26 | 珠海贝海生物技术有限公司 | Formulations and compositions of cabazitaxel |
| CN111135296A (en) * | 2018-11-02 | 2020-05-12 | 四川大学 | Albumin-bound indocyanine green anti-tumor photo-thermal preparation and preparation method thereof |
| CN111135296B (en) * | 2018-11-02 | 2021-07-20 | 四川大学 | Albumin-bound indocyanine green anti-tumor photo-thermal preparation and preparation method thereof |
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