CN106176631A - The freeze-dried composition of antitumor - Google Patents
The freeze-dried composition of antitumor Download PDFInfo
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- CN106176631A CN106176631A CN201610663988.9A CN201610663988A CN106176631A CN 106176631 A CN106176631 A CN 106176631A CN 201610663988 A CN201610663988 A CN 201610663988A CN 106176631 A CN106176631 A CN 106176631A
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- Prior art keywords
- pharmaceutical composition
- cabazitaxel
- protein
- injectable powder
- contact angle
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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
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
-
- 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
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2063—Proteins, e.g. gelatin
Abstract
The present invention relates to the freeze-dried composition of antitumor.Concrete, the present invention relates to the pharmaceutical composition of antitumor, its be active medicine with protein after nano-dispersed technical finesse, the sterile cryo xeraphium injection prepared.The method that the invention still further relates to prepare suspension for injection, the method includes the step adding 0.9% sodium chloride injection in the pharmaceutical composition in lyophilization injectable powder form.Pharmaceutical composition of the present invention has excellent technique effect as described in description of the invention.
Description
Technical field
The present invention relates to the freeze-dried composition of a kind of antitumor, particularly relate to a kind of kappa in powder he
Match pharmaceutical composition, it can be used for treating tumor and/or cancer.The invention still further relates to the above-mentioned Cabazitaxel medicine in powder
The preparation method of compositions, this compositions is that a kind of intravenous that can be used for gives the microgranule load of pharmacological active substance Cabazitaxel
Body.Cabazitaxel pharmaceutical composition in the present invention actually contains the nano-particle colloid disperse system of Cabazitaxel.Kappa
Nano-particle is formed so that association mode is combined in his match is encapsulated in the polymer shell body being made up of protein or with protein,
When this freeze-dried composition is the most soluble in water, pH granule in 5.0～7.0 scopes, and the disperse system formed is the most straight
Footpath is not more than 200nm.Freeze-dried composition of the present invention preparation need not use conventional surfactant or any polymer
Core matrix, and aseptic filtration can be carried out.Particularly, the present invention has the injectable powder of specific moisture content range and has excellence
Stability.
Background technology
Cabazitaxel, English name CABAZITAXEL, its chemical entitled 4-acetoxyl group-2 α-benzoyloxy-5 β, 20-
Epoxy radicals-1-hydroxyl-7 β, 10 β-dimethoxy-9-oxo yew-11-alkene-13 α-base (2R, 3S)-3-tert-butoxycarbonyl ammonia
Base-PLA ester, molecular formula is C45H57NO14, structural formula is as follows:
Cabazitaxel belongs to the freeze-dried composition of taxane antitumor, it by interference cell mitosis and
Microtubular network necessary to inerphosei cells function and rise antitumor action, belong to microtubule depolymerization inhibitor, it can be with free
Tubulin binding, promotes that tubulin is assembled into stable micro-pipe, suppresses its depolymerization simultaneously, cause losing normal function micro-
Producing of tube bank and fixing of micro-pipe, thus suppress the mitosis of cell.
Cabazitaxel injection, trade name: JEVTANA, specification is 60mg, and one is dissolved in 1.5ml for 60mg Cabazitaxel
In Tween 80 solution, another is solvent, for 13% (w/w) ethanol water of 5.7ml, by Sanofi-Aventis
(Sanofi-Aventis) company's research and development, on June 17th, 2010 by FDA approval listing.JEVTANA is recommended for and sprinkles Buddhist nun
Pine combination treatment is previously with containing Docetaxel therapeutic scheme hormone refractory metastatic prostate cancer patient.
Although Cabazitaxel has good antitumor action, but its water solublity is poor, about 6 μ g/ml, the most clinically
The Cabazitaxel injection used need to use surfactant Polysorbate 80 (i.e. tween 80) and cosolvent ethanol to reach molten
Solve the purpose of Cabazitaxel.Although using surface active agent tween 80 can be configured to injection, but Tween 80 should in clinic
It is easily generated untoward reaction in and causes more complication, relatively conventional including serious anaphylaxis, fluid retention etc.,
Therefore hormone medicine need to be used during Clinical practice to be administered in advance and to prevent allergy, and need to slowly instil (generally more than 1 hour).
Additionally, Tween 80 also has hemolytic, stickiness, and can not be used together with polrvinyl chloride conveyer device (tend to leach height greatly
The di (2-ethylhexyl) phthalate of toxicity) etc. problem, therefore bring inconvenience and safety issue to clinical practice.
For reducing the side effect of injection intravenously administrable, pharmacological active substance is wrapped into micron by an effective method exactly
Or in nano level particle.On the one hand, intravenous particle can be with slow release pharmacological active substance and extend its Half-life in vivo；
On the other hand, targeting material can be by the release of the pharmacological active substance targeting in particle.The existing system relating to nanoparticle
In standby technology, such as the preparation method (CN1515244A) of Abraxane, protein solution is uniformly mixed with organic solvent and high pressure
Homogenate, forms the albumin nanoparticle with pharmacological active substance as core.This patent is expressly recited only low-down
In the case of organic facies component (＜ 3%, V/V) granule of preparation could aseptic filtration, someone is repeated several times aforementioned patent embodiment,
Attempt different bearing taxanes (such as paclitaxel, Docetaxel and the Cabazitaxel) protein nanoparticles of preparation, it is impossible to
Realizing embodiment and result described in this description, granule stability is the most undesirable, it is difficult to meet intravenously administrable needs, and
And low-down phase component means bigger aqueous phase volume (when organic facies drug concentration determines) and longer preparation time.
Corresponding with abnormal low phase component, in embodiment, organic facies and aqueous mixture homogenate terminate rear medicinal liquid drug concentration
All it is not higher than 5mg/ml.
In other nanoparticle technology of preparing, the open CN102048695A of Chinese invention patent by the expansion of albumen with
Pharmacological active substance is wrapped into wherein by refolding or self assembly, forms protein nano granule.Someone is repeated several times in aforementioned patent
Embodiment, can not realize embodiment and result described in this description, especially gone by dialysis and other modes
During micromolecular compound, protein nano granule stability is poor, reason may be organic solvent and protein denaturant long
Time is present in nano-particle suspension, stablizes protein nano granule before micromolecular compound completely removes
Property damages.
The storage of medicine long period to be experienced and transport.Above-mentioned use protein is as being suspended in that pharmaceutical carrier is formed
Protein nano granule in liquid, it finally also needs to remove solvent, typically uses freeze-drying method to remove solvent.
Remove the medicine carrying protein nano granule after solvent and form the powder composition of freeze-dried, generally also may be used before lyophilization
To add appropriate freeze drying excipient such as mannitol, sucrose, lactose etc..The powder combinations of this freeze-dried formation
Thing, is sealed in vial and preserves (usually 1～3 year) for long-term, again dissolves (logical with solvent by it before Clinical practice
The most also known as redissolution, reconstruct etc.), formation can intravenous suspension.It is essential, compared to nanometer in preparation process
The grain size parameter of granule, prepared before Clinical practice can intravenous suspension, the grain size parameter of nano-particle therein
It is only clinical meaning, because in some needs the medicine of control particle size, medicine is (the most usually said through long-term storage
Storage period) afterwards the size of microgranule there may be change, once there is this change, medicine with the physically stable of particle size Lambda characterization
Property needs special concern.Regrettably, it has been found that, prior art use albumin made by Cabazitaxel
These nano-particle suspensions and freeze-dried after, this lyophilization powder particle size during Long-term Storage can occur
Disadvantageous change.
Therefore, this area remains a need for new method and prepares the freeze-dried composition of stable antitumor, especially
It is to can be used for intravenous to give the particulate carrier of pharmacological active substance Cabazitaxel.
Summary of the invention
For the deficiencies in the prior art, the main object of the present invention be to provide a kind of preferably for delivering in vivo kappa he
Match or the pharmaceutical composition of its solvate, this compositions is the powder composition of freeze-dried acquisition, and it is being noted by routine
After penetrating solvent redissolution, it is rendered as a kind of nano-particle colloid disperse system that can be used for intravenous administration.Provided by the present invention
Freeze-dried composition need not use the ethanol in current Cabazitaxel injection and Tween 80, it is to avoid anaphylactoid
Raw, solve and Cabazitaxel injection Clinical practice is susceptible to serious toxic and side effects and the longer problem of transfusion time.This
The another object of invention is to provide preferably for the preparation method of delivering in vivo Cabazitaxel nano-particle colloid disperse system.
The advantage of the pharmaceutical composition prepared by the method is to carry out aseptic filtration by the filter of aperture 0.22 μm, with preparation
It is available for the pharmaceutical preparation of intravenous drip.
To this end, first aspect present invention provides the pharmaceutical composition of a kind of antitumor, it is Cabazitaxel and albumen
Matter after nano-dispersed technical finesse, prepare sterile cryo xeraphium injection.
Pharmaceutical composition according to a first aspect of the present invention, wherein said Cabazitaxel is coated in protein or and egg
The nano-particle that white matter combines in the way of association and formed.In one embodiment, will be in lyophilization injectable powder form
Described pharmaceutical composition 1g add to 0.9% sodium chloride solution 20～50ml is uniformly dispersed after, according to " People's Republic of China's medicine
Allusion quotation " the 3rd method i.e. light scattering determining granularity and granularity in 2015 years four Section of 0982 granularities of version and particle size distribution method
Distribution, mean diameter is in 50～200nm scopes, and the particle diameter microgranule less than 50nm is less than 5%, and the particle diameter microgranule more than 350nm is few
In 5%.In one embodiment, mean diameter is in the range of 100～200nm.
Pharmaceutical composition according to a first aspect of the present invention, is the pharmaceutical composition 1g of lyophilization injectable powder form by this
Add to, in 0.9% sodium chloride solution 20ml, shake gently, record to being completely dispersed uniformly and the time of the non-dispersing solid thing of nothing,
As jitter time, this jitter time is 5～20 minutes.In one embodiment, this jitter time is 5～15 minutes.
Pharmaceutical composition according to a first aspect of the present invention, is the pharmaceutical composition 1g of lyophilization injectable powder form by this
Add to, in 0.9% sodium chloride solution 20ml, make to be uniformly dispersed, measure the pH value of this liquid, this pH value in the range of 5.5～7.5,
Such as in the range of 6.0～7.5.
Pharmaceutical composition according to a first aspect of the present invention, it is according to Pharmacopoeia of the People's Republic of China version in 2015 four the
The first method in 0832 moisture content algoscopy is i.e. taken volumetric precipitation method in Xiu Shi method and is measured moisture, and moisture is 0.5～5.0% model
In enclosing.In one embodiment, moisture is in the range of 0.5～3.0%.In one embodiment, moisture 0.8～
In the range of 2.6%.
Pharmaceutical composition according to a first aspect of the present invention, is the pharmaceutical composition pressure of lyophilization injectable powder form by this
Make diameter 10mm, thickness 2.5mm, the circular tablet of hardness 1kg and measure the contact angle of this tablet, this tablet have 30～
The contact angle of 80 °, such as, have the contact angle of 35～75 °, such as, have the contact angle of 40～70 °.By described in lyophilization
It is to it is known in the art that for example to be by especially in pharmaceutics that the pharmaceutical composition of powder type is pressed into the method for described tablet
Method for preparing tablet thereof be pressed into.
In one embodiment, described contact angle is that mode after this manner measures and obtains: at stainless steel, internal diameter
0.2～0.3mm, the drop of 1 μ l pure water is formed at the needle point of the syringe needle of external diameter 0.4～0.6mm, then by contact angle determination device
Measure the contact angle after this water droplet is added to tablet surface 60 milliseconds.
Pharmaceutical composition according to a first aspect of the present invention, is the pharmaceutical composition pressure of lyophilization injectable powder form by this
Making diameter 10mm, thickness 2.5mm, the circular tablet of hardness 1kg, this tablet measures its contact angle according to following manner, its contact
Angle is 30～80 ° (for example, 35～75 °, for example, 40～70 °): stainless steel, internal diameter 0.2～0.3mm, external diameter 0.4～
Form the drop of 1 μ l pure water at the needle point of the syringe needle of 0.6mm, then measure this water droplet by contact angle determination device and be added to tablet table
Contact angle behind 60 milliseconds of face.The present inventor is it has been unexpectedly discovered that work as and make obtained lyophilization injectable powder form
The moisture of pharmaceutical composition in the range of 0.8～2.6%, and contact angle in the range of 40～70 ° time, described medicine
Compositions not only has granularity and the particle size distribution stability of excellence, and the jitter time (i.e. redissolving the time) with excellence is steady
Qualitative, and can not be provided simultaneously with the lyophilization injectable powder compositions of above-mentioned two condition granularity and particle size distribution stability with
And jitter time (i.e. redissolving the time) stability aspect is the most unsatisfactory.
Pharmaceutical composition according to a first aspect of the present invention, the nano-particle that described Cabazitaxel forms with protein, its
Be combined in the way of association in middle Cabazitaxel is coated on protein or with protein.
Contact angle described herein refers to the contact angle with water.Specifically, contact angle refers to drip in solid preparations such as tablets
The angle that the water droplet on compositions surface contacts with compositions surface.Those skilled in the art know many sides measuring contact angle
Method and device, in the present invention, an exemplary assay method is as follows: at syringe needle, (such as model is SNSO52/026；
HAMILTON company produces, stainless steel, internal diameter 0.26mm, external diameter 0.52mm；Or also can be with the syringe needle with similar specification)
Needle point forms 1 μ l pure water (MILLI-Q；MILLIPORE company) drop, then by contact angle determination device (such as OCA-15 type,
Data physics company；Or there is other brand of similar functions or the contact angle determination device of model) measure water droplet add
Contact angle after tablet surface 60 milliseconds.When tablet surface has curvature, measure contact when resolving again after straight line to be corrected to
Angle；It is typically under room temperature to measure.In the present invention, if not otherwise indicated, contact angle of the present invention is to be measured by following methods
: at room temperature, at syringe needle (SNSO52/026；HAMILTON company produces, stainless steel, internal diameter 0.26mm, external diameter 0.52mm)
Needle point form 1 μ l pure water (MILLI-Q；MILLIPORE company) drop, then by contact angle determination device (OCA-15 type,
Data physics company) measure the contact angle after water droplet is added to tablet surface 60 milliseconds.Owing to measuring with above-mentioned conditions of similarity
The contact angle obtained, (such as uses the contact angle that other company produces at varying environment (such as different experiments room), distinct device
Determinator), these results do not have significantly difference, therefore when defining the contact angle of compositions of the present invention, it is not necessary to
Concrete mensuration process and condition determination to contact angle are construed as limiting.
Pharmaceutical composition according to a first aspect of the present invention, described protein is with sulfydryl or disulfide bond.An enforcement
In scheme, the preferred native protein of described protein；Described protein more preferably human albumin.
Pharmaceutical composition according to a first aspect of the present invention, described Cabazitaxel is Cabazitaxel itself or the conjunction of its solvent
Thing.
Pharmaceutical composition according to a first aspect of the present invention, described Cabazitaxel is noncrystal, crystalline solid or both is mixed
Compound；Preferably Cabazitaxel is noncrystal, because noncrystal being easier to is dissolved and absorb, thus reaches higher biological utilisation
Degree.
Pharmaceutical composition according to a first aspect of the present invention, described Cabazitaxel solvate is selected from Cabazitaxel and third
Ketone, ethanol, ethanol/water mixed solvent, butanol compound, methyl tertiary butyl ether(MTBE), normal propyl alcohol, isopropanol, water, dichloromethane, acetic acid
The solvate that ethyl ester, oxolane, toluene, N,N-dimethylformamide etc. are formed.
Pharmaceutical composition according to a first aspect of the present invention, wherein said lyophilization injectable powder form is aseptic freeze-dried
Block or powder.
The Cabazitaxel pharmaceutical composition of the present invention is the sterile cryo drying agent that protein is coated nano-particle, in institute
State in freeze-dried preparation, it is also possible to optional containing freeze drying protectant or referred to as freeze-dried excipient and protein stabiliser；Wherein
Described freeze drying protectant selected from mannitol, aspartic acid, sucrose, sorbitol, lactose, fructose, trehalose, maltose, aminoacid,
One of dextran or its combination in any, wherein preferably freeze drying protectant is mannitol；Described protein stabiliser is selected from Sargassum
One of sugar, mannitol, sucrose, acetyltryptophan, sodium caprylate or its combination in any.
Heretofore described pharmaceutical composition is powder or the block of freeze-dried, and it uses suitable aqueous to be situated between
It is the liquid suspension containing at least about 0.5mg/ml Cabazitaxel that mass-energy enough makes described powder or block redissolve, described suitable
Suitable aqueous medium is molten selected from normal saline, buffer saline, water, the aqueous medium of buffering, Freamine Ⅲ, vitamin
One of liquid, carbohydrate solutions or similar medium or its combination in any.Especially, the powder of freeze-dried of the present invention
Or block, it can use 0.9% sodium chloride injection to redissolve becomes containing at least about 1～the liquid of 5mg/ml Cabazitaxel
Suspension, this suspension is used directly for drug administration by injection.
Cabazitaxel pharmaceutical composition of the present invention is by the Cabazitaxel nano-particle of coating protein and is combined
Floating preteins forms, and such as can keep at least 48 hours under the conditions of 37 DEG C in 0.9% sodium chloride injection at aqueous medium
Stability, it is possible to meet intravenous administrations needs.
Second aspect present invention provides the method that high pressure homogenize emulsion process prepares this pharmaceutical composition.
The key character of the inventive method is by adjusting organic facies and the phase component of aqueous phase, having surprisingly found that and have higher
Machine phase component, can prepare the protein nano granule of high drug level under the conditions of being i.e. higher than 5% (V/V), homogenate terminates in rear medicinal liquid
Cabazitaxel concentration is up to 6～16mg/ml, and its mean diameter is not more than 200nm, and stability is significantly better than low concentration medicinal liquid (＜
5mg/ml) and be prone to aseptic filtration, it is more beneficial for industrialization.
Method according to a second aspect of the present invention, it comprises the following steps:
1) Cabazitaxel is dissolved in organic solvent, as organic facies；Described organic solvent is selected from methanol, ethanol, isopropyl
Alcohol, acetone, N,N-dimethylformamide, dimethyl sulfoxide, dichloromethane, ethyl acetate, chloroform, oxolane, acetonitrile,
The mixture of one of methyl pyrrolidone or similar solvent or its combination in any is [due to Cabazitaxel concentration in organic solvent
Diameter for nano-particle has an impact, so Cabazitaxel concentration range is 5%-40% (w/v) in organic facies]；
2) by described protein dispersibility in aqueous medium, as aqueous phase [owing to the consumption of aqueous medium affects organic
Phase phase component, suspension drug concentration when i.e. affecting homogenate, so, in one embodiment, protein in this step
Concentration range be 5-25% (w/v)]；
3) by step 1) organic facies and step 2) aqueous phase mix, by acid-base modifier (if not otherwise indicated, the present invention
Use 1M hydrochloric acid solution or 1M sodium hydroxide solution) pH value of regulation mixed liquor to 6.5～7.0, this mixed liquor is placed in pressure
Scope 3,000～30, at least 3 circulations of high-pressure homogenate device inner high voltage homogenate of 000psi, the average diameter of particles being prepared as is not
[during homogenate, organic facies phase component is not less than 5% (v/v), example to dispersion system of colloid more than 200nm (can carry out aseptic filtration)
As for 5～10%；Suspension drug concentration is not less than 6mg/ml, and preferably suspension drug concentration is not less than 8mg/ml]；
4) by step 3) gained suspension reduction vaporization, remove organic solvent, formed by the coated Cabazitaxel of protein
Nano-particle and the colloid system of protein composition；
5) by step 4) in gained colloid system carry out aseptic filtration, then lyophilization, i.e. prepare Cabazitaxel albumen
The sterile cryo xeraphium injection drug compositions of matter.
Further, third aspect present invention provides a kind of method preparing suspension for injection, the method include to
Pharmaceutical composition in lyophilization injectable powder form adds the step of 0.9% sodium chloride injection.
Method according to a third aspect of the present invention, the wherein said pharmaceutical composition in lyophilization injectable powder form is card
Ba Tasai and protein after nano-dispersed technical finesse, the sterile cryo xeraphium injection prepared.
Method according to a third aspect of the present invention, wherein in pharmaceutical composition, described Cabazitaxel is coated on protein
In or be combined and the nano-particle that formed in the way of association with protein.In one embodiment, will be in lyophilized powder
After the described pharmaceutical composition 1g of injection form adds to be uniformly dispersed in 0.9% sodium chloride solution 20～50ml, according to " the China people
Republic's pharmacopeia " the 3rd method i.e. light scattering determining grain in 2015 years four Section of 0982 granularities of version and particle size distribution method
Degree and particle size distribution, mean diameter is in 50～200nm scopes, and the particle diameter microgranule less than 50nm is less than 5%, and particle diameter is more than 350nm
Microgranule less than 5%.In one embodiment, mean diameter is in the range of 100～200nm.
Method according to a third aspect of the present invention, wherein adds the pharmaceutical composition 1g that this is lyophilization injectable powder form
To 0.9% sodium chloride solution 20ml, shake gently, record to being completely dispersed uniformly and the time of the non-dispersing solid thing of nothing, make
For jitter time, this jitter time is 5～20 minutes.In one embodiment, this jitter time is 5～15 minutes.
Method according to a third aspect of the present invention, wherein adds the pharmaceutical composition 1g that this is lyophilization injectable powder form
To 0.9% sodium chloride solution 20ml, make to be uniformly dispersed, measure the pH value of this liquid, this pH value in the range of 5.5～7.5, example
As in the range of 6.0～7.5.
Method according to a third aspect of the present invention, wherein said pharmaceutical composition is according to the Pharmacopoeia of the People's Republic of China 2015
The first method in year four the 0832nd moisture content algoscopys of version is i.e. taken the volumetric precipitation method in Xiu Shi method and is measured moisture, and moisture exists
In the range of 0.5～5.0%.In one embodiment, moisture is in the range of 0.5～3.0%.In one embodiment, water
Divide in the range of 0.8～2.6%.
Method according to a third aspect of the present invention, wherein suppresses the pharmaceutical composition that this is lyophilization injectable powder form
Becoming diameter 10mm, thickness 2.5mm, the circular tablet of hardness 1kg and measure the contact angle of this tablet, this tablet has 30～80 °
Contact angle, such as there is the contact angle of 35～75 °, such as, there is the contact angle of 40～70 °.By described in lyophilization powder
It is to it is known in the art that the sheet for example being by especially in pharmaceutics that the pharmaceutical composition of form is pressed into the method for described tablet
Agent preparation method is pressed into.
Method according to a third aspect of the present invention, wherein suppresses the pharmaceutical composition that this is lyophilization injectable powder form
Becoming diameter 10mm, thickness 2.5mm, the circular tablet of hardness 1kg, this tablet measures its contact angle according to following manner, its contact angle
Be 30～80 ° (for example, 35～75 °, for example, 40～70 °): stainless steel, internal diameter 0.2～0.3mm, external diameter 0.4～
Form the drop of 1 μ l pure water at the needle point of the syringe needle of 0.6mm, then measure this water droplet by contact angle determination device and be added to tablet table
Contact angle behind 60 milliseconds of face.
Method according to a third aspect of the present invention, the nano-particle that wherein said Cabazitaxel forms with protein, wherein
Be combined in the way of association in Cabazitaxel is coated on protein or with protein.
Method according to a third aspect of the present invention, wherein said protein is with sulfydryl or disulfide bond.An embodiment party
In case, the preferred native protein of described protein；Described protein more preferably human albumin.
Method according to a third aspect of the present invention, wherein said Cabazitaxel is Cabazitaxel itself or the conjunction of its solvent
Thing.
Method according to a third aspect of the present invention, wherein said Cabazitaxel is noncrystal, crystalline solid or both mixing
Thing；Preferably Cabazitaxel is noncrystal, because noncrystal being easier to is dissolved and absorb, thus reaches higher bioavailability.
Method according to a third aspect of the present invention, wherein said Cabazitaxel solvate selected from Cabazitaxel and acetone,
Ethanol, ethanol/water mixed solvent, butanol compound, methyl tertiary butyl ether(MTBE), normal propyl alcohol, isopropanol, water, dichloromethane, acetic acid second
The solvate that ester, oxolane, toluene, N,N-dimethylformamide etc. are formed.
Method according to a third aspect of the present invention, wherein said lyophilization injectable powder form is aseptic freeze-dried block
Or powder.
Method according to a third aspect of the present invention, described pharmaceutical composition can use 0.9% sodium chloride injection to redissolve into
For containing at least about 1～the liquid suspension of 5mg/ml Cabazitaxel, this suspension is used directly for drug administration by injection.
Method according to a third aspect of the present invention, its suspension for injection formed can keep at least under the conditions of 37 DEG C
The stability of 48 hours, it is possible to meet intravenous administrations needs.
Method according to a second aspect of the present invention, wherein in step 4) in by described suspension be evaporated under reduced pressure before, by suspendible
Liquid acid-base modifier regulates pH value to 9.0～9.5；PH value is regulated with acid-base modifier after removing organic solvent is evaporated under reduced pressure
To 6.5～7.0.Have been found that whole powder pins of embodiment of the present invention 1-5, their moisture and contact angle cannot be simultaneously
Meet 0.8～2.6% and 40～70 ° of the two scopes, i.e. in freezing dry process, when by moisture pump to more than 2.8%
Degree time gained injectable powder contact angle be all higher than 75 °, and when by moisture pump to degree less than 2.7% gained powder pin
The contact angle of agent drastically drops to the scope of respectively less than 38 °, and there are no the contact angle situation 40～70 ° of these scopes；That is,
For whole powder pins of embodiment 1-5, even if controlling its moisture when preparation is by lyophilization 0.8～2.6% model
Enclosing or larger range of value, its contact angle is also unable to reach 40～70 ° of these scopes.Embodiment of the present invention 11-15 whole
Powder pin, their moisture is in the range of 0.8～2.6% and contact angle is in the range of 40～70 °, and supplements these real
Execute example injectable powder when controlling its moisture different value in the range of 0.8～2.6%, the injectable powder of gained different in moisture content
Its contact angle is still in the range of 40～70 °；Such as embodiment 11 is not added with the powder pin of freeze-dried excipient and embodiment 11 adds
With the powder pin of mannitol, the moisture of two kinds of injectable powder is respectively 1.6% and 1.9%, and contact angle is respectively 57 ° and 52 °.
Any embodiment of the either side of the present invention, can be combined with other embodiment, as long as they are not
There will be contradiction.Additionally, in any embodiment of either side of the present invention, it is real that arbitrary technical characteristic goes for other
Execute this technical characteristic in scheme, as long as they do not have contradiction.
Arbitrary technical characteristic that any embodiment of either side of the present invention or this either side is had is equally applicable
Other any embodiment or any embodiment of other either side, as long as they will not be conflicting, certainly mutually
Between where applicable, if necessary can make individual features suitably to modify.Make into one with feature the most to various aspects of the present invention
The description of step.
All documents recited in the present invention, their full content is incorporated herein by, and if these literary compositions
Offer expressed implication and the present invention inconsistent time, be as the criterion with the statement of the present invention.Additionally, the present invention use various terms and
Phrase has and well known to a person skilled in the art general sense, nonetheless, the present invention remain desirable at this these terms and
Phrase is described in more detail and explains, the term mentioned and phrase are if any inconsistent with common art-recognized meanings, with institute of the present invention table
The implication stated is as the criterion.
During the present invention prepares pharmaceutical composition, after aseptic filtration, carry out lyophilization obtain the egg of Cabazitaxel
White nano-particle lyophilized formulations, has good chemical stability and physical stability；Wherein said protein nano granule can wrap
Carry the Cabazitaxel accounting for protein nano granule gross mass 1%～20%.
During the present invention prepares pharmaceutical composition, Cabazitaxel is dissolved in conduct in a kind of suitably organic solvent
Organic facies, and adding protein in aqueous phase has been stabilizer function, is easily formed stable nano-liquid droplet, adds the dense of protein
Degree scope is about 5-25% (w/v), and scope is best at 10%-20% (w/v).Owing to albumin itself i.e. has certain surface
Activity, different from conventional nano-particle forming method, need not in mixture add surfactant (such as, dodecyl
Sodium sulfate, lecithin, Tween 80 and similar compound).The present invention uses albumin to substitute conventional surfactants, it is to avoid often
The serious toxic and side effects of rule surfactant.
During the present invention prepares pharmaceutical composition, organic facies and aqueous mixture are homogenizing in high-pressure homogenate device
Effect, common operation pressure 3,000 to 30,000 pounds per inch2, this process 6,000 to 25,000 pounds per inch2In the range of
Carry out more preferably.By adjusting organic facies and the phase component of aqueous phase in prescription, when organic facies component is more than 5% (V/V), medicinal liquid blocks
Ba Tasai concentration can reach 6～16mg/ml, and the obtained albumin nano granular mean diameter containing Cabazitaxel is not more than
200nm, and describe according to each embodiment in patent CN1515244A, high pressure homogenate terminates rear medicinal liquid drug concentration and is all not higher than
5mg/ml.Have been found that during preparation method of the present invention, in step 4) in by described suspension be evaporated under reduced pressure before regulate extremely
High acid-base value, regulates to normal acid-base value after reduction vaporization, thus process can control obtained in lyophilized powder pin
The moisture of the pharmaceutical composition of agent form is in the range of 0.8～2.6% and contact angle is in the range of 40～70 °, and if subtracted
The regulation then moisture and the contact angle that do not carry out above-mentioned acid-base value before and after pressure evaporation can not reach above-mentioned scope simultaneously.Although at this
Control acid-base value before and after having discovered that by reduction vaporization in bright and can obtain moisture and contact angle in scope of the present invention
The pharmaceutical composition in lyophilization injectable powder form, but should not get rid of the most also can obtain and be provided simultaneously with
The injectable powder compositions of above-mentioned moisture and contact angle scope, i.e. realizes the injectable powder preparation method of above-mentioned moisture and contact angle feature
Can not be exhaustive, the most exhaustive, and the substantive contribution of prior art is to find spy by the present invention
The pharmaceutical composition in lyophilization injectable powder form determining moisture and contact angle possesses granularity and the grain of beat all excellence
Spend distributional stability and there is the jitter time stability of excellence.The present invention is prepared for hereinafter by embodiment 1-5
Powder injection composition.There is provided extra complementary testing at this, the embodiment 11～15 i.e. supplemented, with preparation in lyophilization injectable powder
The pharmaceutical composition of form: embodiment 11～15 respectively refers to Examples below 1-5, different is only to be evaporated under reduced pressure at suspension
Before, by suspension with acid-base modifier regulation pH value to 9.0～9.5；Acid-alkali accommodation is used after removing organic solvent is evaporated under reduced pressure
Agent regulation pH value is to 6.5～7.0 (i.e. adjusting back to the degree before being evaporated under reduced pressure), and obtaining other is lyophilization injectable powder form
Pharmaceutical composition；Being measured these embodiment 11～15 gained powder pins supplemented, it disperses suspension lyophilization 48
Hour, gained block the most easily reconstructs original dispersion liquid after adding sterilized water or normal saline, and the granule after redissolution is big
Little all with lyophilization before identical.
During the present invention prepares pharmaceutical composition, step 3) described in reduction vaporization can use film evaporator, spray
Mist exsiccator, freeze dryer, or similar devices.It is 40 DEG C that temperature is evaporated under reduced pressure, and when temperature is more than 40 DEG C, liquid medicine stability is low,
When temperature is less than 40 DEG C, solvent evaporation rate is slower.During liquid medicine stability is investigated after evaporation, it has been found that, main in homogenate medicinal liquid
When concentration is less than 5mg/ml, placing and within 3～6 hours, i.e. occur that stability declines phenomenon under medicinal liquid room temperature condition, particle diameter presents increasing
After main trend and aseptic filtration, the principal agent response rate declines.Contrary, when in homogenate medicinal liquid, principal agent concentration is not less than 6mg/ml, evaporation
After the medicinal liquid that obtains be stable nano-particle colloid disperse system, its room temperature stability can reach 36 hours, it is furthermore preferred that main
When concentration is 8mg/ml, its room temperature stability was up to 48 hours.
During the present invention prepares pharmaceutical composition, after the Cabazitaxel nano-particle of protein-coated is freeze-dried
Obtaining the lyophilized formulations containing Cabazitaxel and protein, this lyophilized formulations can use suitable aqueous medium to redissolve for liquid suspendible
Liquid, these aqueous mediums have normal saline, buffer saline, water, the aqueous medium of buffering, Freamine Ⅲ, vitamin molten
Liquid, carbohydrate solutions or similar medium, and any two and the mixture of these media two or more.
During the present invention prepares pharmaceutical composition, for obtain diameter less than 200nm and can the granule of aseptic filtration, have
Machine is contained within a kind of organic solvent immiscible with water mutually and is very important.Under the conditions of high pressure homogenate, above-mentioned solvent is at water
Form atomic thin non-aqueous solvent dispersed droplets (pharmacological active substance containing dissolving) in mutually, and the most quickly go
Removing, formation can aseptic filtration nano-particle.
During the present invention prepares pharmaceutical composition, protect owing to protein (such as, human albumin) itself plays lyophilizing
Protect agent effect, therefore can need not add conventional freeze drying protectant and protein stabiliser, such as mannitol, glycerol or similarization
Compound and similar compound combination.Although it is not required, the cryoprotective agent of these routines and protein stabiliser still can add
Enter in the formula of the present invention.
During the present invention prepares pharmaceutical composition, organic solvent removing method (being evaporated under reduced pressure under the conditions of 40 DEG C) includes
But being not limited to above-mentioned reduction vaporization method, other method can include rotary evaporation, decompression distillation, be spray-dried or similar side
Method.
In sum, the invention provides the preparation method of Cabazitaxel protein nanoparticles, this kind of method be not because adopting
Its severe allergic reaction brought is avoided with the ethanol added in Cabazitaxel injection and Tween 80.
The inventive method is compared to the advantage of similar technique: by adjusting organic facies and aqueous phase phase component in prescription,
The high concentration Cabazitaxel nano-particle that stability is superior can be prepared under the conditions of higher organic facies component, and be more beneficial for producing
Industry.
Cabazitaxel protein nano granule prepared by the present invention is enough with smaller size smaller delivery of high doses pharmacological active substance, this
Sense of discomfort and hospital stays when patient can be made to accept large volume liquid infusion are minimized.Additionally, protein coat or bag
Clothing the most in vivo can be degradable by proteolytic enzyme, and therefore this pharmaceutical composition will not bring side effect.
Detailed description of the invention
Example is prepared and test example further illustrates the present invention below by concrete, it should be understood, however, that, these examples
Son is only used for specifically describing in more detail being used, and is not to be construed as limiting in any form the present invention.
The present invention to test used in material and test method carry out generality and/or concrete description.Though
It is so to it is known in the art that still the present invention is still at this for realizing many materials that the object of the invention used and operational approach
Describe in detail as far as possible.It will be apparent to those skilled in the art that hereinafter, if not specified, material therefor of the present invention and
Operational approach is well known in the art.Before and after in example 1 below-5, rotary evaporation removes organic solvent, the pH value of medicinal liquid is basic
Identical, without substantially changing.
Embodiment 1: the preparation of high pressure homogenize emulsion process can the nano-particle of aseptic filtration less than 200nm
The present embodiment introduction can the preparation process of Cabazitaxel granule of aseptic filtration.300mg Cabazitaxel is dissolved in
In the chloroform of 1.35ml and the dehydrated alcohol of 0.15ml, organic facies joins the human albumin of 29ml (10.2%, w/v)
In aqueous solution, mixture is sheared homogenate under the conditions of the slow-speed of revolution and is formed thick emulsion in 3 minutes, is transferred in high-pressure homogenate device, 3,000
～7 circulations of homogenate under 30,000psi pressure condition.The medicinal liquid obtained is transferred in rotary evaporator, reduces pressure under the conditions of 40 DEG C
(10-15KPa) evaporate 30 minutes and remove organic solvent.The dispersion suspension obtained is translucent, and pH is 6.7, Zeta potential is-
25mv, Cabazitaxel average diameter of particles is generally 120～155nm.Dispersion suspension is passed through 0.22 μm filtering with microporous membrane
Device, its turbidity and granular size are without significant change.HPLC method measurement result shows, after filtration, the Cabazitaxel of more than 82% obtains
To reclaiming.
Dispersion suspension lyophilization 48 hours, gained block the most easily reconstructs former after adding sterilized water or normal saline
The dispersion liquid come is identical before the granular size after redissolution and lyophilization.
Appended experimental: add glycine, mannitol, sucrose and lactose four respectively in the present embodiment gained dispersion suspension
Planting freeze-dried excipient, each of which concentration is 5% (w/v), then carries out lyophilization, the various physics and chemistry of gained lyophilization injectable powder
Character is all identical with the injectable powder being not added with them.When carrying out additional testing with method in follow-up embodiment 2-4, also there is phase
Same conclusion.It addition, also carry out this additional testing in embodiment 11 as a result, the various reasons of these additional testing gained powder pins
Change character all identical with embodiment 11 injectable powder being not added with them.
Embodiment 2: the preparation of high pressure homogenize emulsion process can the nano-particle of aseptic filtration less than 200nm
Being dissolved in by 300mg Cabazitaxel in the chloroform of 1.5ml and the dehydrated alcohol of 0.15ml, organic facies joins
In human albumin's aqueous solution of 24ml (12.5%, w/v), mixture is sheared homogenate under the conditions of the slow-speed of revolution and within 3 minutes, is formed thick
Emulsion, is transferred in high-pressure homogenate device, 8 circulations of homogenate under 3,000～30,000psi pressure condition.The medicinal liquid transfer obtained
To rotary evaporator, reduce pressure under the conditions of 40 DEG C (10-15KPa) evaporates 30 minutes and removes dehydrated alcohol and chloroform.Obtain
Dispersion suspension be translucent, pH is 6.5, and Zeta potential is-26mv, Cabazitaxel average diameter of particles be generally 125～
150nm.Dispersion suspension is passed through 0.22 μm nuclepore membrane filter, and its turbidity and granular size are without significant change.HPLC
Method measurement result shows, after filtration, the Cabazitaxel of more than 85% is recycled.
Dispersion suspension lyophilization 48 hours, gained block the most easily reconstructs former after adding sterilized water or normal saline
The dispersion liquid come is identical before the granular size after redissolution and lyophilization.
Embodiment 3: the preparation of high pressure homogenize emulsion process can the nano-particle of aseptic filtration less than 200nm
The present embodiment introduction can the preparation process of Cabazitaxel granule of aseptic filtration.1g Cabazitaxel is dissolved in
In the chloroform of 4.5ml and the dehydrated alcohol of 0.5ml, organic facies joins the human albumin of 57.5ml (20.2%, w/v)
In aqueous solution, mixture is sheared homogenate under the conditions of the slow-speed of revolution and is formed thick emulsion in 3 minutes, is transferred in high-pressure homogenate device, 3,000
～7 circulations of homogenate under 30,000psi pressure condition.The medicinal liquid obtained is transferred in rotary evaporator, reduces pressure under the conditions of 40 DEG C
(10-15KPa) evaporate 30 minutes and remove organic solvent.The dispersion suspension obtained is translucent, and pH is 6.9, Zeta potential is-
29mv, Cabazitaxel average diameter of particles is generally 120～150nm.Dispersion suspension is passed through 0.22 μm filtering with microporous membrane
Device, its turbidity and granular size are without significant change.HPLC method measurement result shows, after filtration, the Cabazitaxel of more than 82% obtains
To reclaiming.
Dispersion suspension lyophilization 48 hours, gained block the most easily reconstructs former after adding sterilized water or normal saline
The dispersion liquid come is identical before the granular size after redissolution and lyophilization.
Embodiment 4: the preparation of high pressure homogenize emulsion process can the nano-particle of aseptic filtration less than 200nm
The present embodiment introduction can the preparation process of Cabazitaxel granule of aseptic filtration.500mg Cabazitaxel is dissolved in
In the chloroform of 3.0ml and the dehydrated alcohol of 0.5ml, organic facies joins human albumin's water of 60ml (8.5%, w/v)
In solution, mixture is sheared homogenate under the conditions of the slow-speed of revolution and is formed thick emulsion in 3 minutes, is transferred in high-pressure homogenate device, 3,000～
5 circulations of homogenate under 30,000psi pressure condition.The medicinal liquid obtained is transferred in rotary evaporator, reduces pressure under the conditions of 40 DEG C
(10-15KPa) evaporate 30 minutes and remove organic solvent.The dispersion suspension obtained is translucent, and pH is 6.6, Zeta potential is-
23mv, Cabazitaxel average diameter of particles is generally 130～150nm.Dispersion suspension is passed through 0.22 μm filtering with microporous membrane
Device, its turbidity and granular size are without significant change.HPLC method measurement result shows, after filtration, the Cabazitaxel of more than 80% obtains
To reclaiming.
Dispersion suspension lyophilization 48 hours, gained block the most easily reconstructs former after adding sterilized water or normal saline
The dispersion liquid come is identical before the granular size after redissolution and lyophilization.
Embodiment 5: high pressure homogenize emulsion process organic phase solvent phase component is to particle size effect
This example demonstrates that the granule that can prepare relatively small particle in the present invention under the conditions of of a relatively high phase component.
In organic facies, ethanol content is maintained at 10% (v/v), changes the phase component of organic solvent, according to embodiment 1
Same steps carries out series of experiments, can it was found that the most only just can prepare under the conditions of abnormal low phase component
The nano-particle of aseptic filtration.
Table 1 organic solvent phase component is to particle size effect
Test example part: physical and chemical property determining
Test example 1: granularity and particle size distribution
Add to the pharmaceutical composition 1g in lyophilization injectable powder form 0.9% sodium chloride solution 20～50ml disperses
After Jun Yun, according to the 3rd in the Pharmacopoeia of the People's Republic of China four Section of 0982 granularities of version in 2015 and particle size distribution method
Method i.e. light scattering determining granularity and particle size distribution.Whole embodiments and additional embodiment gained that the present invention mentions are that freezing is done
After measured, their mean diameter is all in the range of 100～200nm, and particle diameter is less than for the pharmaceutical composition of dry powder form
The microgranule of 50nm is less than 5%, and the particle diameter microgranule more than 350nm is less than 5%.
Test example 2: granularity and the stability test of particle size distribution
Under the conditions of making to put 40 DEG C in the pharmaceutical composition of lyophilization injectable powder form, lower placement 6 months, measure 0 month and 6
The granularity during moon and particle size distribution.Embodiment 1-5 and the various injectable powder of embodiment 11-15 gained were through this high-temperature process 6 months
After, after measured: increasing in terms of percent by the mean diameter that 6 monthly average particle diameters and 0 monthly average particle diameter compare, embodiment 1-5 is each
The mean diameter increase percent of injectable powder is in the range of 71～83%, and the mean diameter of each injectable powder of embodiment 11-15 increases
Percent is in the range of 16～21%；All embodiment 11-15 injectable powder was 0 month and June, and its particle diameter microgranule less than 50nm is equal
Less than 5%, the particle diameter microgranule more than 350nm is all less than 5%.
Test example 3: jitter time
Add to the pharmaceutical composition 1g in lyophilization injectable powder form, in 0.9% sodium chloride solution 20ml, shake gently
Shake, record to being completely dispersed uniformly and the time of the non-dispersing solid thing of nothing, as jitter time.Whole enforcements that the present invention mentions
Example and additional embodiment gained be the pharmaceutical composition of lyophilization injectable powder form after measured, their jitter time is all 5
～in the range of 15 minutes.
Test example 4: the stability test of jitter time
Under the conditions of making to put 40 DEG C in the pharmaceutical composition of lyophilization injectable powder form, lower placement 6 months, measure 0 month and 6
The jitter time during moon.Embodiment 1-5 and the various injectable powder of embodiment 11-15 gained are after this high-temperature process 6 months, through surveying
Fixed: in terms of the jitter time in June jitter time increase percent with 0 month jitter time compared with, each injectable powder of embodiment 1-5
Jitter time increase percent is in the range of 57～64%, and the jitter time of each injectable powder of embodiment 11-15 increases percent 9
～in the range of 16%.
Test example 5: acid-base value (pH value)
Add to the pharmaceutical composition 1g in lyophilization injectable powder form, in 0.9% sodium chloride solution 20ml, make dispersion
Uniformly, the pH value of this liquid is measured.Whole embodiments and additional embodiment gained that the present invention mentions are lyophilization injectable powder
After measured, its pH value is all in the range of 6.0～7.5 for the pharmaceutical composition of form.
Test example 6: moisture
By the pharmaceutical composition in lyophilization injectable powder form according to Pharmacopoeia of the People's Republic of China version in 2015 four
The first method in 0832nd moisture content algoscopy is i.e. taken the volumetric precipitation method in Xiu Shi method and is measured moisture.
Test example 7: contact angle
Pharmaceutical composition in lyophilization injectable powder form is pressed into diameter 10mm, thickness 2.5mm, hardness 1kg
Circular tablet, this tablet measures its contact angle according to following manner: stainless steel, internal diameter 0.2～0.3mm, external diameter 0.4～
Form the drop of 1 μ l pure water at the needle point of the syringe needle of 0.6mm, then measure this water droplet by contact angle determination device and be added to tablet table
Contact angle behind 60 milliseconds of face.
Claims (10)
1. the pharmaceutical composition of antitumor, it is Cabazitaxel with protein after nano-dispersed technical finesse, the nothing prepared
Bacterium lyophilization injectable powder.
Pharmaceutical composition the most according to claim 1, wherein said Cabazitaxel be coated in protein or with protein with
The nano-particle that the mode associated combines and formed.
Pharmaceutical composition the most according to claim 1, wherein:
Add to the described pharmaceutical composition 1g in lyophilization injectable powder form 0.9% sodium chloride solution 20～50ml disperses
After Jun Yun, according to the 3rd in the Pharmacopoeia of the People's Republic of China four Section of 0982 granularities of version in 2015 and particle size distribution method
Method i.e. light scattering determining granularity and particle size distribution, mean diameter 50～200nm scopes (such as mean diameter 100～
In the range of 200nm), the particle diameter microgranule less than 50nm is less than 5%, and the particle diameter microgranule more than 350nm is less than 5%；
Add to the pharmaceutical composition 1g in lyophilization injectable powder form, in 0.9% sodium chloride solution 20ml, shake gently, note
Recording to being completely dispersed uniformly and the time of the non-dispersing solid thing of nothing, as jitter time, this jitter time is 5～20 minutes, example
As for 5～15 minutes；
Add to the pharmaceutical composition 1g in lyophilization injectable powder form, in 0.9% sodium chloride solution 20ml, make to be uniformly dispersed,
Measuring the pH value of this liquid, this pH value is in the range of 5.5～7.5, such as in the range of 6.0～7.5；
This pharmaceutical composition is according to first in the Pharmacopoeia of the People's Republic of China four the 0832nd moisture content algoscopys of version in 2015
Method is i.e. taken volumetric precipitation method in Xiu Shi method and is measured moisture, and moisture is in the range of 0.5～5.0%, such as 0.8～2.6% model
In enclosing；And/or
The pharmaceutical composition that this is lyophilization injectable powder form is pressed into diameter 10mm, thickness 2.5mm, the circle of hardness 1kg
Shape tablet also measures the contact angle of this tablet, and this tablet has the contact angle of 30～80 °, such as, has the contact angle of 35～75 °,
Such as there is the contact angle of 40～70 °.
Pharmaceutical composition the most according to claim 1, wherein:
Described protein is with sulfydryl or disulfide bond；Such as, the preferred native protein of described protein；Described protein is more
Preferably human albumin；
Described Cabazitaxel is Cabazitaxel itself or its solvate；
Described Cabazitaxel is noncrystal, crystalline solid or both mixture；Preferably Cabazitaxel is noncrystal, because noncrystal
It is easier to dissolve and absorb, thus reaches higher bioavailability；
Described Cabazitaxel solvate is selected from Cabazitaxel and acetone, ethanol, ethanol/water mixed solvent, butanol compound, methyl
Tertbutyl ether, normal propyl alcohol, isopropanol, water, dichloromethane, ethyl acetate, oxolane, toluene, N,N-dimethylformamide etc.
The solvate formed.
Pharmaceutical composition the most according to claim 1, wherein:
Described lyophilization injectable powder form is aseptic freeze-dried block or powder；And/or
Wherein possibly together with freeze drying protectant or referred to as freeze-dried excipient and protein stabiliser；Wherein said freeze drying protectant is selected from sweet
Reveal one of alcohol, aspartic acid, sucrose, sorbitol, lactose, fructose, trehalose, maltose, aminoacid, dextran or it is any
Combination, wherein preferably freeze drying protectant is mannitol；Described protein stabiliser is selected from trehalose, mannitol, sucrose, acetyl color
One of propylhomoserin, sodium caprylate or its combination in any.
6. the method preparing suspension for injection, the method includes adding in the pharmaceutical composition in lyophilization injectable powder form
Add the step of 0.9% sodium chloride injection.
Method the most according to claim 6, wherein:
The described pharmaceutical composition in lyophilization injectable powder form is Cabazitaxel with protein through nano-dispersed technical finesse
After, the sterile cryo xeraphium injection prepared；And/or
The nano-particle in described Cabazitaxel is coated on protein or being combined in the way of association with protein and formed.
Method the most according to claim 6, wherein:
Add to the described pharmaceutical composition 1g in lyophilization injectable powder form 0.9% sodium chloride solution 20～50ml disperses
After Jun Yun, according to the 3rd in the Pharmacopoeia of the People's Republic of China four Section of 0982 granularities of version in 2015 and particle size distribution method
Method i.e. light scattering determining granularity and particle size distribution, mean diameter is less than at 50～200nm scopes, the particle diameter microgranule less than 50nm
5%, the particle diameter microgranule more than 350nm is less than 5%；Such as, mean diameter is in the range of 100～200nm；
Add to, in 0.9% sodium chloride solution 20ml, shake gently by the pharmaceutical composition 1g that this is lyophilization injectable powder form,
Recording to being completely dispersed uniformly and the time of the non-dispersing solid thing of nothing, as jitter time, this jitter time is 5～20 minutes,
Such as 5～15 minutes；
Add to, in 0.9% sodium chloride solution 20ml, make dispersion equal by the pharmaceutical composition 1g that this is lyophilization injectable powder form
Even, measure the pH value of this liquid, this pH value is in the range of 5.5～7.5, such as in the range of 6.0～7.5；
Described pharmaceutical composition is according to the in the Pharmacopoeia of the People's Republic of China four the 0832nd moisture content algoscopys of version in 2015
One method is i.e. taken volumetric precipitation method in Xiu Shi method and is measured moisture, moisture in the range of 0.5～5.0%, such as moisture 0.8～
In the range of 2.6%；And/or
The pharmaceutical composition that this is lyophilization injectable powder form is pressed into diameter 10mm, thickness 2.5mm, the circle of hardness 1kg
Shape tablet also measures the contact angle of this tablet, and this tablet has the contact angle of 30～80 °, such as, has the contact angle of 35～75 °,
Such as there is the contact angle of 40～70 °.
Method the most according to claim 6, wherein:
Described protein is with sulfydryl or disulfide bond；
The preferred native protein of described protein；Described protein more preferably human albumin.
Method the most according to claim 6, wherein:
Described Cabazitaxel is Cabazitaxel itself or its solvate；
Described Cabazitaxel is noncrystal, crystalline solid or both mixture；Preferably Cabazitaxel is noncrystal；
Described Cabazitaxel solvate is selected from Cabazitaxel and acetone, ethanol, ethanol/water mixed solvent, butanol compound, methyl
Tertbutyl ether, normal propyl alcohol, isopropanol, water, dichloromethane, ethyl acetate, oxolane, toluene, N,N-dimethylformamide etc.
The solvate formed；
Described lyophilization injectable powder form is aseptic freeze-dried block or powder；
Described pharmaceutical composition uses 0.9% sodium chloride injection to redissolve to be become containing at least about 1～5mg/ml Cabazitaxel
, the liquid suspension being used directly for drug administration by injection.
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| CN201610663988.9A CN106176631A (en) | 2016-08-12 | 2016-08-12 | The freeze-dried composition of antitumor |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110075073A (en) * | 2019-06-03 | 2019-08-02 | 深圳市健开医药有限公司 | A kind of Cabazitaxel protein nano injection and preparation method thereof |
| CN110123786A (en) * | 2019-06-03 | 2019-08-16 | 深圳市健开医药有限公司 | A kind of Cabazitaxel protein nano material and preparation method thereof |
| CN111449055A (en) * | 2020-05-23 | 2020-07-28 | 河北康腾生物科技有限公司 | Adipose tissue cryopreservation liquid, preparation method and adipose tissue storage method |
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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 |
| US20160184452A1 (en) * | 2014-10-06 | 2016-06-30 | Mayo Foundation For Medical Education And Research | Carrier-Antibody Compositions and Methods of Making and Using the Same |
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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 |
| US20160184452A1 (en) * | 2014-10-06 | 2016-06-30 | Mayo Foundation For Medical Education And Research | Carrier-Antibody Compositions and Methods of Making and Using the Same |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110075073A (en) * | 2019-06-03 | 2019-08-02 | 深圳市健开医药有限公司 | A kind of Cabazitaxel protein nano injection and preparation method thereof |
| CN110123786A (en) * | 2019-06-03 | 2019-08-16 | 深圳市健开医药有限公司 | A kind of Cabazitaxel protein nano material and preparation method thereof |
| CN110075073B (en) * | 2019-06-03 | 2021-09-07 | 深圳市健开医药有限公司 | Cabazitaxel protein nano injection and preparation method thereof |
| CN111449055A (en) * | 2020-05-23 | 2020-07-28 | 河北康腾生物科技有限公司 | Adipose tissue cryopreservation liquid, preparation method and adipose tissue storage method |
| CN111449055B (en) * | 2020-05-23 | 2021-07-23 | 河北康腾生物科技有限公司 | Adipose tissue cryopreservation liquid, preparation method and adipose tissue storage method |
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Application publication date: 20161207 |