CN106310221B - A kind of pharmaceutical composition and preparation method thereof containing Carfilzomib - Google Patents
A kind of pharmaceutical composition and preparation method thereof containing Carfilzomib Download PDFInfo
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- CN106310221B CN106310221B CN201610722435.6A CN201610722435A CN106310221B CN 106310221 B CN106310221 B CN 106310221B CN 201610722435 A CN201610722435 A CN 201610722435A CN 106310221 B CN106310221 B CN 106310221B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
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- A—HUMAN NECESSITIES
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- 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
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- 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
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- 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
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Abstract
The present invention provides a kind of pharmaceutical composition and preparation method thereof containing Carfilzomib, pharmaceutical composition in the present invention, include the Carfilzomib, protein and acidity-basicity regulator as active constituent, pH value range 2.0 ~ 5.0, average grain diameter≤200nm, the mass ratio of Zeta potential -20 ~ -30mv, Carfilzomib and protein is 1:6 ~ 12.The main object of the present invention is to provide a kind of preferably for delivering the pharmaceutical composition of Carfilzomib in vivo, this composition avoids caused vasopasm and phlebitis in anaphylactoid generation and clinical use without the sulphur butyl betadex in listing Carfilzomib injection at present.The lyophilized preparation of the composition can be prepared by high pressure homogenate method, and the block or powder that can disperse again can be converted into, the product that its stability after dispersing again in an aqueous medium lists more at present significantly improves, and enhances the safety of medication in clinical application.
Description
Technical field
The invention belongs to technical field of medicine.More particularly to a kind of pharmaceutical composition containing Carfilzomib, the medicine
The sterile cryo drying agent of compositions and the preparation method of the sterile cryo drying agent.
Background technique
Huppert's disease (MM) is the malignant plasma cell dyscrasia occurred in bone-marrow-derived lymphocyte, it is characterised in that malignant plasma cell
In bone marrow microenvironment clonal expansion, m protein matter and relevant Organ Dysfunction in blood or urine；It is second, the whole world
The most common hematological system tumor accounts for about the 13% of 1% and neoplastic hematologic disorder of tumor disease.In western countries, every annual morbidity
For 5.6/100,000 people.
Carfilzomib, English name Carfilzomib, chemistry entitled (S) -2- ((S) -2- (2- (2H-1,4- oxazines -4
(3H)-yl) acetylamino)-4- phenylbutanamides)-4- methyl-N- ((S)-1- ((S)-4- methyl-1-((R)-2- methyl epoxy
Ethane -2- base) -1- oxo-pentane -2- base amino) -1- oxo -3- phenyl propyl- 2- yl) pentanamide, molecular formula C40H57N5O7,
Structural formula is as follows:
Carfilzomib is a kind of tetrapeptide basic ring oxygen skelemin enzyme body inhibitor, optionally, is irreversibly bound to
The end N- of the threonine active site of 20S proteasome, the core granule 26S proteasome of proteolysis.Carfilzomib exists
There are antiproliferative and apoptosis activity to solid tumor and blood tumor cell in vitro.In animal experiment, Carfilzomib inhibits in blood
Proteasome activity in liquid and tissue, and postpone tumour growth in Huppert's disease, hematology and solid tumor models.
On July 20th, 2012, U.S.'s food have approved Ao Nike through preferential examination and approval procedures with Drug Administration (FDA)
Carfilzomib injection (carfilzomib) list marketing of this (Onyx) drugmaker exploitation, trade name: Kyprolis, rule
Lattice are 60mg, have previously at least received two kinds of therapies including bortezomib (bortezomib/ for single therapy
Velcade) and a kind of immunomodulator treatment and have complete it is last 1 time treatment after in 60 days progression of disease evidence it is multiple
Patients with malignant myeloma.
Although Carfilzomib has good antitumor action, water solubility is poor, and stability is bad, freeze-drying system
Agent is ideal dosage form, in the Kyprolis prescription listed at present containing 60mg Carfilzomib, 3000mg sulphur butyl times he
Cyclodextrin sodium and 57.7mg citric acid and appropriate sodium hydroxide, although cyclodextrin inclusion compound improves medicine to a certain extent
The dissolubility of object, but its drugloading rate is still less than 2%, and has used larger amount of cyclodextrin, into blood circulation of human body system
Kidney burden can be aggravated after system, while cyclodextrin can have an effect with blood vessel cell membrane, cause cell damage, be used for a long time
It may cause venospasm and phlebitis, there are security risks, and dexamethasone prevention infusion must be given before each administration
Reaction.In addition, the drug is highly unstable in aqueous medium solution, at most stablize under room temperature 4 hours, in actual clinical
It is also challenge to the safety of medication in.
In conclusion the Carfilzomib injection listed at present has preferable effect in the treatment of Huppert's disease
Fruit, but inconvenience and safety issue also are brought to clinical application simultaneously.
Summary of the invention
To solve the above problems, the present inventor provides a kind of effective method: the better drug of replacement biocompatibility carries
Pharmacological active substance is packed in nanoscale particle by body, to increase solubility, drugloading rate and the stability of Carfilzomib.Separately
Outside, pharmacological active substance can be sustained provided by the present invention for the nanoparticle of intravenous injection and extend its Half-life in vivo,
And it can be by the pharmacological active substance Targeting delivery in particle.
In view of the deficiencies of the prior art, the main object of the present invention is to provide a kind of preferably for delivering Ka Feizuo in vivo
The pharmaceutical composition of rice, this composition are actually a kind of nano-particle colloid decentralized system, and the composition is free of current Ka Feizuo
Sulphur butyl betadex in rice injection, avoids anaphylactoid generation, while avoiding Carfilzomib injection and facing
Caused vasopasm and phlebitis in bed use.In addition, the stabilization of pharmaceutical composition of the invention in aqueous medium solution
Property is significantly better than existing preparation, enhances the safety of medication in clinical application.
A kind of Carfilzomib pharmaceutical composition of the invention, includes the Carfilzomib, protein and acid as active constituent
Alkalinity regulator, pH value range are 2.0~5.0, and average grain diameter≤200nm, Zeta potential is -20~-30mv, wherein blocking non-
The mass ratio for helping rice and protein is 1:6~12.
Carfilzomib pharmaceutical composition in the present invention is actually the Carfilzomib protein nano particle that can be injected intravenously
And its floating preteins combined, aseptic filtration can be carried out by 0.22 μm of the filter in aperture, to prepare for intravenous drip
Pharmaceutical preparation；It is not needed in this pharmaceutical composition using conventional surfactant, solubilizer or any polymer core base
Matter can at most be held up to 8 hours stability under room temperature in aqueous medium solution, ensure that the safety of medication
Property.
Carfilzomib pharmaceutical composition of the invention, wherein the work that protein plays dispersion in nano particle, stablizes particle
Stable protein nano particle can not be prepared with, enzyme protein dosage is less, enzyme protein dosage excessively then drugloading rate it is lower and without
Ji.
A kind of Carfilzomib pharmaceutical composition of the invention, pH value range are 3.0~5.0.
A kind of Carfilzomib pharmaceutical composition of the invention, wherein the Carfilzomib is noncrystal, crystalline solid or both
Mixture；It is preferred that Carfilzomib is noncrystal.Because noncrystal be easier to dissolve and absorb, to reach higher biology benefit
Expenditure.
A kind of Carfilzomib pharmaceutical composition of the invention, wherein the protein belt has sulfydryl or disulfide bond；Preferably,
The protein is human serum albumin.
A kind of Carfilzomib pharmaceutical composition of the invention, wherein the acidity-basicity regulator be selected from citric acid, tartaric acid,
One of phosphoric acid, malic acid, hydrochloric acid, sodium hydroxide, potassium hydroxide, disodium hydrogen phosphate, sodium bicarbonate or any combination thereof；It is preferred that Chinese holly
The combination of rafter acid and sodium hydroxide.
The present invention also provides a kind of Carfilzomib sterile cryo drying agent, the sterile cryo drying agent is protein
It include above-mentioned Carfilzomib medicine group in the sterile cryo drying agent in conjunction with the sterile cryo drying agent of Carfilzomib
Object and protein stabiliser are closed, freeze drying protectant is not contained；Wherein the protein stabiliser be selected from acetyltryptophan, Sodium Caprylate it
One or combinations thereof, and the protein stabiliser is added simultaneously with the protein.Protein stabiliser used in the present invention is excellent
Choosing is not added individually, but protein product itself is selected to be added to the protein of this kind of stabilizer, and stabilizer is as albumen production
Use is added with protein in the fixation component of product itself.
Since protein (for example, human serum albumin) itself plays freeze drying protectant, conventional freeze-drying is not needed
Protective agent, as mannitol, glycerol or similar compound and similar compound combine.Although it is not required, these conventional freezings
Protective agent and protein stabiliser can also be added in formula of the invention.
Carfilzomib sterile cryo drying agent of the invention, can be converted into the powder or block that can disperse again,
It uses suitable aqueous medium that the powder or block can be made to redissolve to mix for the liquid containing at least 1mg/ml Carfilzomib
Suspension；It is molten that the suitable aqueous medium is selected from physiological saline, buffer saline, water, the aqueous medium of buffering, amino acid
One of liquid, vitamin solution, carbohydrate solutions or similar mediums or any combination thereof.
The present invention also provides a kind of preparation methods of above-mentioned Carfilzomib sterile cryo drying agent, comprising the following steps:
1) Carfilzomib is dissolved in organic solvent, is organic phase；The organic solvent is selected from ethyl alcohol, acetone, N, N- bis-
One of methylformamide, methylene chloride, ethyl acetate, chloroform, tetrahydrofuran, acetonitrile, methyl pyrrolidone or it is any
Combined mixture, wherein concentration range of the Carfilzomib in organic phase is 5%~30% (w/v)；
It 2) is water phase, the concentration model of the protein in an aqueous medium by the protein dispersibility in aqueous medium
It encloses for 10~20% (w/v)；
3) organic phase of step 1) is mixed with the water phase of step 2), by the mixture be placed in pressure limit 10,000~
High pressure homogenate at least three recycles in 30,000psi high-pressure homogenate device, average diameter of particles≤200nm of preparation；Have when homogenate
Machine phase component concentration >=5% (v/v), concentration >=5mg/ml of Carfilzomib in suspension；
4) suspension obtained by step 3) is evaporated under reduced pressure, removes organic solvent, generated by the coated Carfilzomib of protein
The colloid system of nano particle and free protein composition；
5) acidity-basicity regulator is added into colloid system obtained by step 4) and adjusts its pH value to 2.0~5.0；
6) gained colloid system in step 5) is subjected to aseptic filtration, freeze-drying is dry to get Carfilzomib sterile cryo
Dry preparation.
Preparation method of the invention, it is preferable that the pressure limit of high-pressure homogenate device described in step 3) is 15,000~25,
000；The concentration of Carfilzomib may be up to 6~16mg/ml in suspension.Inventors have found that main ingredient concentration < in the suspension
It when 5mg/ml, places stability decline phenomenon occur within 3~4 hours under room temperature, increase tendency and degerming is presented in partial size
The main ingredient rate of recovery declines after filter.On the contrary, the medical fluid obtained after evaporation is steady as main ingredient concentration >=6mg/ml in the suspension
Fixed nano-particle colloid decentralized system, room temperature stability can reach 6 hours, it is highly preferred that main ingredient is dense in the suspension
When degree is 8mg/ml, room temperature stability was easy to aseptic filtration up to 8 hours, was conducive to industrialization.
Preparation method of the invention, it is preferable that the temperature of reduction vaporization described in step 4) is 40 DEG C.Temperature is greater than 40 DEG C
Liquid medicine stability is low, and less than 40 DEG C solvent evaporation rates are slower.The equipment selection of reduction vaporization uses film evaporator, spray drying
Device, freeze-dryer or similar devices.
For the particle that obtains diameter≤200nm and can be sterile filtered, containing a kind of unmixing with water organic in organic phase
Solvent is very important.Under the conditions of high pressure homogenate, above-mentioned solvent forms atomic thin non-aqueous solvent dispersion in water phase
Droplet (pharmacological active substance containing dissolution), and quickly removal, formation can be sterile filtered nano particle at reduced pressure conditions.
The protein nano particle lyophilized preparation for the Carfilzomib that above-mentioned preparation method of the invention obtains has goodization
Learn stability and physical stability；Wherein the protein nano particle, which can contain, accounts for protein nano particle gross mass 1%~14%
Carfilzomib, drugloading rate is high.And because used with the better human serum albumin of human-body biological compatibility, do not use Ka Feizuo
The a large amount of cyclodextrin added in rice injection, avoid allergic reaction, and do not need to carry out aquation to patient before and after medication, show
Write the compliance and safety for improving clinical application.
According to above-mentioned preparation method, Carfilzomib is dissolved in as organic phase in a kind of suitable solvent, and
It has been stabilizer function that protein is added in water phase, easily forms stable nano-liquid droplet.Since albumin itself has centainly
Surface-active, it is different from conventional nano particle forming method, do not need a large amount of conventional surface is added in mixture active
Agent or solubilizer (for example, cyclodextrin, lauryl sodium sulfate, lecithin, Tween 80 and similar compound).The present invention preferably adopts
With the good human serum albumin substitution conventional surfactants of biocompatibility or solubilizer, toxic side effect and injection are avoided
The stimulate the reaction at position.
Carfilzomib sterile cryo drying agent of the invention, can also use second of preparation method: albuminous degeneration is multiple
Property method
The purpose of albuminous degeneration renaturation method is to incite somebody to action after being unfolded using albumen and polypeptide with the high-pressure homogeneous method combined
Pharmacological active substance is packed in protein nano particle, for delivering in vivo.The important feature of this method be for using albumen and
Directly prepare the shortcomings that being easy to appear coacervation during albumin nano granular after polypeptide expansion, provide one it is more stable
The method for preparing high concentration Carfilzomib nano particle, liquid medicine stability are significantly better than low concentration medicine prepared by prior art
Liquid, and aseptic filtration can be carried out, and be more advantageous to industrialization.
Albuminous degeneration renaturation method the following steps are included:
1) protein solution is obtained with aqueous medium solubilising protein, it is molten that the aqueous medium is selected from water, physiological saline, sugar
Liquid；
2) Carfilzomib is dissolved in organic solvent, is organic phase；The organic solvent be selected from methanol, ethyl alcohol, isopropanol,
Acetone, N,N-dimethylformamide, dimethyl sulfoxide, methylene chloride, ethyl acetate, chloroform, tetrahydrofuran, acetonitrile, first
The mixture of one of base pyrrolidones or similar solvent or any combination thereof；
3) protein structure solvent is added in protein solution obtained by step 1), sustained response 0.1~4 hour, is removed
Protein structure solvent；The protein structure solvent is selected from 2 mercapto ethanol, dithiothreitol (DTT), guanidine hydrochloride, urea, first mercapto
The third, performic acid, penicillamine, glutathione, methimazole, acetylcysteine or their combination；
4) it is added to organic obtained by step 2) in step 3) acquired solution, pressure limit 3,000~30 is added after mixing,
In the high-pressure homogenate device of 000psi, high pressure homogenate at least three circulation, protein nano average diameter of particles≤200nm of preparation is mixed
Suspension drug concentration is not less than 5mg/ml, it is preferable that suspension drug concentration is not less than 6mg/ml；
5) suspension obtained by step 4) is evaporated under reduced pressure, removes organic solvent, generated by the coated Carfilzomib of protein
The colloid system of nano particle and protein composition；
6) gained colloid system in step 5) is subjected to aseptic filtration, is then freeze-dried, it is sterile obtains Carfilzomib
Freeze-dried preparation.
Wherein, the preferred glutathione of protein structure solvent described in step 3), due to concentration is too low can not be by protein chain
It is sufficiently spread out, is unfavorable for the package of drug；Protein concentration is excessively high then excessively high to protein structure extent of the destruction, is difficult repeatability, because
This its concentration is 1~16mM.
A kind of organic solvent unmixing with water, the protein nano particle of acquisition can be contained in this preparation method in organic phase
Average grain diameter≤200nm, this particle is particularly advantageous due to that can be subjected to aseptic filtration, and it is more strong to avoid high-temperature sterilization etc.
Strong degerming method.
This preparation method is before being added Carfilzomib by timely removing extra albumen solvent and other small molecules
Compound, inventor have surprisingly found that protein nano particle maintains good stabilization in subsequent dialysis and other operations
Property, Zeta potential is between -20~-30mv, and room temperature stability was up to 48 hours.Sharp contrast is formed, inventor is multiple
Repeat the embodiment in patent CN102048695A, never realize embodiment and illustrated in claims as a result, outstanding
During removing small molecule compound by dialysis and other modes, protein nano granule stability is poor, usually in room for it
There is flocculent deposit in 6 hours in temperature.
The mode of above-mentioned removing organic solvent includes but is not limited to above-mentioned reduction vaporization method, and other methods may include
Rotary evaporation, vacuum distillation, spray drying or the like.
In above-mentioned albuminous degeneration renaturation method, since protein denaturant exists for protein for a long time in solution system
Structure itself and the stability of protein particulate can damaging property influence, cause the unstable of whole system, because
This timely removes removing protein solvent before Carfilzomib is added, to make protein nano particle subsequent after albumen expansion
Good stability is maintained in dialysis and other operations, has prepared the superior Carfilzomib nano particle of stability.
Carfilzomib protein nano particle prepared by the present invention is reached with smaller size smaller delivery of high doses pharmacological active substance, this
Sense of discomfort and hospital stays when patient can be made to receive large volume liquid infusion minimize.In addition, protein coat or packet
Clothing usually in vivo can be degradable by proteolytic enzyme, therefore this pharmaceutical composition will not bring side effect.
Specific embodiment
By referring to following embodiment, present invention be described in more detail, but not limited to this.
Embodiment 1 uses water phase solvent as organic phase solvent --- control group
600mg Carfilzomib is dissolved in 2ml dehydrated alcohol as organic phase.50ml human serum albumin (10%, w/v) water
Solution is water phase.Water phase and organic phase in high pressure microjet (Microfulidics), homogenate 5 under 15,000psi pressure conditions
Secondary circulation, obtained medical fluid are transferred in rotary evaporator, and (10-15KPa) is depressurized under the conditions of 40 DEG C and evaporates 30 minutes removing nothings
Water-ethanol.Carfilzomib average diameter of particles is greater than 300nm (Malvern Zetasizer) in obtained dispersion suspension.
The preparation process for the Carfilzomib particle that embodiment 2 can be sterile filtered
1000mg Carfilzomib is dissolved in the mixed solution of 3.3ml chloroform and 0.58ml dehydrated alcohol, as
Organic phase.The human serum albumin aqueous solution of 60ml (20%, w/v) is water phase.Carfilzomib and protein by weight ratio are 1:12.Oil
Water phase is transferred in high-pressure homogenate device (Microfulidics), homogenate 3 times circulations, obtained medicine under 25,000psi pressure conditions
Liquid is transferred in rotary evaporator, and (10-15KPa) is depressurized under the conditions of 40 DEG C and evaporates 30 minutes removing organic solvents.Obtained point
Dissipate suspension be it is translucent, pH to 2.0 is adjusted with citric acid and sodium hydroxide, Zeta potential is -30mv, and Carfilzomib particle is flat
Equal diameter is generally 110~130nm (Malvern Zetasizer).Dispersion suspension is passed through into 0.22 μm of filtering with microporous membrane
Device, turbidity and granular size are without significant change.HPLC method measurement result shows that 85% or more Carfilzomib obtains after filtering
To recycling.
Disperse suspension to be freeze-dried 48 hours, gained block easily reconstructs original after sterile water or physiological saline is added very much
The dispersion liquid come, the granular size after redissolution are identical as before freeze-drying.
The preparation process for the Carfilzomib particle that embodiment 3 can be sterile filtered
1000mg Carfilzomib is dissolved in 3.3ml chloroform, as organic phase.People's blood of 60ml (10%, w/v)
Albumin aqueous solution is water phase.Carfilzomib and protein by weight ratio are 1:6.In grease phase transfer to high-pressure homogenate device
(Microfulidics), homogenate 3 times circulations under 25,000psi pressure condition.Obtained medical fluid is transferred in rotary evaporator,
(10-15KPa) is depressurized under the conditions of 40 DEG C evaporates 30 minutes removing chloroforms.Obtained dispersion suspension be it is translucent, with salt
Acid and sodium bicarbonate adjustment pH are 5.0, and Zeta potential is -20mv, and Carfilzomib average diameter of particles is generally 120~160nm
(Malvern Zetasizer).Will dispersion suspension by 0.22 μm of nuclepore membrane filter, turbidity and granular size without
Significant change.HPLC method measurement result shows that 80% or more Carfilzomib is recycled after filtering.
Disperse suspension to be freeze-dried 48 hours, gained block easily reconstructs original after sterile water or physiological saline is added very much
The dispersion liquid come, the granular size after redissolution are identical as before freeze-drying.
The preparation process for the Carfilzomib particle that embodiment 4 can be sterile filtered
1000mg Carfilzomib is dissolved in 3.3ml methylene chloride, as organic phase.People's blood of 60ml (10%, w/v)
Albumin aqueous solution is water phase.Carfilzomib and protein by weight ratio are 1:6.In grease phase transfer to high-pressure homogenate device
(Microfulidics), homogenate 3 times circulations under 25,000psi pressure condition.Obtained medical fluid is transferred in rotary evaporator,
(10-15KPa) is depressurized under the conditions of 40 DEG C evaporates 30 minutes removing methylene chloride.Obtained dispersion suspension be it is translucent, with Chinese holly
Rafter acid and sodium bicarbonate adjustment pH are 5.0, and Zeta potential is -21mv, Carfilzomib average diameter of particles is generally 130~
160nm(Malvern Zetasizer).Dispersion suspension is passed through into 0.22 μm of nuclepore membrane filter, turbidity and particle
Size is without significant change.HPLC method measurement result shows that 80% or more Carfilzomib is recycled after filtering.
Disperse suspension to be freeze-dried 48 hours, gained block easily reconstructs original after sterile water or physiological saline is added very much
The dispersion liquid come, the granular size after redissolution are identical as before freeze-drying.
5 Carfilzomib of embodiment and protein by weight ratio are that 1:4 prepares nano particle-control group
1000mg Carfilzomib is dissolved in 3.3ml chloroform, as organic phase.The people of 60ml (6.67%, w/v)
Blood albumin aqueous solution is water phase.Carfilzomib and protein by weight ratio are 1:4.In grease phase transfer to high-pressure homogenate device
(Microfulidics), homogenate 3 times circulations under 25,000psi pressure condition.Obtained medical fluid is transferred in rotary evaporator,
(10-15KPa) is depressurized under the conditions of 40 DEG C evaporates 30 minutes removing chloroforms.Obtained dispersion suspension be it is translucent, with Chinese holly
Rafter acid and sodium hydroxide adjustment pH are 5.0, and Zeta potential is -25mv, Carfilzomib average diameter of particles is generally 220~
280nm(Malvern Zetasizer).Dispersion suspension is passed through into 0.22 μm of nuclepore membrane filter, filtrability is very poor, can not
Effective aseptic filtration.
Influence of the test example pH value to product quality
A series of experiments is carried out according to 2 same steps of embodiment, solvent is divided after evaporating with citric acid and sodium hydroxide
Not Tiao Jie pH to 1.0,2.0,3.0,4.0,5.0,6.0, while with listed formulation products(Carfilzomib ring
Cyclodextrin inclusion compound product) solution-stabilized Journal of Sex Research of progress under the conditions of 25 DEG C, as a result as shown in the table:
According to upper table data, Yuan Yanpin solution can only maintain 4 hours stability under the conditions of 25 DEG C, and this product is in pH value
At least 8 hours stability can be maintained in 2.0~5.0 ranges under the conditions of 25 DEG C, optimal pH range is 3.0~5.0.
Claims (7)
1. a kind of Carfilzomib pharmaceutical composition, which is characterized in that by the Carfilzomib, protein and soda acid as active constituent
Regulator composition is spent, pH value range is 3.0~5.0, and average grain diameter≤200nm, Zeta potential is -20~-30mv, wherein blocking
The mass ratio of Fei Zuo meter and protein is 1:6~12；
Wherein, the protein is human serum albumin；
The acidity-basicity regulator is selected from the combination of citric acid and sodium hydroxide；
The Carfilzomib pharmaceutical composition is prepared by the following method to obtain:
1) Carfilzomib is dissolved in organic solvent, is organic phase；The organic solvent is selected from ethyl alcohol, acetone, N, N- dimethyl
One of formamide, methylene chloride, ethyl acetate, chloroform, tetrahydrofuran, acetonitrile, methyl pyrrolidone or any combination thereof
Mixture, wherein concentration range of the Carfilzomib in organic phase be 5%~30% (w/v)；
It 2) is water phase by the protein dispersibility in aqueous medium, the concentration range of the protein in an aqueous medium is
10~20% (w/v)；
3) organic phase of step 1) is mixed with the water phase of step 2), which is placed in pressure limit 10,000~30,
High pressure homogenate at least three recycles in the high-pressure homogenate device of 000psi, average diameter of particles≤200nm of preparation；It is organic when homogenate
Phase component concentration >=5% (v/v), concentration >=5mg/ml of Carfilzomib in suspension；
4) suspension obtained by step 3) is evaporated under reduced pressure, removes organic solvent, generated by the coated Carfilzomib nanometer of protein
The colloid system of particle and free protein composition；
5) acidity-basicity regulator is added into colloid system obtained by step 4) and adjusts its pH value to 3.0~5.0；
6) gained colloid system in step 5) is subjected to aseptic filtration, freeze-drying.
2. Carfilzomib pharmaceutical composition according to claim 1, which is characterized in that the Carfilzomib be it is noncrystal,
The mixture of crystalline solid or both.
3. Carfilzomib pharmaceutical composition according to claim 1, which is characterized in that high-pressure homogenate device described in step 3)
Pressure limit be 15,000~25,000；The concentration of Carfilzomib is 6~16mg/ml in the suspension.
4. Carfilzomib pharmaceutical composition according to claim 1, which is characterized in that block in suspension described in step 3)
The concentration of Fei Zuo meter is 8mg/ml.
5. Carfilzomib pharmaceutical composition according to claim 1, which is characterized in that reduction vaporization described in step 4)
Temperature is 40 DEG C.
6. a kind of Carfilzomib sterile cryo drying agent, which is characterized in that the sterile cryo drying agent is protein knot
The sterile cryo drying agent for closing Carfilzomib, it is non-comprising card described in claim 1 in the sterile cryo drying agent
Rice pharmaceutical composition and protein stabiliser are helped, freeze drying protectant is not contained；Wherein the protein stabiliser be selected from acetyltryptophan,
One or a combination set of Sodium Caprylate, and the protein stabiliser is added simultaneously with the protein.
7. Carfilzomib sterile cryo drying agent according to claim 6, which is characterized in that the dry system of the sterile cryo
Agent can be converted into the powder or block that can disperse again, the powder or block can be made multiple using suitable aqueous medium
Molten is the liquid suspension containing at least 1mg/ml Carfilzomib；The suitable aqueous medium is selected from physiological saline, water, amino
One of acid solution, vitamin solution, carbohydrate solutions or any combination thereof.
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| CN111153964B (en) * | 2020-01-20 | 2023-12-19 | 江苏希迪制药有限公司 | Carfilzomib crystal form, preparation method and application thereof |
| CN115475230B (en) * | 2021-06-15 | 2024-07-26 | 山东新时代药业有限公司 | Carfilzomib nanoemulsion suspension freeze-dried preparation and preparation method thereof |
| CN118440147A (en) * | 2024-07-08 | 2024-08-06 | 南京道尔医药研究院有限公司 | Carfilzomib eutectic crystal and preparation method thereof |
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| CN1157185C (en) * | 1996-10-01 | 2004-07-14 | 美国生物科学有限公司 | Protein stabilized pharmacologically active agents, methods for preparation thereof and methods for use thereof |
| CN102048695A (en) * | 2009-08-11 | 2011-05-11 | 南京大学 | Preparation method of protein nanoparticle for in vivo delivery of pharmacologically active agent |
| CN103393632A (en) * | 2013-07-26 | 2013-11-20 | 齐鲁制药有限公司 | Cabazitaxel drug composition and preparation method thereof |
| CN105640912A (en) * | 2014-11-12 | 2016-06-08 | 天津市汉康医药生物技术有限公司 | Carfilzomib pharmaceutical composition and preparation method thereof |
| CN105641676A (en) * | 2014-11-12 | 2016-06-08 | 天津市汉康医药生物技术有限公司 | Stable carfilzomib pharmaceutical composition |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1157185C (en) * | 1996-10-01 | 2004-07-14 | 美国生物科学有限公司 | Protein stabilized pharmacologically active agents, methods for preparation thereof and methods for use thereof |
| CN102048695A (en) * | 2009-08-11 | 2011-05-11 | 南京大学 | Preparation method of protein nanoparticle for in vivo delivery of pharmacologically active agent |
| CN103393632A (en) * | 2013-07-26 | 2013-11-20 | 齐鲁制药有限公司 | Cabazitaxel drug composition and preparation method thereof |
| CN105640912A (en) * | 2014-11-12 | 2016-06-08 | 天津市汉康医药生物技术有限公司 | Carfilzomib pharmaceutical composition and preparation method thereof |
| CN105641676A (en) * | 2014-11-12 | 2016-06-08 | 天津市汉康医药生物技术有限公司 | Stable carfilzomib pharmaceutical composition |
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