CN103908432B - A kind of freeze-dried composition and preparation method thereof of Ipsapirone albumin - Google Patents
A kind of freeze-dried composition and preparation method thereof of Ipsapirone albumin Download PDFInfo
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Abstract
The present invention relates to a kind of Ipsapirone albumin freeze-dried compositions, and the method for preparing the freeze-dried composition by simple technique.The method of the present invention for preparing Ipsapirone albumin freeze-dried composition, keeps the particle diameter distribution of freeze-dried composition uniform, clinical application requirement standard can be fully achieved, and simple for process, is suitble to industrialization amplification.
Description
Technical field
The present invention relates to pharmaceutical fields, and in particular to nanometer formulation technology is more particularly to a kind of Ipsapirone freeze-drying group
Close object and preparation method thereof.
Background technology
Ipsapirone (ixabepilone) is a kind of derivative of semi-synthetic epothilone B, has following chemical constitution：
Ipsapirone can be bonded directly on the β subunits of tubulin, inhibit the depolymerization of micro-pipe, to promote tumour thin
Born of the same parents' microtubule stabilization and play antitumor action.
Although Ipsapirone has notable curative effect, due to its poorly water-soluble, it is difficult to use aqueous medium preparation, make it
There are larger difficulty for preparation research.
Food and drug administration (FDA) ratifies the injection listing of Ipsapirone on October 16th, 2007, makes
With 52.8% (w/v) Emulsifier EL-60（Polyoxyethylated castor oil, trade name Cremophor-EL）
Be injection solvent with the mixed liquor of 39.8% (w/v) absolute ethyl alcohol, be then diluted further to lactic acid Ge Linshi injections or
The uses such as 0.9% sodium chloride injection.
It is similar with the commercial preparation of increase drug solubility based on Emulsifier EL-60, excessive concentrations
Cremophor-EL is easy that patient is made to generate serious allergic reaction, therefore, it has to use antihistamine drug in advance before medication
The risk of drug is reduced with glucocorticoid.Moreover, Cremophor-EL has stronger peripheral nerve toxicity, Cremophor-
The micella that EL is formed can extend the time that drug contacts in vivo, enhance drug to the toxic side effect of whole body, cause Yi Sha
Grand Drug safety declines, and limits being widely used for its clinic.
Therefore, it is necessary to a kind of reduction formulations toxics, increase the drugloading rate of Ipsapirone, improve tolerance of the human body to drug
With the targeting to tumor tissues, toxic side effect of the drug to other normal structures, the Ipsapirone with stability are reduced
New dosage form.
Largely studies have shown that the methods of nanosuspension, nano-emulsion, nanocrystal reduce drug granule grain size, increase
Its surface area controls its physical state, can increase the dissolubility of drug, improve its bioavilability.Currently, having a large amount of
Nano medication preparation process and prescription be developed, and up to the present have 12 in nanometer formulation successfully list.But
Due to the unique pharmaceutical properties of Ipsapirone, at present also not about the development technique and pharmacy prescription of the nanometer formulation of Ipsapirone
It appears in the newspapers.
Albumin accounts for about the 60% of plasma protein composition, is most abundant nutrient protein, while logical in lacuna vasorum albumin
It crosses increase osmotic pressure and plays important physiological function to adjust the volume of blood plasma.Since albumin is long-pending in various tumor tissues
It is tired, it is utilized by the various amino acid moleculars that are degraded to of encytosis and lysosome for synthesizing new protein molecule, becomes fast
The most important energy and nitrogen source of the cancer cell of speed proliferation, therefore be ideal tumour medicine carrier molecule.Nearly ten years, it researches and develops
Personnel have developed the albumin nano granular of a large amount of anticancer drug, wherein most famous is the Nab of Bioscience
The Abraxane of (nanoparticle albumin bound) technological development was ratified to list in 2005 by FDA, and was ground
The most widely used technology based on the precipitation method of hair personnel.The above method makes the dissolution rate of anticancer drug obtain significantly carrying
Height, but high pressure homogenization method complex process, preparation is of high cost and is not easy amplification production；Precipitation method etc. prepare composite nano-powder or
Nano suspension grain size is larger, and it is not easy to control that there are homogeneity, the poor problem of reproducibility between batch；And Ipsapirone/white egg
White nanoparticle has not been reported so far.
Therefore it is still necessary to a kind of preparation of the searching high Ipsapirone of dissolution rate using safer auxiliary material.
Invention content
The purpose of the present invention is have higher biological safety and more uniform particle size point by a kind of easy technique preparation
The Ipsapirone albumin freeze-dried composition of cloth.
The present invention provides a kind of using albumin as the Ipsapirone freeze-dried composition of carrier, wherein the matter of Ipsapirone
Amount percentage composition is 5%-30%, and the mass percentage of albumin is 70%-95%.Grain size is after the freeze-dried composition rehydration
50-1000nm, preferably 100-500nm, more preferable 100-300nm.
The albumin is the animal blood serum albumen that quality standard is transfused in accordance with human vein, including bovine serum albumin, and
The seralbumin of people, preferably human serum albumins（HSA）.
Seralbumin of the present invention is the product of commercially available acquisition, such as grinds that raw, Shanghai hundred million is glad, northern by Shanghai
The purchases such as capital high-tech perseverance brightness obtain.
Another invention of the present invention is to provide a kind of using albumin as the preparation side of the Ipsapirone freeze-dried composition of carrier
Method, the method include：
（1）By Ipsapirone be dissolved in organic solvent be used as dispersed phase, make wherein ixabepilone concentration be 5mg/ml ~
100mg/ml, preferably 10 ~ 60 mg/ml, more preferable 10 ~ 40 mg/ml；
（2）Albumin is dissolved in the water as continuous phase solution, it is 20mg/ml ~ 600mg/ml to make albumin concentration, excellent
Select 20 ~ 200 mg/ml, more preferable 20 ~ 60 mg/ml；Adjusting pH is 5-6, preferably 5.3-5.5；
（3）By step（1）Dispersion be added in membrane emulsifier liquid storage device, by step（2）Continuous phase solution pass through film
It is pressed into continuous phase container, is emulsified by the method that film emulsifies, obtain emulsion；
（4）By step（3）Emulsion concentration, freeze-drying, obtain Ipsapirone freeze-dried composition.
Above-mentioned steps（1）Described in organic solvent include but not limited to：Ethyl alcohol, chloroform, acetone, tetrahydrofuran or dichloro
The mixture of methane or two or more solvent.The mixed solvent of preferred alcohol and chloroform.
Above-mentioned steps（2）In, it can select hydrochloric acid, citric acid, phosphoric acid, the winestone acid for adjusting pH, preferred pH adjusting agent to be
Citric acid.
Above-mentioned steps（3）In, the film used in the film emulsion process includes but not limited to metal film, ceramic membrane, SPG
Film, preferably SPG films.The membrane aperture is 50-1000nm, preferably 50-400nm.Dispersed phase is set to press through in film emulsion process
Film enters in continuous phase, and pressure used is 10-300KPa, preferably 50-200KPa.The use of the dispersed phase and continuous phase
Amount volume ratio is 1/2-1/25, preferred volume ratio 1/3-1/15, more preferable 1/5-1/10.
Flow velocity of the continuous phase in film emulsion process is 20mL/min-400 mL/min, preferably 20 mL/min-
50 mL/min。
Step 3）Middle continuous phase can cycle through continuous phase container, and the cycle-index of the continuous phase can be 1-20
It is secondary, and it has been found that cycle-index has increased trend, the upper carrying capacity of circulation primary drug in 5 times or more nanoparticle grain sizes
It is not high, preferably 2-5 times.
Applicant has found under study for action, in film emulsion process, white egg in the concentration and continuous phase of Ipsapirone in dispersed phase
The amount ratio and fenestra pore size of white concentration, dispersed phase and continuous phase directly influence the homogeneity of emulsion and big
It is small, further influence the stability of nanoparticle；Pressure in film emulsion process determines dispersibility with continuous phase flow velocity collective effect
Membrane pressure, influence the size and homogeneity of nanoparticle.Therefore applicant carries out the parameter in above-mentioned film emulsifying step deep
Enter research, finds white when preparing Ipsapirone of the present invention with aperture, pressure and the flow parameters of the above-mentioned selection of the present invention
When albumen freeze-dried composition, grain size, homogeneity and the stability of the nanoparticle of acquisition are all ensured.In addition, applicant is logical
It crosses a large amount of creative works to study the parameter in preparation process, particular, it is found that preparing the present invention's with above-mentioned preparation method
When Ipsapirone albumin freeze-dried composition, reproducibility is well controlled between batch, amplifies particularly suitable for production.
Above-mentioned steps（4）Described in method for concentration, conventional method for concentration may be used, including centrifuge, rotate.Institute
The freeze drying process stated is conventional means well known to those skilled in the art, such as is freeze-dried under conditions of -70 ~ 30 DEG C.
Film of the present invention emulsifies：Pressure official post dispersed phase by film both sides is by microporous barrier, with droplet
Form, which is dispersed in continuous phase, forms emulsion.Method can be with bibliography：The films emulsifying technology such as Gu Li is administered in particle
Research [J] Chinese Journal of Pharmaceuticals in system, 2007,38（11）.
The advantage of the invention is that the following aspects：
1, the preparation method is simple for process, easy to operate, only need to prepare dispersed phase respectively with continuous phase, is emulsified by film
Device emulsifies up to Ipsapirone nanosuspension.
2, the preparation method there is no conventional lab scale, pilot scale, production amplification step by step, need to only expand dispersed phase container and
Continuous phase container simultaneously accordingly increases membrane tube quantity, you can realizes amplification of the lab scale to production.
3, the present invention has efficiently controlled Ipsapirone albumin nanometer especially by controlling membrane tube aperture, crossing film pressure
For the particle size of the grain of rice in the range of suitable for injection use, the Ipsapirone albumin nano granular prepared through the invention is uniform
Property is good.
4, Ipsapirone freeze-dried composition of the invention has a good redispersible, and average grain diameter is less than after rehydration
500nm。
5, auxiliary material used in the present invention is few, and albumin biological safety is high, is conducive to target target tissue after drug enters blood.
Description of the drawings：
Fig. 1 is the stereoscan photograph at 1 Ipsapirone nanosuspension frozen powder end of embodiment.
Fig. 2 is the grain size distribution after 1 Ipsapirone nano suspension rehydration of embodiment.
Fig. 3 is the stereoscan photograph at 7 Ipsapirone nanosuspension frozen powder end of embodiment, and particle is at spherical shape.
Fig. 4 is the grain size distribution after 7 Ipsapirone nano suspension rehydration of embodiment.
Specific implementation mode
The electron-microscope scanning instrument of freeze-dried powder selects HITACHI S-4800 in the embodiment of the present invention；Nanoparticle is remake to use
Malvern Nano-ZS90 are measured.Other not specified instrument and equipments use the conventional equipment of those skilled in the art.
Embodiment 1
Ipsapirone bulk pharmaceutical chemicals 0.20g is weighed, 20.0ml absolute ethyl alcohols and chloroform are dissolved in（1:5）In the mixed solvent, obtain
To the solution of a concentration of 10mg/mL, and pour into dispersed phase container fluid reservoir；Human serum albumins 2.0g is weighed again is dissolved in injection
Use water（Lemon acid for adjusting pH is to 5.5）It is used as continuous phase in 100ml, will continuously be added in continuous phase container, opening plunger pump
Continuous phase is set to recycle, holding continuous phase flow velocity is 20mL/min, and opening valve keeps dispersed phase slow under the constant pressure of 50KPa
Cross film（Aperture 0.1um）It being pressed into continuous phase until pressure indicator declines, collection centrifuges gained suspension, collects precipitation,
Pre-freeze is to -40 DEG C or less and is lyophilized 24 hours, while being warming up to 25 DEG C to get Ipsapirone freeze-dried composition.Contain what is obtained
Have 9.09%（w/w）The freeze-dried powder of Ipsapirone remakes the solution to form a concentration of 5mg/mL with 0.9% sodium-chloride water solution, obtains
To the nanosuspension that average grain diameter is 112nm, PDI 0.061, stability is more than 12 hours.Attached drawing 1 is prepared for embodiment 1
The stereoscan photograph (HITACHI S4800) of obtained sample freeze-dried powder, particle is at spherical shape, grain size 100nm or so.It is attached
Fig. 2 is the grain-size graph after sample recasting（Malvern Nano-ZS90）.
Embodiment 2
Ipsapirone bulk pharmaceutical chemicals 0.20g is weighed, 20.0ml absolute ethyl alcohols and chloroform are dissolved in（1:5）In the mixed solvent, obtain
To the solution of a concentration of 10mg/mL, and pour into dispersed phase container fluid reservoir；Human serum albumins 2.0g is weighed again is dissolved in injection
Use water（Lemon acid for adjusting pH is to 5.5）It is used as continuous phase in 100ml, will continuously be added in continuous phase container, opening plunger pump
Continuous phase is set to recycle, holding continuous phase flow velocity is 50mL/min, and opening valve makes dispersed phase delay under the constant pressure of 200KPa
It is slow to cross film（Aperture 0.1um）It is pressed into continuous phase until pressure indicator declines, collection centrifuges gained suspension, and it is heavy to collect
It forms sediment, pre-freeze is to -40 DEG C or less and is lyophilized 24 hours, while being warming up to 25 DEG C to get Ipsapirone freeze-dried composition.By what is obtained
Contain 9.09%（w/w）The freeze-dried powder of Ipsapirone remakes the solution to form a concentration of 5mg/mL with 0.9% sodium-chloride water solution,
The nanosuspension that average grain diameter is 163nm, PDI 0.072 are obtained, stability is more than 12 hours.
Embodiment 3
Ipsapirone bulk pharmaceutical chemicals 0.20g is weighed, 20.0ml absolute ethyl alcohols and chloroform are dissolved in（1:5）In the mixed solvent, obtain
To the solution of a concentration of 10mg/mL, and pour into dispersed phase container fluid reservoir；Human serum albumins 2.0g is weighed again is dissolved in injection
Use water（Lemon acid for adjusting pH is to 5.5）It is used as continuous phase in 100ml, will continuously be added in continuous phase container, opening plunger pump
Continuous phase is set to recycle, holding continuous phase flow velocity is 50mL/min, and opening valve makes dispersed phase delay under the constant pressure of 200KPa
It is slow to cross film（Aperture 0.4um）It is pressed into continuous phase until pressure indicator declines, collection centrifuges gained suspension, and it is heavy to collect
It forms sediment, pre-freeze is to -40 DEG C or less and is lyophilized 24 hours, while being warming up to 25 DEG C to get Ipsapirone freeze-dried composition.By what is obtained
Contain 9.09%（w/w）The freeze-dried powder of Ipsapirone remakes the solution to form a concentration of 5mg/mL with 0.9% sodium-chloride water solution,
The nanosuspension that average grain diameter is 214nm, PDI 0.107 are obtained, stability is more than 12 hours.
Embodiment 4
Ipsapirone bulk pharmaceutical chemicals 0.80g is weighed, 20.0ml absolute ethyl alcohols and chloroform are dissolved in（1:5）In the mixed solvent, obtain
To the solution of a concentration of 40mg/mL, and pour into dispersed phase container fluid reservoir；Human serum albumins 2.0g is weighed again is dissolved in injection
Use water（Lemon acid for adjusting pH is to 5.5）It is used as continuous phase in 200ml, will continuously be added in continuous phase container, opening plunger pump
Continuous phase is set to recycle, holding continuous phase flow velocity is 20mL/min, and opening valve keeps dispersed phase slow under the constant pressure of 50KPa
Cross film（Aperture 0.1um）It being pressed into continuous phase until pressure indicator declines, collection centrifuges gained suspension, collects precipitation,
Pre-freeze is to -40 DEG C or less and is lyophilized 24 hours, while being warming up to 25 DEG C to get Ipsapirone freeze-dried composition.Contain what is obtained
Have 28.57%（w/w）The freeze-dried powder of Ipsapirone remakes the solution to form a concentration of 5mg/mL with 0.9% sodium-chloride water solution,
The nanosuspension that average grain diameter is 173nm, PDI 0.080 are obtained, stability is more than 12 hours.
Embodiment 5
Ipsapirone bulk pharmaceutical chemicals 0.80g is weighed, 20.0ml absolute ethyl alcohols and chloroform are dissolved in（1:5）In the mixed solvent, obtain
To the solution of a concentration of 40mg/mL, and pour into dispersed phase container fluid reservoir；Human serum albumins 12.0g is weighed again is dissolved in note
It penetrates and uses water（Lemon acid for adjusting pH is to 5.5）It is used as continuous phase in 200ml, will continuously be added in continuous phase container, opening plunger
Pump makes continuous phase recycle, and holding continuous phase flow velocity is 20mL/min, and opening valve makes dispersed phase delay under the constant pressure of 50KPa
It is slow to cross film（Aperture 0.1um）It is pressed into continuous phase until pressure indicator declines, collection centrifuges gained suspension, and it is heavy to collect
It forms sediment, pre-freeze is to -40 DEG C or less and is lyophilized 24 hours, while being warming up to 25 DEG C to get Ipsapirone freeze-dried composition.By what is obtained
Contain 6.25%（w/w）The freeze-dried powder of Ipsapirone remakes the solution to form a concentration of 5mg/mL with 0.9% sodium-chloride water solution,
The nanosuspension that average grain diameter is 122nm, PDI 0.137 are obtained, stability is more than 12 hours.
Embodiment 6
Ipsapirone bulk pharmaceutical chemicals 0.50g is weighed, 20.0ml absolute ethyl alcohols and chloroform are dissolved in（1:5）In the mixed solvent, obtain
To the solution of a concentration of 25mg/mL, and pour into dispersed phase container fluid reservoir；Human serum albumins 6.0g is weighed again is dissolved in injection
Use water（Lemon acid for adjusting pH is to 5.5）It is used as continuous phase in 150ml, will continuously be added in continuous phase container, opening plunger pump
Continuous phase is set to recycle, holding continuous phase flow velocity is 35mL/min, and opening valve makes dispersed phase delay under the constant pressure of 100KPa
It is slow to cross film（Aperture 0.1um）It is pressed into continuous phase until pressure indicator declines, collection centrifuges gained suspension, and it is heavy to collect
It forms sediment, pre-freeze is to -40 DEG C or less and is lyophilized 24 hours, while being warming up to 25 DEG C to get Ipsapirone freeze-dried composition.By what is obtained
Contain 7.69%（w/w）The freeze-dried powder of Ipsapirone remakes the solution to form a concentration of 5mg/mL with 0.9% sodium-chloride water solution,
The nanosuspension that average grain diameter is 141nm, PDI 0.094 are obtained, stability is more than 12 hours.
Embodiment 7
Direct precipitation method prepares Ipsapirone nano suspension
Ipsapirone bulk pharmaceutical chemicals 0.20g is weighed, 20.0ml absolute ethyl alcohols and chloroform are dissolved in（1:5）In the mixed solvent, obtain
To the raw material medicine solution of a concentration of 10mg/mL；Human serum albumins 2.0g is weighed again is dissolved in water for injection（Lemon acid for adjusting pH is extremely
5.5）100ml, and pour into blender.Under the lasting stirring of 500rpm, raw material medicine solution is slowly added in blender, is tieed up
Stirring one hour is held, gained suspension is centrifuged, collects precipitation, pre-freeze is to -40 DEG C or less and is lyophilized 24 hours, is warming up to simultaneously
25 DEG C to get Ipsapirone freeze-dried composition.Contain 9.09% by what is obtained（w/w）0.9% chlorine of the freeze-dried powder of Ipsapirone
Change sodium water solution and remake the solution to form a concentration of 5mg/mL, obtain the nanosuspension that average grain diameter is 139nm, PDI is
0.215, stability is less than 12 hours.
The electron microscope grain size distribution of comparing embodiment 1 and embodiment 7 can be seen that relative to direct precipitation method, this hair
The bright method for preparing Ipsapirone albumin freeze-dried composition, has better homogeneity.
Embodiment 8
By 1 technique of embodiment repeat three batches, investigate technology stability, scanning electron microscopic observation powder morphology, it is seen that particle at
Spherical shape, homogeneity is preferable, and three batches of sample morphologies are similar；It is 5.5 to measure freeze-dried powder to redissolve the pH value after recasting all；Investigate weight
The grain size and Zeta potential of sample solution processed, for three batches of average grain diameters all in 100nm or so, monodispersity is good, energy continual and steady 12
Hour or more；HPLC methods measure nanometer formulation drugloading rate.As a result it see the table below 1.
Medication amount/nanosuspension frozen powder total amount × 100 in drugloading rate (%)=nanosuspension frozen powder
1. embodiment of table, 1 technique prepares the various indexs of Ipsapirone nanosuspension frozen powder end rehydration
Claims (1)
1. a kind of prepare using albumin as the method for the Ipsapirone freeze-dried composition of carrier, it is characterised in that：
1), Ipsapirone is dissolved in organic solvent and is used as dispersed phase, it is 10mg/ml to make wherein ixabepilone concentration；Wherein,
The organic solvent refers to that volume ratio is 1:5 absolute ethyl alcohol and the mixed solvent of chloroform；
2), albumin is dissolved in the water as continuous phase solution, it is 20mg/ml to make albumin concentration；Adjusting pH is 5-6；
3), the dispersion of step 1) is added in membrane emulsifier liquid storage device, the continuous phase solution of step 2) is entered to connect by membrane pressure
In continuous phase container, is emulsified by the method that film emulsifies, obtain emulsion, the membrane aperture wherein used in film emulsion process is
100nm；The pressure that dispersed phase is pressed through to film in film emulsion process is 50KPa；The dosage volume ratio of dispersed phase and continuous phase is
1/5；The flow velocity of continuous phase is 20ml/min in film emulsion process；In film emulsion process, continuous phase recycles 2-5 times；
4), the emulsion of step 3) is concentrated, freeze-drying obtains Ipsapirone freeze-dried composition.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1515246A (en) * | 1997-06-27 | 2004-07-28 | �Ϻ���ͨ��ѧ | New preparation of medicine, its preparation and application method |
| CN101155584A (en) * | 2005-03-31 | 2008-04-02 | 布里斯托尔-迈尔斯斯奎布公司 | Methods for administering ixabepilone |
| CN101422458A (en) * | 2007-10-29 | 2009-05-06 | 浙江海正药业股份有限公司 | Epothilone freeze-drying composition |
| CN101951956A (en) * | 2007-12-19 | 2011-01-19 | 阿登尼亚投资有限公司 | Drug delivery system for administration of poorly water soluble pharmaceutically active substances |
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2013
- 2013-01-02 CN CN201310000252.XA patent/CN103908432B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1515246A (en) * | 1997-06-27 | 2004-07-28 | �Ϻ���ͨ��ѧ | New preparation of medicine, its preparation and application method |
| CN101155584A (en) * | 2005-03-31 | 2008-04-02 | 布里斯托尔-迈尔斯斯奎布公司 | Methods for administering ixabepilone |
| CN101422458A (en) * | 2007-10-29 | 2009-05-06 | 浙江海正药业股份有限公司 | Epothilone freeze-drying composition |
| CN101951956A (en) * | 2007-12-19 | 2011-01-19 | 阿登尼亚投资有限公司 | Drug delivery system for administration of poorly water soluble pharmaceutically active substances |
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Address after: Building C25, nanotechnology Park, 218 Xinghu street, Suzhou Industrial Park, Jiangsu Province Patentee after: Borui biomedical (Suzhou) Co.,Ltd. Patentee after: Borui Pharmaceutical (Suzhou) Co., Ltd Address before: Building C25, nanotechnology Park, 218 Xinghu street, Suzhou Industrial Park, Jiangsu Province Patentee before: Borui biomedical (Suzhou) Co.,Ltd. Patentee before: XINTAI PHARMACEUTICAL (SUZHOU) Co.,Ltd. |
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