CN109106688A - A kind of preparation method of octreotide acetate microballoon - Google Patents
A kind of preparation method of octreotide acetate microballoon Download PDFInfo
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Abstract
A method of preparing octreotide acetate microball preparation, comprising: (1) octreotide acetate is dissolved in methanol, forms solution A；(2) PLGA is dissolved in methylene chloride, forms solution B；(3) solution A and solution B are mixed under stiring, forms uniform solution C；(4) silicone oil is at the uniform velocity added in solution C under stiring, forms condensation product；(5) obtained condensation product is added in solidify liquid, forms microballoon；(6) microballoon obtained in filtration step (5), cleaning, is added appropriate mannitol solution, is dried in vacuo, sieving.This method is easy to operate, and the product quality of preparation is high, can matching while using, sphere is quickly evenly distributed, do not assemble.The suspending step that the microballoon of method preparation of the invention needs is less, easy to operate, for formulator without particular/special requirement, is not necessarily to Special Training, can dramatically increase the convenience of terminal hospital, patient when using the drug.
Description
Technical field
The present invention relates to microsphere medicinal preparation technical fields, and in particular to a kind of to prepare octreotide acetate using phase separation method
The method of microballoon.
Background technique
Octreotide is a kind of octapeptide derivative of artificial synthesized spontaneous growth chalone, by chemist Wilfried Bauer
It was synthesized for the first time in 1979, remains pharmacological action identical with growth hormone, many hormones, including stomachial secretion can be inhibited
Element, cholecystokinin, glucagon, growth hormone (GH), insulin, pancreatic polypeptide, thyroid-stimulating hormone and vasoactive intestinal peptide etc.
Secretion.Clinically it is mainly used for treating acromegalia, stomach pancreas enteroendocrine tumour (class cancer, somatotropin releasing factor gland
Tumor, Glucagonoma, gastrinoma/zes, insulinoma, vasoactive intestinal peptide tumor), clinical application is very extensive.
There are two types of the octreotide acetate preparations of FDA approval listing, and one is injectionsSubcutaneous injection,
Three times a day；Another kind is reservoir type microsphere for injectionDepot, intramuscular injection, monthly.Clinical effectiveness show that it can permanently effective control growth hormone and type-1 insulin like growth factor
Level, and tumour can be effectively reduced.However, the octreotide acetate microballoon of the listing is needed using special glucose-
PLGA star-shape polymer (GLU-PLGA) is used as matrix.
Currently, the research of many scholars is all that double emulsion-solvent evaporation technique is utilized to prepare octreotide acetate microballoon.It is now logical
Often there are two types of the modes for preparing emulsion:
(1) disposable preparation: the volume ratio of colostrum and outer aqueous phase is generally 1:10-1:40, is holding after the completion of emulsion preparation
Solvent volatilization is directly carried out in device.Such as entitled " organism degradable star-type structure poly (glycolide-lactide) medicine carrier microballoon and preparation method thereof "
Patent of invention CN1927906A disclosed in " colostrum is injected into outer aqueous phase under stiring, the volume of colostrum and outer aqueous phase
Than forming W/O/W lotion through emulsification for 4-10:100, stirring to methylene chloride is all volatilized, and makes to solidify balling-up ".It is for another example entitled
" by produce 1 newborn phase disclosed in the patent of invention CN1330921A of " as the method for multi-emulsion method manufacture slow release microballoon "
Or emulsion is dispersed in a kind of water phase, and organic solvent is removed from the microballoon for be dispersed with drug, and encapsulating is made such as drug
The stage of particle "." water packet disclosed in the United States Patent (USP) US7846479 of for another example entitled " microsphere composition and preparation method "
The lotion of Water-In-Oil is prepared by following step: water phase and the organic solvent containing polymer being mixed and prepare water in oil emulsion
The lotion being prepared and the water phase containing surfactant are mixed with water-in-oil-in-water compositions by liquid ".
(2) emulsion preparation carries out respectively with solvent volatilization: colostrum and continuous media are mixed with emulsion, then emulsion is added
Organic solvent is extracted into a effective amount of Extraction medium and forms microballoon.Such as entitled " pharmaceutical composition comprising octreotide grains "
Patent of invention CN17110073A disclosed in it is " dispersion liquid (i.e. colostrum) and a effective amount of continuous work medium is mixed
It closes to form lotion, which contains the working media and comprising the octreotide acetate, the solvent and described linear
The droplet of poly- (lactide coglycolide)；It is formed after the lotion and a effective amount of Extraction medium is all added in the lotion immediately
In the particle is formed to extract the solvent from the droplet.Preferably 10 times of Extraction medium or higher volume ".
However, there are many deficiencies for the above method.Specifically, it when carrying out microballoon production, is produced when using the first emulsion
When method, in order to meet the volume requirement of microballoon output and outer aqueous phase, it is necessary to be equipped with the emulsion tank of large capacity.Microballoon production pair
The requirement of emulsion tank is relatively high, it is often necessary to have emulsification stirring, i.e., quickly (revolving speed 500rpm-2000rpm, is used for for stirring
Prepare emulsion) and mix slowly (revolving speed 200rpm-500rpm is used for solvent volatilization process).For the emulsion tank of large capacity,
It is relatively difficult to be equipped with efficient, steady and high quality quick mixing plant.And outer aqueous phase volume is excessive, the balling-up of microballoon
Also it is difficult to control proper.When using second of emulsion production method, the capacity of emulsion tank can suitably reduce, but large quantities of
Often emulsifying effectiveness is bad in the production of amount microballoon, and the adhesion of microballoon is be easy to cause when output is larger, influences final microballoon
Quality.And emulsion is limited by emulsion tankage size, and maximum output is relatively fixed, can not further increase output.
Patent US5538739 discloses the method for preparing Octreotide microballoon, and this method simple process is suitble to technique to produce institute
With.However, the obtained product microballoon of this method is unevenly distributed, even matching while using is also easy to happen aggregation feelings very much
Condition seriously hinders the use of the drug clinically.
Therefore, it is highly desirable to research and develop a kind of preparation process that is easy, meeting production requirement, and the microballoon prepared
It is evenly distributed, easily with easy-to-use, offers convenience for clinical use.
Summary of the invention
The present invention overcomes the deficiencies in the prior art, provide that prepare octreotide acetate using phase detachment technique micro-
The octreotide acetate microsphere particle size of the completely new method of ball, this method preparation is evenly distributed, and is quickly evenly distributed when preparing, no
Assemble.
On the one hand, the present invention provides a kind of methods for preparing octreotide acetate microballoon, comprising the following steps:
(1) octreotide acetate is dissolved in methanol, forms solution A；
(2) PLGA is dissolved in methylene chloride, forms solution B；
(3) solution A and solution B are mixed under stiring, forms uniform solution C；
(4) silicone oil is at the uniform velocity added in solution C under stiring, forms condensation product；
(5) obtained condensation product is added in solidify liquid, forms microballoon；
(6) microballoon that filtration step (5) is formed, cleaning, is added appropriate mannitol solution, is dried in vacuo, sieving.
Preferably, the mass ratio of the octreotide acetate in step (1) and methanol is 1:5-1:36；It is highly preferred that the ratio
For 1:20.It finds after study, the usage amount of methanol has a certain impact to experimental result, and need to carry out strict control: methanol is used
When measuring very few, solution C is easily caused milky turbidity occur, makes drug crystallization.
Preferably, the mass ratio of the PLGA in step (2) and methylene chloride is 1:25-1:50；It is highly preferred that the ratio is
1:34.5-1:50；Most preferably, which is 1:34.5-1:40.It finds after study, the usage amount of methylene chloride is to experiment
As a result it has a certain impact, strict control need to be carried out: when PLGA concentration increases, i.e., methylene chloride additional amount is reduced, releasing in vitro
It puts and slows down, and when increasing to a certain concentration, balling-up is significantly deteriorated, and will will form a large amount of deformed spheres in production process；And work as
PLGA concentration reduces, i.e., when methylene chloride additional amount is more, does not make significant difference to partial size and release, but easily cause solidification process
Middle sphere aggregation, and final products organic solvent removal difficulty increases.
Preferably, the mass ratio of the methanol in step (1) and the methylene chloride in step (2) is 1:11-1:86, more preferably
Ground, the ratio are 1:11-1:45；It is further preferred that the ratio is 1:11-1:36；Most preferably, which is 1:26.7.
It finds after study, the usage amount of methanol has a certain impact to experimental result, need to carry out strict control: when methanol usage amount subtracts
When few, microspherulite diameter shows a increasing trend, release in vitro decline；When methanol usage amount increases, microspherulite diameter is in decreasing trend, but
When ratio is reduced to a certain extent, partial size no longer occurs significantly to sexually revise, and burst release dramatically increases.
Preferably, the viscosity of the silicone oil in step (4) is 350-600cs (centistoke), more preferably 350cs.After study
It was found that silicon oil viscosity has a certain impact to experimental result, need to carry out strict control: it is average that silicon oil viscosity increase will lead to microballoon
Partial size is reduced；Meanwhile higher silicon oil viscosity input power churned mechanically for agglomeration phase requires to increase, and increases degerming
Filter difficulty.
Preferably, the mass/volume ratio of the methylene chloride in step (2) and the silicone oil in step (4) is 1g:1ml-1g:
2ml, more preferably 1g:1ml-1g:1.6ml, most preferably 1g:1.6ml.It finds after study, the ratio of methylene chloride and silicone oil
Example has a certain impact to experimental result, and need to carry out strict control: when the large percentage of methylene chloride and silicone oil, balling-up is significant
Decline, when ratio is reduced to 1g:1.6ml or so, balling-up and partial size tend towards stability.The ratio mistake of methylene chloride and silicone oil
It is big or too small will lead to slowing down for release in vitro.
Preferably, the addition time of silicone oil is 10min-40min, more preferably 10-20min in step (4).Silicone oil is added
Time is too short, that is, be added it is too fast, easily cause particle size uniformity part decline；But when silicone oil addition overlong time, it will lead to emulsion droplet
Aggregation forms bulky grain, the decline of the microspherulite diameter uniformity, and surface pore becomes larger.
Preferably, in step (4), system temperature is controlled at 8 DEG C -10 DEG C.Condensation temperature influences release behavior, temperature
When higher, release slows down, and when temperature is too low, burst effect is obvious.
Preferably, the solidify liquid in step (5) can be with are as follows: normal heptane, the mixture of water and Span80 or normal heptane, water,
The mixture of Span80 and silicone oil；It is highly preferred that the volume ratio of normal heptane and water is 70:30-95:5；It is further preferred that just
The volume ratio of the total volume and Span80 of heptane and water is 120:1-360:1, preferably 180:1；It is further preferred that normal heptane with
The volume ratio for the silicone oil being added in step (4) is 3.5:1-7:1.Different solidify liquid compositions have certain influence for release behavior,
Temperature when solidifying is influenced simultaneously.When the volume ratio of normal heptane and water is too low, solution is sticky in solidification process, and sphere is difficult to point
It dissipates；When the volume ratio of normal heptane and water is excessively high, it may appear that phenomenon of burst release.
Preferably, in step (5), system temperature is controlled at 0 DEG C -20 DEG C, more preferably 2 DEG C -10 DEG C.It is being higher than 20
DEG C when, it may occur that between sphere aggregation, caking phenomenon, be unfavorable for collect washing.
Preferably, the vacuum drying in step (6) uses temperature programming boulton process, and wherein the first stage is dried in vacuo
Temperature is 15-25 DEG C, preferably 20 DEG C；Second stage vacuum drying temperature is 35-50 DEG C, preferably 40-45 DEG C；Phase III
Vacuum drying temperature is 45-50 DEG C, preferably 50 DEG C.It is dried in vacuo program (time, temperature) by setting, it can be effectively by dichloro
Methane level is down to 0.1% or less.
On the other hand, the present invention provides a kind of octreotide acetate microballoons prepared according to the above method.
Another aspect, the present invention provides the octreotide acetate microballoon prepared according to the above method in preparation for treating limb
Hold loose disease and such as class cancer, somatotropin releasing factor adenoma, Glucagonoma, gastrinoma/zes, pancreas islet
Plain tumor, the stomach pancreas enteroendocrine tumour of vasoactive intestinal peptide tumor drug in application.
The invention has the advantages that and good effect:
1. method and step of the invention is simple, it is suitble to produce and use.
2. high with microspheres quality prepared by method of the invention, can matching while using, sphere is quickly evenly distributed, do not gather
Collection.
3. the suspending step needed is less, easy to operate when the microballoon prepared using method of the invention.
4., to formulator without particular/special requirement, it is not necessarily to Special Training when preparing the microballoon of method preparation of the invention, it can
Dramatically increase the convenience of terminal hospital, patient when using the drug.
Detailed description of the invention
Hereinafter, carrying out the embodiment that the present invention will be described in detail in conjunction with attached drawing, in which:
Fig. 1 shows SEM (electron-microscope scanning figure) figure of 1 thus obtained microsphere of embodiment；
Fig. 2 shows SEM figure of 1 thus obtained microsphere of embodiment under more high magnification；
Fig. 3 shows the SEM figure of 2 thus obtained microsphere of embodiment；
Fig. 4 shows SEM figure of 2 thus obtained microsphere of embodiment under more high magnification；
Fig. 5 shows the SEM figure of 3 thus obtained microsphere of embodiment；
Fig. 6 shows SEM figure of 3 thus obtained microsphere of embodiment under more high magnification；
Fig. 7 shows the schematic diagram of the suspension result of embodiment 5；
Fig. 8 shows the schematic diagram of the result of 7 experimental group A group of embodiment；
Fig. 9 shows the schematic diagram of the result of 7 experimental group B group of embodiment；
Figure 10 shows the schematic diagram of the result of 7 experimental group C group of embodiment；
Figure 11 shows the schematic diagram of the result of 7 experimental group D group of embodiment；
Specific embodiment
The present invention is further described in detail With reference to embodiment, and the embodiment provided is only for explaining
The bright present invention, the range being not intended to be limiting of the invention.
Embodiment 1
The octreotide acetate for weighing 0.75g is dissolved in 15g methanol；The PLGA of 10g is taken to be dissolved in 400g methylene chloride；It will be with
Upper two parts of solution is stirred, rated speed 120rpm, forms uniform solution；640ml silicone oil (viscosity 350cs) is taken, in 13min
It is inside at the uniform velocity added and finishes, continue to stir 5min, 8-10 DEG C of temperature control, form condensation product；It is added by normal heptane (3200ml), water
The solidify liquid of (400ml), Span80 (20ml), silicone oil (100ml) composition, are solidified, and 2h is solidified；Microballoon is formed after solidification,
It is collected by filtration, is cleaned 3-4 times with normal heptane, appropriate mannitol solution is added, be dried in vacuo, be sieved up to product.SEM figure referring to
Fig. 1 and 2.
The accelerated release in vitro result of products obtained therefrom is as follows:
Table 1-1
Note: accumulative accelerated release in vitro degree of the result for accelerated release in vitro 1h, 4h and for 24 hours
The particle diameter distribution of products obtained therefrom is as follows:
Table 1-2
| Lot number | D10 | D50 | D90 | Span |
| W03-171107-3-1-1 | 35.79 | 50.87 | 72.39 | 0.719 |
Note: D10It is the physical parameter of particle diameter distribution, indicates that 10% particle is less than this grain diameter value, other and so on；
Span is used to characterize particle diameter distribution uniformity span=D90-D10/D50。
Embodiment 2
The octreotide acetate for weighing 0.75g is dissolved in 15g methanol；The PLGA of 10g is taken to be dissolved in 345g methylene chloride；It will be with
Upper two parts of solution is stirred, rated speed 120rpm, forms uniform solution；640ml silicone oil (viscosity 350cs) is taken, in 13min
It is inside at the uniform velocity added and finishes, continue to stir 5min, 8-10 DEG C of formation condensation product of temperature control；It is added by normal heptane (3200ml), water
The solidify liquid of (400ml), Span80 (20ml), silicone oil (100ml) composition, are solidified, and 2h is solidified；Microballoon is formed after solidification,
It is collected by filtration, is cleaned 3-4 times with normal heptane, appropriate mannitol solution is added, be dried in vacuo 20 hours, be sieved up to product.SEM
Figure ginseng is seen figures 3 and 4.
The accelerated release in vitro result of products obtained therefrom is as follows:
Table 2-1
| Drugloading rate | 1h | 4h | 24h | |
| W03-171031-1-1-1 | 4.60% | 2.06% | 32.27% | 56.65% |
The particle diameter distribution of products obtained therefrom is as follows:
Table 2-2
| Lot number | D10 | D50 | D90 | Span |
| W03-171031-1-1-1 | 36.225 | 49.63 | 67.89 | 0.638 |
Embodiment 3
The octreotide acetate for weighing 0.75g is dissolved in 15g methanol；The PLGA of 10g is taken to be dissolved in 400g methylene chloride；It will be with
Upper two parts of solution is stirred, rated speed 120rpm, forms uniform solution；640ml silicone oil (viscosity 600cs) is taken, in 13min
It is inside at the uniform velocity added and finishes, continue to stir 5min, 8-10 DEG C of temperature control, form condensation product；It is added by normal heptane (3200ml), water
The solidify liquid of (400ml), Span80 (20ml), silicone oil (100ml) composition, are solidified, and 2h is solidified；Microballoon is formed after solidification,
It is collected by filtration, is cleaned 3-4 times with normal heptane, appropriate mannitol solution is added, be dried in vacuo 20 hours, be sieved up to product.SEM
Figure is referring to Figures 5 and 6.
The accelerated release in vitro result of products obtained therefrom is as follows:
Table 3-1
| Drugloading rate | 1 | 4 | 24 | |
| W03-171113-2-0-1 | 4.72% | 2.51% | 28.55% | 54.97% |
The particle diameter distribution of products obtained therefrom is as follows:
Table 3-2
| Lot number | D10 | D50 | D90 | Span |
| W03-171113-2-0-1 | 36.9 | 51.55 | 71.49 | 0.67 |
Embodiment 4It is dried in vacuo the influence to dissolvent residual
Microballoon intermediate is prepared using the preparation process of above-described embodiment 1, and carries out the vacuum drying under different condition, with
Improve dissolvent residual；
One: 20 DEG C of condition is for 24 hours → 40 DEG C for 24 hours → 45 DEG C for 24 hours；
Two: 20 DEG C of condition is for 24 hours → 40 DEG C for 24 hours → 40 DEG C for 24 hours → 40 DEG C for 24 hours；
Three: 20 DEG C of condition is for 24 hours → 45 DEG C for 24 hours → 45 DEG C for 24 hours；
Four: 20 DEG C of condition is for 24 hours → 40 DEG C for 24 hours → 50 DEG C for 24 hours；
Experimental result:
Table 4 is in relation to substance and dissolvent residual result:
| Lot number | DCM is molten residual | Normal heptane is molten residual |
| W03-170817-1 (initial level) | 2.28% | 2.15% |
| Condition one | 0.30% | 2.37% |
| Condition two | 0.53% | 2.44% |
| Condition three | 0.19% | 2.14% |
| Condition four | 0.08% | 1.83% |
According to impurity and dissolvent residual bound requirements: DCM, which must not remain, is higher than 0.5%, and normal heptane residual must not exceed
2.5%.In view of ICH solvent classes, DCM belongs to two class solvents, has carcinogenicity, daily maximal oxygen taken amount was 60ppm, by 30 days
The sustained-release administration time, DCM concentration must not exceed 0.18%；And normal heptane belongs to three classes solvent, low poison solvent, daily limit exists
5000ppm。
As can be seen from Table 4, condition one, three, four can achieve Octreotide impurity and dissolvent residual bound requirements；
But condition three, four is safer to human body；When condition four, DCM dissolvent residual, normal heptane solvent residual are limited to minimum, safety
Property is best.
Embodiment 5With patent US5538739 preparation preparation comparative experiments:
(1) experimental products:
Patent US5538739 preparation is experimental group A group, prepares microspheres product using the preparation process of above-described embodiment 1, is
Test B group.
(2) experimental program:
Experiment A, B set product is taken out from 4 DEG C of cold storage environments, is placed in 5min under room temperature, is added that 2.5ml is identical to be helped
(suspending agent is mixed to form solution by sodium carboxymethylcellulose, mannitol and deionized water to suspension, and wherein mannitol concentration is
6mg/ml, sodium carboxymethylcellulose concentration are 5mg/ml) jog mixing (can not acutely shake) afterwards, observe suspension result.
(3) experimental result: aggregation situation occurs for experiment A group, and be suspended failure, can not be administered；Testing B group, quickly distribution is equal
It is even, it is suspended successfully.
As a result referring to Fig. 7.
Embodiment 6Influence of the PLGA/DCM amount ratio to experimental result
The octreotide acetate for weighing 0.75g is dissolved in 15g methanol；A certain amount of PLGA is taken to be dissolved in a certain amount of methylene chloride
In；Above two parts of solution is stirred, rated speed 120rpm, controlled at 10 DEG C, forms uniform solution；Take 640ml
Silicone oil (viscosity 350cs) is at the uniform velocity added in 13min and finishes, and continues to stir 5min, forms condensation product；It is added by normal heptane
The solidify liquid of (3200ml), water (400ml), Span80 (20ml), silicone oil (100ml) composition, is solidified, and 2h is solidified；Solidification
After form microballoon, be collected by filtration, cleaned 3-4 times with normal heptane, be added appropriate mannitol solution, be dried in vacuo 20 hours, sieving
Up to product.Different PLGA/ methylene chloride ratios are investigated, observation experiment phenomenon simultaneously studies release in vitro, as a result sees
Following table.
The influence of table 5-1 PLGA and methylene chloride control experiment result
Release in vitro Comparative result:
Table 5-2
For PLGA/DCM amount ratio in 1:34.5 or less, release, which is presented, slows down trend it can be seen from table 5-1,5-2,
Between 1:34.5-1:50, release behavior is more excellent；But as DCM dosage increases, it will increase the possibility that sphere is assembled in solidification process
Property, cause solidification to fail.Comprehensively consider, the amount ratio range of PLGA and DCM are 1:25-1:50, it is preferable that range 1:34.5
To 1:50；Most preferably, range is 1:34.5 to 1:40.
Embodiment 7The influence of methylene chloride and silicon oil dosage control experiment result
The octreotide acetate for weighing 0.75g is dissolved in 15g methanol；The PLGA of 10g is taken to be dissolved in 400g methylene chloride；It will be with
Upper two parts of solution is stirred, rated speed 120rpm, controlled at 10 DEG C, forms uniform solution；Take a certain amount of silicone oil
(viscosity 350cs) is at the uniform velocity added in 13min and finishes, and continues to stir 5min, forms condensation product；It is added by normal heptane
The solidify liquid of (3200ml), water (400ml), Span80 (20ml), silicone oil (100ml) composition, is solidified, and 2h is solidified；Solidification
After form microballoon, be collected by filtration, cleaned 3-4 times with normal heptane, be added appropriate mannitol solution, be dried in vacuo 20 hours, sieving
Up to product.Different methylene chloride/silicon oil dosage ratio is investigated, observation experiment phenomenon simultaneously studies release in vitro, as a result sees
Following table.
The influence of table 6-1 methylene chloride and silicone oil doses ratio to experimental result
Table 6-2
Conclusion: when silicone oil/methylene chloride ratio is low it can be seen from upper table data and scanning electron microscope (SEM) photograph (attached drawing 8-11)
When 1:1.6, release is in slow down trend；And when being lower than 1:1, balling-up is remarkably decreased, and drugloading rate reduces；When silicone oil/dichloromethane
When alkane ratio increases, release behavior is influenced without conspicuousness, but sphere is easily assembled in solidification process, and the later period is easily caused to clean sphere
Upper silicone oil is difficult.Comprehensively consider, when methylene chloride is 1:1-1:2 with silicone oil mass ratio, experiment can be smoothly completed；When it
When ratio is 1:1-1:1.6, experiment is preferable；When its ratio be 1:1.6 (B group), experimental result is best.
Embodiment 8Select influence of the different silicon oil viscosities to experimental result
The octreotide acetate for weighing 0.75g is dissolved in 15g methanol；The PLGA of 10g is taken to be dissolved in 400g methylene chloride；It will be with
Upper two parts of solution is stirred, rated speed 120rpm, controlled at 10 DEG C, forms uniform solution；640ml silicone oil is taken (to divide
Xuan Ze different viscosities), it is at the uniform velocity added and finishes in 13min, continue to stir 5min, form condensation product；It is added by normal heptane
The solidify liquid of (3200ml), water (400ml), Span80 (20ml), silicone oil (100ml) composition, is solidified, and 2h is solidified；Solidification
After form microballoon, be collected by filtration, cleaned 3-4 times with normal heptane, appropriate mannitol solution, vacuum drying hour is added, sieving is
Obtain product.Influence to different silicon oil viscosities to preparation is investigated, as a result observation experiment phenomenon see the table below.
Influence of the different silicon oil viscosity of table 7 to experimental result
| Experimental group | Different silicon oil viscosities | Experimental result or phenomenon description |
| A | 250cs | Can room temperature filtration sterilization, but solidify in sphere easily assemble |
| B | 350cs | Room temperature filtration sterilization |
| C | 600cs | Room temperature filtration sterilization is more difficult |
| D | 1000cs | It is difficult to room temperature filtration sterilization |
Conclusion: for aseptic injection, when production, need to consider aseptic filtration difficulty.It therefore, can from the experimental result of upper table
Find out, selects the silicone oil of 350cs-600cs viscosity, be conducive to subsequent filtration sterilization technique；When viscosity is 350cs, experiment
Effect is best.
Embodiment 9The different influences to experimental result of time are added in silicone oil
The preparation of microballoon is according to embodiment 1, the difference is that the addition time of silicone oil is different.When different silicone oil are added
Between investigated, study particle diameter distribution, as a result see the table below.
Influence of the time to experimental result is added in 8 silicone oil of table
| Experimental group | The time is added in silicone oil | Experimental result or phenomenon description |
| A | 30s | Not balling-up |
| B | 2.5min | D50About 55um, particle size distribution span increase |
| C | 10min | D50About 50um, particle diameter distribution are more uniform |
| D | 13min | D50About 50um, particle diameter distribution are uniform |
| E | 20min | D50About 50um, particle diameter distribution are uniform |
| F | 40min | D50About 50um, particle diameter distribution are uniform |
| G | 100min | D50About 80um, particle size distribution span increase |
Conclusion: when excessive velocities (30s) is added in silicone oil, DCM extraction rate is too fast, and then emulsion droplet is caused not yet to be formed,
PLGA has been precipitated, preparation not balling-up；Reduce when the time is added in silicone oil to 2.5min, average grain diameter changes without conspicuousness, partial size across
Degree increases；100min is extended to when the time is added in silicone oil, average grain diameter significantly increases, and particle size span is remarkably decreased；When silicone oil plus
When the angle of incidence is between 10-40min, balling-up is preferable, is formed by that agent particle is uniform, and particle size span value is smaller；It considers
Preparation process time, optimal selection 10min-20min.
Embodiment 10Influence of the agglomeration phase temperature to experimental result
The octreotide acetate for weighing 0.75g is dissolved in 15g methanol；The PLGA of 10g is taken to be dissolved in 400g methylene chloride；It will be with
Upper two parts of solution is stirred, rated speed 120rpm, controlled at 10 DEG C, forms uniform solution；640ml silicone oil
(350cs), interior be at the uniform velocity added finishes in 13min, continues to stir 5min, controls certain temperature, forms condensation product；It is added by just
The solidify liquid of heptane (3200ml), water (400ml), Span80 (20ml), silicone oil (100ml) composition, is solidified, and 2h is solidified；
Microballoon is formed after solidification, is collected by filtration, is cleaned 3-4 times with normal heptane, appropriate mannitol solution, vacuum drying is added, and sieving is
Obtain product.
Influence of the 9 agglomeration phase temperature of table to experimental result
| Experimental group | Temperature range (DEG C) | Experimental result or phenomenon description |
| A | 3-4 | Release is accelerated, and burst release dramatically increases |
| B | 8-10 | Rate of release is qualified |
| C | 14-15 | Release slows down |
| D | 25 | Release significantly slows down |
Conclusion: can be seen that from the experimental result in table 9, and experiment condensation product need to be under conditions of 8-10 DEG C, and product release is closed
Lattice.When temperature be higher or lower than 8-10 DEG C, can all influence product release.
Embodiment 11Influence of the variety classes solidify liquid to experimental result
Using operating in embodiment 1, condensation product is formed；It is added to different solidify liquids, 10 DEG C are solidified, and 2h is solidified；Gu
Microballoon is formed after change, is collected by filtration, is cleaned 3-4 times with normal heptane, and appropriate mannitol solution, vacuum drying 20 hours, mistake is added
It sieves up to product.
Influence of the different solidify liquids of table 10 to experimental result
Conclusion: selecting normal heptane and water ratio between 70:30-95:5, and balling-up is preferable, and there is no burst release rows
For.
Embodiment 12The influence of normal heptane and agglomeration phase silicone oil ratio to experimental result
According to embodiment 1, different amounts of silicone oil and normal heptane is respectively adopted in agglomeration phase and cure stage, investigates different
The influence of normal heptane and agglomeration phase silicone oil ratio for preparation.
The influence of table 11 different normal heptanes and agglomeration phase silicone oil ratio to experimental result
Conclusion: it finally can determine that sphere gathers by conspicuousness occurs when normal heptane and agglomeration phase silicone oil ratio are less than 3:1
Collection.
Embodiment 13Influence of the solidification temperature to experimental result
According to embodiment 1, investigating different solidification temperatures influences preparation.
Influence of the different solidification temperatures of table 12 to experimental result
Conclusion: solidification temperature does not make significant difference to release, but at 20 DEG C of higher temperature, it may occur that assembles between sphere, ties
Block phenomenon increases the difficulty for collecting washing in next step.
Although present invention has been a degree of descriptions, it will be apparent that, do not departing from the spirit and scope of the present invention
Under the conditions of, the appropriate variation of each condition can be carried out.It is appreciated that the present invention is not limited to the embodiments, and it is attributed to right
It is required that range comprising the equivalent replacement of each factor.
Claims (10)
1. a kind of method for preparing octreotide acetate microballoon, comprising the following steps:
(1) octreotide acetate is dissolved in methanol, forms solution A, it is preferable that the mass ratio of octreotide acetate and methanol is 1:5-
1:36；More preferably 1:20；
(2) PLGA is dissolved in methylene chloride, forms solution B, it is preferable that the mass ratio of PLGA and methylene chloride is 1:25-1:
50；More preferably 1:34.5-1:50；Most preferably 1:34.5-1:40；
(3) solution A and solution B are mixed under stiring, forms uniform solution C；
(4) silicone oil is at the uniform velocity added in solution C under stiring, forms condensation product, it is preferable that the viscosity of the silicone oil is 350-
600cs, more preferably 350cs；
(5) obtained condensation product is added in solidify liquid, forms microballoon；
(6) microballoon obtained in filtration step (5), cleaning, is added appropriate mannitol solution, is dried in vacuo, sieving.
2. according to the method described in claim 1, it is characterized in that the methanol in step (1) and the methylene chloride in step (2)
Mass ratio be 1:11-1:86, it is preferable that the ratio be 1:11-1:45；It is highly preferred that the ratio is 1:11-1:36；It is optimal
Selection of land, the ratio are 1:26.7.
3. method according to claim 1 or 2, it is characterised in that the silicon in methylene chloride and step (4) in step (2)
The mass/volume ratio of oil is 1g:1ml-1g:2ml, preferably 1g:1ml-1g:1.6ml, more preferably 1g:1.6ml.
4. method according to claim 1-3, it is characterised in that the addition time of silicone oil is in step (4)
10min-40min, preferably 10-20min.
5. method according to claim 1-4, it is characterised in that in step (4), system temperature is controlled 8
℃-10℃。
6. method according to claim 1-5, it is characterised in that the solidify liquid in step (5) is normal heptane, water
With the mixture or normal heptane of Span80, water, Span80 and silicone oil mixture；Preferably, the volume ratio of normal heptane and water is
70:30-95:5；It is further preferred that the volume ratio of the total volume and Span80 of normal heptane and water is 120:1-360:1, preferably
For 180:1；It is further preferred that the volume ratio for the silicone oil being added in normal heptane and step (4) is 3.5:1-7:1.
7. method according to claim 1-6, it is characterised in that in step (5), system temperature is controlled 0
DEG C -20 DEG C, more preferably 2 DEG C -10 DEG C.
8. method according to claim 1-7, it is characterised in that the vacuum drying in step (6) uses program liter
Warm boulton process, wherein first stage vacuum drying temperature is 15-25 DEG C, preferably 20 DEG C；Second stage vacuum drying temperature
Degree is 35-50 DEG C, preferably 40-45 DEG C；Phase III vacuum drying temperature is 45-50 DEG C, preferably 50 DEG C.
9. a kind of octreotide acetate microballoon of method preparation according to claim 1-8.
10. octreotide acetate microballoon according to claim 9 is in preparation for treating acromegalia and such as class cancer, life
Long releasing factor adenoma, Glucagonoma, gastrinoma/zes, insulinoma, vasoactive intestinal peptide tumor
Application in the drug of stomach pancreas enteroendocrine tumour.
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