CN101579356A - Deproteinated calf blood ingredient brain targeting nanosphere and preparation method thereof - Google Patents
Deproteinated calf blood ingredient brain targeting nanosphere and preparation method thereof Download PDFInfo
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- CN101579356A CN101579356A CNA2009100624606A CN200910062460A CN101579356A CN 101579356 A CN101579356 A CN 101579356A CN A2009100624606 A CNA2009100624606 A CN A2009100624606A CN 200910062460 A CN200910062460 A CN 200910062460A CN 101579356 A CN101579356 A CN 101579356A
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Abstract
The invention discloses a deproteinated calf blood ingredient brain targeting nanosphere preparation method, specifically comprising: according to the parts by weight, dissolving 5-30 parts of stabilizing agent in distilled water, then dissolving 5-30 parts of pluronic F-68 in distilled water, mixing the two obtained solution, shaking well, adding 50-100 parts of deproteinated calf blood extractive injection, shaking well, after constant volume, adjusting the PH value to 1-4, slowly adding 5-30 parts of polybutylcyanoacrylate while stirring; stirring for 1-6h, adjusting PH value to 6-8, stirring for 1-6h to obtain the colloid solution of deproteinated calf blood ingredient nanosphere, filtering, freeze drying; dissolving the freezedrying powder of deproteinated calf blood ingredient nanosphere, adding 5-30 parts of tween 80 and stirring for 0.5-3h to obtain deproteinated calf blood ingredient brain targeting nanophere. The invention has the advantages of simple preparation method, low cost, easy storage, short time to reach the brain, rapid blood clearance rate and the like.
Description
Technical field
The present invention relates to medical technical field, be specifically related to treat the preparation method of a kind of nanometer formulation of brain dementia, apoplexy medicine calf blood protein-removed extraction.
Background technology
(Central nervous system, CNS) sickness rate has been higher than the summation of cancer and cardiovascular disease to the central nervous system, as the cerebral tumor, senile dementia, parkinson's syndrome, viral infection etc.Because the brain active center that is human central nervous also is the most complicated part of nervous system.(blood-brainbarrier BBB), causes the diagnosis of many cerebral diseases and treatment to have difficulties etc. but most of active medicine can not see through blood-brain barrier.Therefore, solve the key that has become the brain diseases Drug therapy by the drug delivery problem of BBB.Calf blood protein-removed extraction injection is used for the treatment of diseases such as apoplexy, and general one day/1 time intravenous injection is pretty troublesome, can improve its curative effect if make nanometer formulation.
Summary of the invention
Technical problem to be solved by this invention is: with PBCA (PBCA) is calf blood (protein removed) component carrier material, and a kind of nanometer formulation that can pass blood brain barrier is provided, to improve the curative effect of treatment cerebral disease.
The present invention solves its technical problem and adopts following technical scheme:
Deproteinated calf blood ingredient brain targeting nanosphere provided by the invention, by weight, its composition comprises: 5～30 parts of dextrans, 5～30 parts of pluronic F-68,50～100 parts of calf blood protein-removed extraction injections, 5～30 parts of PBCAs, 5～30 parts of Tween 80s.
Deproteinated calf blood ingredient brain targeting nanosphere provided by the invention, it prepares the method that adopts following steps:
Step 1: by weight, 5～30 parts of dextrans are dissolved in the distilled water, use 5～30 parts of pluronic F-68 of dissolved in distilled water simultaneously, both mix, and shake up, and add 50～100 parts of calf blood protein-removed extraction injections, shake up standardize solution;
Step 2: adjust pH to 1～4, the PBCA that under agitation slowly adds 5～30 parts by weight, stir after 1～6 hour, adjust pH to 6～8, continue to stir 0.5～4 hour, get calf blood (protein removed) component nanoparticle colloid solution, filter, lyophilization gets calf blood (protein removed) component nano-granule freeze-dried powder;
Step 3: with the dissolving of calf blood (protein removed) component nano-granule freeze-dried powder, add 5～30 parts of Tween 80s more by weight,, promptly get Deproteinated calf blood ingredient brain targeting nanosphere through stirring 0.5～3 hour.
The present invention compared with prior art has following major advantage:
1. can be used for resisting the development and use of brain diseases medicine.
2. have following advantage with the medicine that is used at present brain diseases on the market:
Easily store, the arrival brain time is short, the blood removing speed is fast.
3. preparation method is simple: do not need special installation, just can produce with conventional equipment and technology.Easy to implement.
4. test relatively: adopt intravenous injection animal (Cavia porcellus).Get its heart, liver, spleen, lung, kidney, brain, measure the distribution of Deproteinated calf blood ingredient brain targeting nanosphere in each tissue of institute's medicine of selling and the present invention's preparation on the market, draw Deproteinated calf blood ingredient brain targeting nanosphere than on the market the calf blood protein-removed extraction of selling many in the brain distribution.Thereby release Deproteinated calf blood ingredient brain targeting nanosphere and have brain targeting.
Description of drawings
Fig. 1 is a Deproteinated calf blood ingredient brain targeting nanosphere release in vitro curve.
Fig. 2 is Deproteinated calf blood ingredient brain targeting nanosphere and calf blood protein-removed extraction injection distribution in vivo.
The specific embodiment
The invention will be further described below in conjunction with embodiment and accompanying drawing, and content involved in the present invention is not limited only in these three examples.
By weight, its composition comprises: 5 parts of dextrans, 30 parts of pluronic F-68,75 parts of calf blood protein-removed extraction injections, 30 parts of PBCAs, 5 parts of Tween 80s.
Embodiment 2. Deproteinated calf blood ingredient brain targeting nanospheres
By weight, its composition comprises: 30 parts of dextrans, 5 parts of pluronic F-68,100 parts of calf blood protein-removed extraction injections, 5 parts of PBCAs, 30 parts of Tween 80s.
By weight, its composition comprises: 18 parts of dextrans, 18 parts of pluronic F-68,50 parts of calf blood protein-removed extraction injections, 18 parts of PBCAs, 18 parts of Tween 80s.
Embodiment 4.
By weight, 5 parts of stabilizing agent dextrans are dissolved in an amount of distilled water, use 5 parts of pluronic F-68 of an amount of dissolved in distilled water simultaneously, both mix, and shake up, and add 50 parts of calf blood protein-removed extraction injections, shake up standardize solution.Adjust pH to 1 is that 200 rotating speed lower magnetic forces stir in speed, slowly adds 5 parts PBCA.Stir after 1 hour, adjust pH to 6 continues to stir 1 hour, gets calf blood (protein removed) component nanoparticle colloid solution, filters lyophilization.After getting the dissolving of calf blood (protein removed) component nano-granule freeze-dried powder, add 5 parts of Tween 80s, stirred 0.1 hour, promptly get Deproteinated calf blood ingredient brain targeting nanosphere.
Embodiment 5.
By weight, 30 parts of stabilizing agent dextrans are dissolved in an amount of distilled water, use 30 parts of pluronic F-68 of an amount of dissolved in distilled water simultaneously, both mix, and shake up, and add 100 parts of calf blood protein-removed extraction injections, shake up standardize solution.Adjust pH to 4 is that 800 rotating speed lower magnetic forces stir in speed, slowly adds 30 parts PBCA.Stir after 6 hours, adjust pH to 8 continues to stir 4 hours, gets calf blood (protein removed) component nanoparticle colloid solution, filters lyophilization.After getting the dissolving of calf blood (protein removed) component nanoparticle lyophilizing part, add 30 parts of Tween 80s,, promptly get Deproteinated calf blood ingredient brain targeting nanosphere through stirring 3 hours.
Embodiment 6.
By weight, 10 parts of stabilizing agent dextrans are dissolved in an amount of distilled water, use 10 parts of pluronic F-68 of an amount of dissolved in distilled water simultaneously, both mix, and shake up, and add 75 parts of calf blood protein-removed extraction injections, shake up standardize solution.Adjust pH to 2 is that 600 rotating speed lower magnetic forces stir in speed, slowly adds 15 parts PBCA.Stir after 4 hours, adjust pH to 7 continues to stir 2 hours, gets calf blood (protein removed) component nanoparticle colloid solution, filters lyophilization.After getting the dissolving of calf blood (protein removed) component nanoparticle lyophilizing part, add 10 parts of Tween 80s,, promptly get Deproteinated calf blood ingredient brain targeting nanosphere through stirring 1 hour.
Embodiment 7.
By weight, 20 parts of stabilizing agent dextrans are dissolved in an amount of distilled water, use 20 parts of pluronic F-68 of an amount of dissolved in distilled water simultaneously, both mix, and shake up, and add 75 parts of calf blood protein-removed extraction injections, shake up standardize solution.Adjust pH to 3 is that 750 rotating speed lower magnetic forces stir in speed, slowly adds 20 parts PBCA.Stir after 4 hours, adjust pH to 7 continues to stir 2 hours, gets calf blood (protein removed) component nanoparticle colloid solution, filters lyophilization.After getting the dissolving of calf blood (protein removed) component nanoparticle lyophilizing part, add 20 parts of Tween 80s,, promptly get Deproteinated calf blood ingredient brain targeting nanosphere through stirring 2 hours.
Embodiment 8.
By weight, 10 parts of stabilizing agent dextrans are dissolved in an amount of distilled water, use 10 parts of pluronic F-68 of an amount of dissolved in distilled water simultaneously, both mix, and shake up, and add 62 parts of calf blood protein-removed extraction injections, shake up standardize solution.Adjust pH to 2 is that 600 rotating speed lower magnetic forces stir in speed, slowly adds 10 parts PBCA.Stir after 2 hours, adjust pH to 6.5 continues to stir 1 hour, gets calf blood (protein removed) component nanoparticle colloid solution, filters lyophilization.After getting the dissolving of calf blood (protein removed) component nanoparticle lyophilizing part, add 10 parts of Tween 80s,, promptly get Deproteinated calf blood ingredient brain targeting nanosphere through stirring 1 hour.
Embodiment 9.
By weight, 15 parts of stabilizing agent dextrans are dissolved in an amount of distilled water, use 15 parts of pluronic F-68 of an amount of dissolved in distilled water simultaneously, both mix, and shake up, and add 82 parts of calf blood protein-removed extraction injections, shake up standardize solution.Adjust pH to 1.5 is that 700 rotating speed lower magnetic forces stir in speed, slowly adds 15 parts PBCA.Stir after 3 hours, adjust pH to 7.4 continues to stir 3 hours, gets calf blood (protein removed) component nanoparticle colloid solution, filters lyophilization.After getting the dissolving of calf blood (protein removed) component nanoparticle lyophilizing part, add 15 parts of Tween 80s,, promptly get Deproteinated calf blood ingredient brain targeting nanosphere through stirring 1.5 hours.
Embodiment 10.
By weight, 25 parts of stabilizing agent dextrans are dissolved in an amount of distilled water, use 25 parts of pluronic F-68 of an amount of dissolved in distilled water simultaneously, both mix, and shake up, and add 92 parts of calf blood protein-removed extraction injections, shake up standardize solution.Adjust pH to 2.5 is that 720 rotating speed lower magnetic forces stir in speed, slowly adds 25 parts PBCA.Stir after 5 hours, adjust pH to 7.8 continues to stir 2.5 hours, gets calf blood (protein removed) component nanoparticle colloid solution, filters lyophilization.After getting the dissolving of calf blood (protein removed) component nanoparticle lyophilizing part, add 25 parts of Tween 80s,, promptly get Deproteinated calf blood ingredient brain targeting nanosphere through stirring 2.5 hours.
The colloid solution that the foregoing description 4-10 provides after testing, all can be used as the preparation method of Deproteinated calf blood ingredient brain targeting nanosphere, and wherein embodiment 6 effects are relatively good, and selects for use the particle diameter of macrodex less, and drug loading and envelop rate are all higher.Dextran among the above embodiment is meant dextran 20, Dextran 40 or macrodex.
The colloid solution that the foregoing description 4-10 provides, can adopt following method to detect:
1. laser particle size analyzer is measured size and distribution:
It is an amount of to get above-mentioned calf blood (protein removed) component brain protein nano grain, adds the injection water and makes dispersion, accommodates grain of rice particle size determination instrument and measures particle diameter, and mean diameter is 73.56nm ± 2.38nm.
2. transmission electron microscope is observed the nanoparticle form down:
Calf blood (protein removed) component brain protein nano grain appearance is faint yellow gluey liquid, gets 1～2 solution and places on the copper mesh, with 1.5% phosphotungstic acid negative staining, room temperature is dried, and observes form under transmission electron microscope, and nanoparticle is circle or similar round, size is comparatively even, does not have obviously and assembles.
3. high effective liquid chromatography for measuring envelop rate and drug loading:
It is an amount of to get calf blood (protein removed) component brain protein nano grain, centrifugal in 4 ℃ of following 8000r/min, and behind the supernatant via hole diameter 0.22 μ m membrane filtration, sample introduction 20 μ l measure respectively.
Envelop rate, the drug loading of medicine calculate as follows:
EE＝(W
total-W
free)÷W
total×100％＝(A
0-A
1)÷A
0×100％
Wherein: the envelop rate of EE-medicine (Entrapment Efficiency);
W
TotalTotal dose in the-system; W
FreeNon-encapsulated free drug amount in the-medium;
A
0The peak area of total medicine in the-system; A
1-do not seal the peak area of medicine;
DL＝W
E÷W
total×100％
In the formula: DL is drug loading (Drug Loading), W
EBe the medication amount of wrapping up in the nanoparticle, W
TotalThe gross weight that feeds intake for nanoparticle.
Getting average envelop rate scope is 20～80%, and the drug loading scope is 25～90%.
4. the extracorporeal releasing test of Deproteinated calf blood ingredient brain targeting nanosphere:
It is an amount of to get Deproteinated calf blood ingredient brain targeting nanosphere, changes in the bag filter, and tighten two ends and be suspended in the tool plug conical flask that fills an amount of release medium, 37 ℃ of constant temperature water bath vibrations, timing sampling 2ml adds the equivalent medium simultaneously.Institute's sample thief is carried out high-efficient liquid phase analysis, calculating concentration, and calculate cumulative release mark Q, and record corresponding release curve, see Fig. 1 (A is a calf blood protein-removed extraction injection among the figure, and B is a Deproteinated calf blood ingredient brain targeting nanosphere).
The very fast release of the visible calf blood protein-removed extraction injection of result, and Deproteinated calf blood ingredient brain targeting nanosphere has prominent releasing the stage in earlier stage, then keeps milder release rhythm, integral body presents certain slow release effect.
5. stability test
Envelop rate and drug loading are measured in the placement under centrifugal, high temperature of the Deproteinated calf blood ingredient brain targeting nanosphere for preparing respectively, be the results are shown in Table 1.
6. animal experiment research:
In order further to verify the brain targeting of nanometer formulation, we have carried out zoopery, adopt high performance liquid chromatography (HPLC) to measure drug level in the Mus brain, animal is a healthy Mus in 6-8 age in week, measure in the different time administration, the result proves: see that (A is a calf blood protein-removed extraction injection to Fig. 2 among the figure, B is a calf Deproteinization ingredient brain targeting nanoparticle, 1 is the heart among the figure, 2 is lung, 3 is liver, 4 is spleen, 5 is kidney, 6 is brain), the prepared Deproteinated calf blood ingredient brain targeting nanosphere of the present invention in brain concentration far above commercially available calf blood protein-removed extraction injection.
Detection through said method, it is simple that the prepared Deproteinated calf blood ingredient brain targeting nanosphere of the present invention has preparation method, and production cost is low, easily stores, advantages such as the arrival brain time is short, the blood removing speed is fast, treatment has a clear superiority in for brain diseases.
Subordinate list
Table 1 Deproteinated calf blood ingredient brain targeting nanosphere stability test result
Claims (10)
1. Deproteinated calf blood ingredient brain targeting nanosphere, it is characterized in that by weight, its composition comprises: 5～30 parts of dextrans, 5～30 parts of pluronic F-68,50～100 parts of calf blood protein-removed extraction injections, 5～30 parts of PBCAs, 5～30 parts of Tween 80s.
2. the preparation method of a Deproteinated calf blood ingredient brain targeting nanosphere is characterized in that adopting the following steps method:
Step 1: by weight, 5～30 parts of dextrans are dissolved in the distilled water, use 5～30 parts of pluronic F-68 of dissolved in distilled water simultaneously, both mix, and shake up, and add 50～100 parts of calf blood protein-removed extraction injections, shake up standardize solution;
Step 2: adjust pH to 1～4, the PBCA that under agitation slowly adds 5～30 parts by weight, stir after 1～6 hour, adjust pH to 6～8, continue to stir 0.5～4 hour, get calf blood (protein removed) component nanoparticle colloid solution, filter, lyophilization gets calf blood (protein removed) component nano-granule freeze-dried powder;
Step 3: dissolving calf blood (protein removed) component nano-granule freeze-dried powder, add 5～30 parts of Tween 80s more by weight, stirred 0.1～3 hour, promptly get Deproteinated calf blood ingredient brain targeting nanosphere.
3. preparation method according to claim 2 is characterized in that adopting the following steps method:
Step 1: by weight, 5 parts of dextrans are dissolved in the distilled water, use 5 parts of pluronicF-68 of dissolved in distilled water simultaneously, both mix, and shake up, and add 50 parts of calf blood protein-removed extraction injections, shake up standardize solution;
Step 2: adjust pH to 1, the PBCA that under agitation slowly adds 5 parts by weight, stir after 1 hour, adjust pH to 6, continue to stir 0.5 hour, get calf blood (protein removed) component nanoparticle colloid solution, filter, lyophilization gets calf blood (protein removed) component nano-granule freeze-dried powder;
Step 3: dissolving calf blood (protein removed) component nano-granule freeze-dried powder, add 5 parts of Tween 80s more by weight, stirred 0.1 hour, promptly get Deproteinated calf blood ingredient brain targeting nanosphere.
4. preparation method according to claim 2 is characterized in that adopting the following steps method:
Step 1: by weight, 30 parts of dextrans are dissolved in the distilled water, use 30 parts of pluronicF-68 of dissolved in distilled water simultaneously, both mix, and shake up, and add 100 parts of calf blood protein-removed extraction injections, shake up standardize solution;
Step 2: adjust pH to 4, the PBCA that under agitation slowly adds 30 parts by weight, stir after 6 hours, adjust pH to 8, continue to stir 4 hours, get calf blood (protein removed) component nanoparticle colloid solution, filter, lyophilization gets calf blood (protein removed) component nano-granule freeze-dried powder;
Step 3: with the dissolving of calf blood (protein removed) component nano-granule freeze-dried powder, add 30 parts of Tween 80s more by weight, stirred 3 hours, promptly get Deproteinated calf blood ingredient brain targeting nanosphere.
5. preparation method according to claim 2 is characterized in that adopting the following steps method:
Step 1: by weight, 20 parts of dextrans are dissolved in the distilled water, use 20 parts of pluronicF-68 of dissolved in distilled water simultaneously, both mix, and shake up, and add 75 parts of calf blood protein-removed extraction injections, shake up standardize solution;
Step 2: adjust pH to 3, the PBCA that under agitation slowly adds 20 parts by weight, stir after 4 hours, adjust pH to 7, continue to stir 2 hours, get calf blood (protein removed) component nanoparticle colloid solution, filter, lyophilization gets calf blood (protein removed) component nano-granule freeze-dried powder;
Step 3: with the dissolving of calf blood (protein removed) component nano-granule freeze-dried powder, add 20 parts of Tween 80s more by weight, stirred 2 hours, promptly get Deproteinated calf blood ingredient brain targeting nanosphere.
6. preparation method according to claim 2 is characterized in that adopting the following steps method:
Step 1: by weight, 10 parts of dextrans are dissolved in the distilled water, use 10 parts of pluronicF-68 of dissolved in distilled water simultaneously, both mix, and shake up, and add 62 parts of calf blood protein-removed extraction injections, shake up standardize solution;
Step 2: adjust pH to 2, the PBCA that under agitation slowly adds 10 parts by weight, stir after 2 hours, adjust pH to 6.5, continue to stir 1 hour, get calf blood (protein removed) component nanoparticle colloid solution, filter, lyophilization gets calf blood (protein removed) component nano-granule freeze-dried powder;
Step 3: with the dissolving of calf blood (protein removed) component nano-granule freeze-dried powder, add 10 parts of Tween 80s more by weight, stirred 1 hour, promptly get Deproteinated calf blood ingredient brain targeting nanosphere.
7. preparation method according to claim 2 is characterized in that adopting the following steps method:
Step 1: by weight, 15 parts of dextrans are dissolved in the distilled water, use 15 parts of pluronicF-68 of dissolved in distilled water simultaneously, both mix, and shake up, and add 82 parts of calf blood protein-removed extraction injections, shake up standardize solution;
Step 2: adjust pH to 1.5, the PBCA that under agitation slowly adds 15 parts by weight, stir after 3 hours, adjust pH to 7.4, continue to stir 3 hours, get calf blood (protein removed) component nanoparticle colloid solution, filter, lyophilization gets calf blood (protein removed) component nano-granule freeze-dried powder;
Step 3: with the dissolving of calf blood (protein removed) component nano-granule freeze-dried powder, add 15 parts of Tween 80s more by weight, stirred 1.5 hours, promptly get Deproteinated calf blood ingredient brain targeting nanosphere.
8. preparation method according to claim 2 is characterized in that adopting the following steps method:
Step 1: by weight, 25 parts of dextrans are dissolved in the distilled water, use 25 parts of pluronicF-68 of dissolved in distilled water simultaneously, both mix, and shake up, and add 92 parts of calf blood protein-removed extraction injections, shake up standardize solution;
Step 2: adjust pH to 2.5, the PBCA that under agitation slowly adds 25 parts by weight, stir after 5 hours, adjust pH to 7.8, continue to stir 2.5 hours, get calf blood (protein removed) component nanoparticle colloid solution, filter, lyophilization gets calf blood (protein removed) component nano-granule freeze-dried powder;
Step 3: with the dissolving of calf blood (protein removed) component nano-granule freeze-dried powder, add 25 parts of Tween 80s more by weight, stirred 2.5 hours, promptly get Deproteinated calf blood ingredient brain targeting nanosphere.
9. according to the described preparation method of arbitrary claim in the claim 2 to 8, it is characterized in that: dextran is Dextran-20, Dextran 40 or macrodex.
10. according to the described preparation method of arbitrary claim in the claim 2 to 8, it is characterized in that: the described stirring of step 2 and step 3 is to be that 200～800 rev/mins of lower magnetic forces stir in speed.
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| WO2017143967A1 (en) * | 2016-02-24 | 2017-08-31 | 首都医科大学宣武医院 | Poly(butyl cyanoacrylate) nanoparticle with dual modifications, preparation method thereof and application of same |
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| WO2017143967A1 (en) * | 2016-02-24 | 2017-08-31 | 首都医科大学宣武医院 | Poly(butyl cyanoacrylate) nanoparticle with dual modifications, preparation method thereof and application of same |
| US11351125B2 (en) | 2016-02-24 | 2022-06-07 | Xuanwu Hospital Of Capital Medical University | Poly(n-butyl cyanoacrylate) nanoparticle with dual modifications, preparation method and use thereof |
| US11634257B2 (en) | 2017-10-09 | 2023-04-25 | Terumo Bct Biotechnologies, Llc | Lyophilization container and method of using same |
| US11604026B2 (en) | 2019-03-14 | 2023-03-14 | Terumo Bct Biotechnologies, Llc | Lyophilization loading tray assembly and system |
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| US11815311B2 (en) | 2019-03-14 | 2023-11-14 | Terumo Bct Biotechnologies, Llc | Lyophilization container fill fixture, system and method of use |
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Open date: 20091118 |