CN107334746A - A kind of magnetic targeted nanometer INH/HBPE DDSA/Fe3O4The preparation method of composite drug carried microsphere - Google Patents
A kind of magnetic targeted nanometer INH/HBPE DDSA/Fe3O4The preparation method of composite drug carried microsphere Download PDFInfo
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- CN107334746A CN107334746A CN201710446981.6A CN201710446981A CN107334746A CN 107334746 A CN107334746 A CN 107334746A CN 201710446981 A CN201710446981 A CN 201710446981A CN 107334746 A CN107334746 A CN 107334746A
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- hbpe
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- 239000004005 microsphere Substances 0.000 title claims abstract description 61
- 239000003814 drug Substances 0.000 title claims abstract description 55
- 239000002131 composite material Substances 0.000 title claims abstract description 46
- 229940079593 drug Drugs 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title claims abstract description 33
- WVRNUXJQQFPNMN-VAWYXSNFSA-N 3-[(e)-dodec-1-enyl]oxolane-2,5-dione Chemical compound CCCCCCCCCC\C=C\C1CC(=O)OC1=O WVRNUXJQQFPNMN-VAWYXSNFSA-N 0.000 title abstract description 9
- SZVJSHCCFOBDDC-UHFFFAOYSA-N ferrosoferric oxide Chemical compound O=[Fe]O[Fe]O[Fe]=O SZVJSHCCFOBDDC-UHFFFAOYSA-N 0.000 claims abstract description 53
- 238000000034 method Methods 0.000 claims abstract description 39
- 230000008569 process Effects 0.000 claims abstract description 17
- 238000006243 chemical reaction Methods 0.000 claims abstract description 14
- 239000002245 particle Substances 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 claims description 16
- 238000002604 ultrasonography Methods 0.000 claims description 14
- 238000001816 cooling Methods 0.000 claims description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 5
- 229910001868 water Inorganic materials 0.000 claims description 5
- 229910000359 iron(II) sulfate Inorganic materials 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- 229910019931 (NH4)2Fe(SO4)2 Inorganic materials 0.000 claims description 3
- 229910017626 NH4Fe(SO4)2 Inorganic materials 0.000 claims description 3
- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 claims description 3
- 229910000360 iron(III) sulfate Inorganic materials 0.000 claims description 3
- 229910021577 Iron(II) chloride Inorganic materials 0.000 claims description 2
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims description 2
- 239000006185 dispersion Substances 0.000 claims description 2
- NMCUIPGRVMDVDB-UHFFFAOYSA-L iron dichloride Chemical compound Cl[Fe]Cl NMCUIPGRVMDVDB-UHFFFAOYSA-L 0.000 claims description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 2
- VCJMYUPGQJHHFU-UHFFFAOYSA-N iron(III) nitrate Inorganic materials [Fe+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O VCJMYUPGQJHHFU-UHFFFAOYSA-N 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- 229910021642 ultra pure water Inorganic materials 0.000 claims description 2
- 239000012498 ultrapure water Substances 0.000 claims description 2
- 201000008827 tuberculosis Diseases 0.000 claims 1
- QRXWMOHMRWLFEY-UHFFFAOYSA-N isoniazide Chemical compound NNC(=O)C1=CC=NC=C1 QRXWMOHMRWLFEY-UHFFFAOYSA-N 0.000 abstract description 63
- 238000013268 sustained release Methods 0.000 abstract description 8
- 239000012730 sustained-release form Substances 0.000 abstract description 8
- 230000008901 benefit Effects 0.000 abstract description 7
- 230000008685 targeting Effects 0.000 abstract description 5
- 238000005516 engineering process Methods 0.000 abstract description 4
- 229920006150 hyperbranched polyester Polymers 0.000 abstract description 4
- 239000000463 material Substances 0.000 abstract description 4
- 230000005855 radiation Effects 0.000 abstract description 4
- 229940056319 ferrosoferric oxide Drugs 0.000 abstract 1
- 239000002114 nanocomposite Substances 0.000 abstract 1
- 230000003014 reinforcing effect Effects 0.000 abstract 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 25
- 230000000694 effects Effects 0.000 description 10
- 239000000243 solution Substances 0.000 description 9
- 238000004108 freeze drying Methods 0.000 description 6
- 229960003350 isoniazid Drugs 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000012620 biological material Substances 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 5
- 238000007306 functionalization reaction Methods 0.000 description 5
- 229920000728 polyester Polymers 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- -1 dodecenylsuccinic acid acid anhydride Chemical class 0.000 description 3
- 230000005415 magnetization Effects 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 206010067484 Adverse reaction Diseases 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 230000000845 anti-microbial effect Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000008367 deionised water Substances 0.000 description 2
- 229910021641 deionized water Inorganic materials 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- NQXWGWZJXJUMQB-UHFFFAOYSA-K iron trichloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].Cl[Fe+]Cl NQXWGWZJXJUMQB-UHFFFAOYSA-K 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000002539 nanocarrier Substances 0.000 description 2
- 239000002086 nanomaterial Substances 0.000 description 2
- 239000002105 nanoparticle Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 208000008128 pulmonary tuberculosis Diseases 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- 229920001661 Chitosan Polymers 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229910052688 Gadolinium Inorganic materials 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010057249 Phagocytosis Diseases 0.000 description 1
- 229920002146 Twinwall plastic Polymers 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- XGGLLRJQCZROSE-UHFFFAOYSA-K ammonium iron(iii) sulfate Chemical compound [NH4+].[Fe+3].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O XGGLLRJQCZROSE-UHFFFAOYSA-K 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- SURQXAFEQWPFPV-UHFFFAOYSA-L iron(2+) sulfate heptahydrate Chemical compound O.O.O.O.O.O.O.[Fe+2].[O-]S([O-])(=O)=O SURQXAFEQWPFPV-UHFFFAOYSA-L 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000012567 medical material Substances 0.000 description 1
- 210000000865 mononuclear phagocyte system Anatomy 0.000 description 1
- 239000002073 nanorod Substances 0.000 description 1
- 230000008782 phagocytosis Effects 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 229920000151 polyglycol Polymers 0.000 description 1
- 239000010695 polyglycol Substances 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- HBMUMVMGBLMQJT-UHFFFAOYSA-N pyrrolo[2,1-a]isoquinoline Chemical group C12=CC=CC=C2C=CN2C1=CC=C2 HBMUMVMGBLMQJT-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- 238000013517 stratification Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000005421 thermomagnetic effect Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
- A61K9/0009—Galenical forms characterised by the drug release technique; Application systems commanded by energy involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
- A61K9/5153—Polyesters, e.g. poly(lactide-co-glycolide)
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Nanotechnology (AREA)
- Physics & Mathematics (AREA)
- Optics & Photonics (AREA)
- Biomedical Technology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention relates to one kind to be used for tuberculotherapy medicine magnetic targeted nanometer isoniazid (INH)/functional hyperbranched polyester (HBPE DDSA)/ferroso-ferric oxide (INH/HBPE DDSA/Fe3O4) composite drug carried microsphere preparation method, belong to pharmaceutical technology field, be related to a kind of nano composite material.Described nanometer INH/HBPE DDSA/Fe3O4The preparation method of drug bearing microsphere is：Using the method for process intensification, vacuumizing with the conditions of Ultrasonic Radiation, preparing nanometer Fe3O4While add INH and HBPE DDSA, a step prepares nanometer INH/HBPE DDSA/Fe3O4Drug bearing microsphere.It is characterized in that using one-step method, and introduce vacuum and Ultrasonic Radiation reinforcing course of reaction.The advantage of the invention is that process is simple, controllable；The nanometer INH/HBPE DDSA/Fe of preparation3O4Drug bearing microsphere has the characteristics that particle diameter is small, is uniformly dispersed, drugloading rate is high；In addition, it has superparamagnetism, good biocompatibility and control sustained release performance, the drug targeting treatment of tuberculotherapy process can be applied to.
Description
Technical field
The present invention relates to a kind of preparation method for pulmonary tuberculosis treatment isoniazid composite drug carried microsphere, more particularly to
A kind of magnetic targeted nanometer INH/HBPE-DDSA/Fe3O4The preparation method of composite drug carried microsphere, belong to pharmaceutical pharmaceutical carrier technology
Field.
Background technology
Magnetic Nano material refers to the solid matter that there is the ultra micron of nanometer scale to form, and applies to biomedical sector
Magnetic Nano material be referred to as magnetic Nano biomaterial.Magnetic Nano biomaterial can be under additional magnetic fields by medicine
Orientation is delivered to lesion tissue, realizes purpose of the medicine in focal zone Targeting delivery.Magnetic Nano biomaterial has magnetic because of it
The advantages that targeting, control slow release, biocompatibility and thermo-magnetic effect, conveying medical medicine can be targetted by being widely used in manufacture
In magnetic composite microsphere, and as the emphasis direction of current medical material research.
HBPE is because having the advantages that functional group's intensive is high, viscosity is low and the good medical slow release that turns into of functional modification performance carries
Research and most widely used one kind in body material.The A of patent CN 103172869 disclose a kind of single point using HBPE as kernel
Sub- multiwall polymer.The circulation time of the polymer in blood is long, toxic side effect is small, biodegradable, and contains gadolinium simultaneously
And cis-platinum, realize diagnosis and treatment integration.It is the anti-of carrier that the A of patent CN 101474411, which disclose a kind of novel amphiphilic HBPE,
Tumour prodrug, and by adjusting the degree of polymerization and chemical composition, to adjust internal degradation speed, realize to the rate of release of medicine and
Regulating and controlling effect.Poly glycol monomethyl ether is connected to modified terminal hydroxy group HBPE surfaces and carried out by the A of Chinese patent CN 103169977
Functional modification so that nano-medicament carrier can flee from the phagocytosis of reticuloendothelial system, extend anticancer preparation in human body
Circulation time, improve the effect curative effect of medicine.
Isoniazid (INH) is one of most important antimicrobial during current tuberculotherapy, have antibacterial action power it is strong,
Selectivity height, half-life short, good effect, it is inexpensive the advantages that.Traditional INH application methods generally require it is long-term frequently enter medicine, this
Kind, which enters prescription formula, easily causes medicine to occur certain resistance to medicine to a series of toxic side effects caused by human body, and germ
Phenomena such as property.MagneticphamaceuticaMicrophere Microphere can be oriented to specific region by the targeted therapy of magnetic guiding by the effect of externally-applied magnetic field,
And orient and release the drug in this region, to reach purpose of the medicine in focal zone Targeting delivery, solve isoniazid and go out using process
The problem of existing adverse reaction.Develop with active targeting, long circulating action and can take in suitable material so INH is supported on
Nanometer magnetic composite microspheres with the excellent antimicrobial of the property of medicine (INH), it is significant in terms of tuberculotherapy.Patent CN
104146962 A disclose a kind of complex microsphere prepared using chitosan as carrier, and microballoon has superparamagnetism, particle diameter small and life
The advantages that thing compatibility, solves the adverse reaction that isoniazid uses process to a certain extent.
At present, use functionalization HBPE prepared for carrier INH magnet composite drug-carrying microspheres report it is seldom.Chinese patent CN
1044990791 A disclose a kind of magnetic Nano INH/HBPE-DDSA/Fe3O4The preparation method of composite drug carried microsphere, it is used
Two-step method first prepares magnetic Nano Fe3O4, then add carrier and medicine preparation nanometer INH/HBPE-DDSA/Fe3O4It is compound
Microballoon.In this process, nanometer Fe3O4The problem of twice dispersing be present, the HBPE and INH of functionalization can be caused in microballoon
The defects of disperseing low uneven problem, microballoon drugloading rate and control sustained release performance difference.Article (Zhao CL, Han QR, Qin H, et
al.Biocompatible hyperbranched polyester magnetic nanocarrier for stimuli-
Responsive drug release.Journal of Biomaterials Science, 2017, DOI:10.1080/
Nanometer INH/HBPE-DDSA/Fe prepared by two-step method of 09205063.2017.1289630) also having reported for work3O preparation, it controls slow
Releasing performance needs further to improve.
The content of the invention
Goal of the invention
For above-mentioned technical problem, it is an object of the invention to overcome the preparation technology of current isoniazid sustained-release micro-spheres to answer
Miscellaneous, microsphere component disperses the deficiencies of uneven, drugloading rate is low, control slow release effect difference, there is provided a kind of simple process intensification of technique
A step prepare the preparation method of isoniazid complex microsphere, pass through magnetic targeted isoniazid composite drug carried microsphere prepared by this method and have
There is the advantages that particle diameter distribution is narrow, component is uniformly dispersed, drugloading rate is high, and sustained release performance is good.
Technical scheme
In order to reach foregoing invention purpose, the method that the present invention uses process intensification, vacuumizing and Ultrasonic Radiation bar
Under part, nanometer Fe is being prepared3O4While add INH and HBPE-DDSA, a step prepares nanometer INH/HBPE-DDSA/Fe3O4Carry
Medicine microballoon, the technical solution adopted in the present invention are as follows：
A kind of magnetic targeted nanometer INH/HBPE-DDSA/Fe3O4The preparation method of composite drug carried microsphere, first in ultrasound and very
Under empty condition, by INH, INH/HBPE-DDSA, containing Fe3+Compound and contain Fe2+Compound mixing, then again in vacuum
React with aqueous slkali is added under ultrasound condition, separated after terminating, wash, produce the magnetic targeted nanometer INH/HBPE-DDSA/
Fe3O4Composite drug carried microsphere.
More specifically preparation method, comprise the following steps：
A, ultrasound and vacuum dispersion process：During INH is dissolved in ultra-pure water, HBPE-DDSA is dissolved in ethanol, and two kinds molten
Liquid mixes, and adds and contains Fe in right amount3+Compound and contain Fe2+Compound, ultrasound and vacuum state under be stirred
Uniformly；
B, the course of reaction under ultrasound and vacuum state：Certain temperature is heated to, alkali is added under vacuum and ultrasound condition
Solution, reaction a period of time, a nanometer INH/HBPE-DDSA/Fe is prepared3O4Drug bearing microsphere；
C, separation and washing process：Magneto separate after above-mentioned solution fully reacts, washing and ethanol are washed 3 times respectively, and freezing is dry
It is dry, you can to obtain described magnetic targeted nanometer INH/HBPE-DDSA/Fe3O4Composite drug carried microsphere.
Contain Fe described in step A3+Compound be Fe2(SO4)3、FeCl3、Fe(NO3)3、NH4Fe(SO4)2In one kind
It is or several；It is described to contain Fe2+Compound be FeCl2、FeSO4、Fe(NO3)2、(NH4)2Fe(SO4)2In one or more；
The Fe3+And Fe2+Mol ratio be 2:1~3:2.
The concentration of INH solution described in step A is 5mg/mL~50mg/mL；HBPE-DDSA concentration be 0.5mg/mL~
6mg/mL。
Ultrasonic frequency is 20~80kHz in step A, and ultrasonic time is 20~100min, vacuum is -0.01~-
0.1MPa。
Aqueous slkali described in step B is NaOH or NH3·H2O；Ultrasonic frequency is 20~80kHz, ultrasonic time is 20~
100min；Vacuum is -0.01~-0.1Mpa；Reaction temperature is 20 DEG C~100 DEG C, reaction time 20min~120min.
It is -50 DEG C~-10 DEG C that temperature is freeze-dried described in step C, and cooling time is 0.5h~6h.
The invention also discloses the magnetic targeted nanometer INH/HBPE-DDSA/Fe obtained by above-mentioned preparation method3O4Compound load
Medicine microballoon, magnetic targeted nanometer INH/HBPE-DDSA/Fe3O4The particle diameter of composite drug carried microsphere is 10nm~200nm.
Magnetic targeted nanometer INH/HBPE-DDSA/Fe obtained by the present invention3O4Composite drug carried microsphere can be used in treating lung
Tuberculosis.
Technique effect
Relative to prior art, the present invention has following technical advantage：
1st, magnetic targeted nanometer INH/HBPE-DDSA/Fe is prepared using the one-step method of process intensification3O4Complex microsphere, the present invention
Vacuum and ultrasonic radiation condition are introduced in preparation process, contributes to INH and Fe3O4It is dispersed in microballoon.Process is simple,
It is controllable, cost is low, can be widely applied to the preparation of sustained-release micro-spheres；
2nd, the magnetic targeted nanometer INH/HBPE-DDSA/Fe being prepared3O4Complex microsphere particle diameter is small, each component is dispersed
Good, drugloading rate height, magnetic property is preferable, control sustained release performance is excellent.
Brief description of the drawings
Fig. 1 is the Fe prepared in embodiment 13O4With S-1 samples INH/HBPE-DDSA/Fe3O4The XRD of composite nano-microsphere
Figure, wherein：(a) it is Fe3O4, (b) is INH/HBPE-DDSA/Fe3O4Composite nano-microsphere；
Fig. 2 is the INH/HBPE-DDSA/Fe of S-1 samples in embodiment 13O4Complex microsphere at various ph values external slow
Release lab diagram；
Fig. 3 is the INH/HBPE-DDSA/Fe prepared in embodiment 23O4The TEM figures of composite drug carried microsphere；
Fig. 4 is Fe3O4INH/HBPE-DDSA/Fe in nano-particle and embodiment 23O4The B-H loop of composite nano-microsphere
Figure, wherein：(a) it is Fe3O4, (b) is INH/HBPE-DDSA/Fe3O4Composite nano-microsphere.
Embodiment
The present invention is further described below with reference to specific embodiment.
Further to illustrate the present invention to reach the technological means and effect that predetermined goal of the invention is taken, to according to this
Technical scheme embodiment, feature and its effect proposed is invented, is described in detail as after.
HBPE in example below refers to hyper-branched polyester, and DDSA refers to dodecenylsuccinic acid acid anhydride.HBPE and HBPE-
DDSA is prepared according to documents below respectively
Document 1.Han QR, Jiang YL, Jin C, et al.Hyperbranched polyester nanorods
with pyrrolo[2,1-a]isoquinoline end group for fluorescent recognition of Fe3
+.Polymer Chemistry,2014；5(20):5900-5905
Document 2.Zhao CL, Han QR, Qin H, et al.Biocompatible hyperbranched
polyester magnetic nanocarrier for stimuli-responsive drug release.Journal of
Biomaterials Science, 2017, DOI:10.1080/09205063.2017.1289630
Embodiment 1
0.2gINH is dissolved in 15mL pure water, 0.05gHBPE-DDSA is dissolved in 15mL ethanol, two kinds of mixing are molten
Liquid pours into 250ml three-necked flasks, is stirred under ultrasound condition, accurately weighs the hydration chlorine of Iron(III) chloride hexahydrate 0.364g and four
Change ferrous 0.134g and add three-necked flask, sealing.After vacuumize process, vacuum is obtained -0.1MPa, 40min be stirred by ultrasonic,
Ultrasonic frequency is 80kHz.80 DEG C are then heated to, is slowly added to 15ml ammoniacal liquor, continues vacuum and ultrasonic wave bar more than
After reacting 1h under part, room temperature is cooled to, is washed with deionized water three times, ethanol cleans three times, is freeze-dried after Magneto separate, dries temperature
Spend for -50 DEG C, cooling time 1h, obtain INH/HBPE-DDSA/Fe3O4Composite nano-microsphere.Sample number into spectrum S-1.
Embodiment 2
0.1gINH is dissolved in 15mL pure water, 0.15gHBPE-DDSA is dissolved in 15mL ethanol, two kinds of mixing are molten
Liquid pours into 250ml three-necked flasks, accurately weighs Iron(III) chloride hexahydrate 0.297g and green vitriol 0.153g and adds three
Mouth flask, sealing.After vacuumize process, vacuum is obtained -0.08MPa, 40min is stirred by ultrasonic, ultrasonic frequency is
60kHz.60 DEG C are then heated to, is slowly added to 10ml ammoniacal liquor, continues to react 60min under above-mentioned vacuum and Ultrasonic Conditions
Afterwards, room temperature is cooled to, is washed with deionized water three times, ethanol cleans three times, is freeze-dried after Magneto separate, and drying temperature is -30 DEG C,
Cooling time is 3h, obtains INH/HBPE-DDSA/Fe3O4Composite nano-microsphere.
Embodiment 3
Using the same identical method of embodiment 1, the difference is that only as follows：
Contain Fe3+Compound be Fe2(SO4)3；Contain Fe2+Compound be FeSO4；The Fe3+And Fe2+Mole
Than for 2:1.
In mixed process：The concentration of the INH solution is 5mg/mL；HBPE-DDSA concentration is 0.5mg/mL.Ultrasonic wave
Frequency is 20kHz, and ultrasonic time 100min, vacuum is -0.01MPa.
In course of reaction：Ultrasonic frequency is 20kHz, ultrasonic time 100min；Vacuum is -0.01Mpa；Reaction temperature
Spend for 20 DEG C, reaction time 120min.
During freeze-drying：The freeze-drying temperature is -50 DEG C, cooling time 0.5h.
Embodiment 4
Using the same identical method of embodiment 2, the difference is that only as follows：
Contain Fe3+Compound be Fe (NO3)3；Contain Fe2+Compound be Fe (NO3)2；The Fe3+And Fe2+Rub
You are than being 3:2.
In mixed process：The concentration of the INH solution is 50mg/mL；HBPE-DDSA concentration is 6mg/mL.Ultrasonic wave
Frequency is 80kHz, and ultrasonic time 20min, vacuum is -0.1MPa.
In course of reaction：Ultrasonic frequency is 80kHz, ultrasonic time 20min；Vacuum is -0.1Mpa；Reaction temperature
For 100 DEG C, reaction time 20min.
During freeze-drying：The freeze-drying temperature is -10 DEG C, cooling time 6h.
Embodiment 5
Using the same identical method of embodiment 1, the difference is that only as follows：
Contain Fe3+Compound be NH4Fe(SO4)2；Contain Fe2+Compound be (NH4)2Fe(SO4)2In one kind or
It is several；The Fe3+And Fe2+Mol ratio be 1:1.
In mixed process：The concentration of the INH solution is 28mg/mL；HBPE-DDSA concentration is 3.2mg/mL.Ultrasound
Wave frequency rate is 50kHz, and ultrasonic time 60min, vacuum is -0.05MPa.
In course of reaction：Ultrasonic frequency is 50kHz, ultrasonic time 60min；Vacuum is -0.05Mpa；Reaction temperature
Spend for 60 DEG C, reaction time 70min.
During freeze-drying：The freeze-drying temperature is -30 DEG C, cooling time 3h.
Comparative example 1
Using the same identical method of embodiment 1, vacuumize and be not added with ultrasonic wave.Sample number into spectrum S-2.
Comparative example 2
Using the same identical method of embodiment 1, add ultrasonic wave without vacuumizing.Sample number into spectrum S-3.
Comparative example 3
Using the same identical method of embodiment 1, do not vacuumize and be not added with ultrasonic wave.Sample number into spectrum S-4.
Comparative example 4
It is made with the following method, wherein the dosage of each raw material is the same as embodiment 1：
1) magnetic Nano Fe3O4Preparation：Fe will be contained3+Compound and contain Fe2+Compound it is soluble in water, lead to it is lazy
Property gas, at a certain temperature, add aqueous slkali, stirring, you can magnetic Fe3O4；
2) preparation of the hyper-branched polyester of functionalization：Hyper-branched polyester HBPE (1.02g) is weighed to be dissolved in 60mL DMF,
Weigh dodecenylsuccinic acid acid anhydride (DDSA：5.59g) triethylamine with 1.0mL is dissolved in 60mL DMF, is flowed back at room temperature
After 20h, filtering, filtrate is removed, white sticky material is dissolved in ethanol, is precipitated 3 times with tetrahydrofuran, filtering, filtrate tetrahydrochysene
Furans is washed 3 times, vacuum drying, unwrought product bag filter (MWCO：500) purify, be then dried in vacuo, functionalization is made
Dissaving polymer HBPE-DDSA；
3) preparation of composite drug carried microsphere：The aqueous solution of isoniazid (INH) and the hyper-branched polyester of functionalization it is organic molten
Liquid mixes, and stirring, stratification, takes upper solution, magnetic Fe3O4Upper solution ultrasonic disperse is added, rotary evaporation, that is, is obtained
Magnetic hyper-branched polyester composite drug carried microsphere.
Gained sample number into spectrum S-5.
5 groups of INH/HBPE-DDSA/Fe are prepared for by method made above3O4Composite nano-microsphere, calculate not same
The drugloading rate of product and in pH=5.7 sample respectively in 1h, 2h and 5h preparation.Its comparative result such as table 1.From table 1
Data, which can be seen that, introduces ultrasonic wave and vacuum condition, can improve the drugloading rate of microballoon, weakens to dash forward and releases behavior, is favorably improved
The control sustained release performance of microballoon.Contrast preparations of the S-1 and S-5 in different time, it is known that the INH/ that one-step method is prepared
HBPE-DDSA/Fe3O4The control sustained release performance of composite nano-microsphere is greatly enhanced.It is main reason is that using a step
The INH/HBPE-DDSA/Fe that method is prepared3O4In composite nano-microsphere, the dispersiveness of medicine in the carrier is preferably.
The drugloading rate of the sample of table 1 and in pH=5.7 sample respectively in 1h, 2h and 5h preparation
Fig. 1 is the Fe prepared in embodiment 13O4With S-1 samples INH/HBPE-DDSA/Fe3O4The XRD of composite nano-microsphere
Figure, wherein：(a) it is Fe3O4, (b) is INH/HBPE-DDSA/Fe3O4Composite nano-microsphere；As a result showing can be into using one-step method
Prepare INH/HBPE-DDSA/Fe work(3O4Composite nano-microsphere.INH/HBPE-DDSA/Fe3O4Middle Fe3O4The intensity of characteristic peak
Relatively pure Fe3O4Relatively low, this is mainly by Fe3O4Surface demonstrates INH in compound particle caused by being modified from another angle
With HBPE-DDSA presence.
Fig. 2 is the INH/HBPE-DDSA/Fe of S-1 samples in embodiment 13O4Complex microsphere at various ph values external slow
Release lab diagram；
Fig. 3 is the INH/HBPE-DDSA/Fe prepared in embodiment 23O4The TEM figures of composite drug carried microsphere；As a result show
INH/HBPE-DDSA/Fe3O4The particle diameter of composite nano-microsphere is about 20nm.
Fig. 4 is Fe3O4INH/HBPE-DDSA/Fe in nano-particle and embodiment 23O4The B-H loop of composite nano-microsphere
Figure, wherein：(a) it is Fe3O4, (b) is INH/HBPE-DDSA/Fe3O4Composite nano-microsphere.As a result magnetic Fe is shown3O4Saturation
The intensity of magnetization is 69.85emu/g, INH/HBPE-DDSA/Fe3O4The saturation magnetization of composite nano-microsphere is 45.06emu/
g。INH/HBPE-DDSA/Fe3O4Enough saturation magnetizations are maintained, are laid the first stone for follow-up magnetic targeted application.
Technical scheme is described in detail above-described embodiment, it should be understood that described above
Specific embodiment only of the invention, is not intended to limit the invention, it is all done in the spirit of the present invention any repair
Change or improve, should be included within the scope of the invention.
Claims (10)
- A kind of 1. magnetic targeted nanometer INH/HBPE-DDSA/Fe3O4The preparation method of composite drug carried microsphere, it is characterised in that first Under ultrasound and vacuum condition, by INH, INH/HBPE-DDSA, containing Fe3+Compound and contain Fe2+Compound mixing, so Add aqueous slkali reaction under vacuum and ultrasound condition again afterwards, separated after terminating, wash, produce the magnetic targeted nanometer INH/ HBPE-DDSA/Fe3O4Composite drug carried microsphere.
- 2. magnetic targeted nanometer INH/HBPE-DDSA/Fe according to claim 13O4The preparation method of composite drug carried microsphere, It is characterised in that it includes following steps：A, ultrasound and vacuum dispersion process：During INH is dissolved in ultra-pure water, HBPE-DDSA is dissolved in ethanol, and two kinds of solution mix Close, add and contain Fe in right amount3+Compound and contain Fe2+Compound, ultrasound and vacuum state under be stirred It is even；B, the course of reaction under ultrasound and vacuum state：Certain temperature is heated to, aqueous slkali is added under vacuum and ultrasound condition, Reaction a period of time, a nanometer INH/HBPE-DDSA/Fe is prepared3O4Drug bearing microsphere；C, separation and washing process：Magneto separate after above-mentioned solution fully reacts, washing and ethanol are washed 3 times respectively, are freeze-dried, i.e., It can obtain described magnetic targeted nanometer INH/HBPE-DDSA/Fe3O4Composite drug carried microsphere.
- 3. magnetic targeted nanometer INH/HBPE-DDSA/Fe according to claim 23O4The preparation method of composite drug carried microsphere, Characterized in that, contain Fe described in step A3+Compound be Fe2(SO4)3、FeCl3、Fe(NO3)3、NH4Fe(SO4)2In It is one or more of；It is described to contain Fe2+Compound be FeCl2、FeSO4、Fe(NO3)2、(NH4)2Fe(SO4)2In one kind or several Kind；The Fe3+And Fe2+Mol ratio be 2:1~3:2.
- 4. magnetic targeted nanometer INH/HBPE-DDSA/Fe according to claim 23O4The preparation method of composite drug carried microsphere, Characterized in that, the concentration of INH solution described in step A is 5mg/mL~50mg/mL；HBPE-DDSA concentration is 0.5mg/mL ~6mg/mL.
- 5. magnetic targeted nanometer INH/HBPE-DDSA/Fe according to claim 23O4The preparation method of composite drug carried microsphere, Characterized in that, ultrasonic frequency is 20~80kHz in step A, ultrasonic time is 20~100min, vacuum is -0.01~- 0.1MPa。
- 6. magnetic targeted nanometer INH/HBPE-DDSA/Fe according to claim 23O4The preparation method of composite drug carried microsphere, Characterized in that, aqueous slkali described in step B is NaOH or NH3·H2O；Ultrasonic frequency is 20~80kHz, ultrasonic time 20 ~100min；Vacuum is -0.01~-0.1Mpa；Reaction temperature is 20 DEG C~100 DEG C, reaction time 20min~120min.
- 7. magnetic targeted nanometer INH/HBPE-DDSA/Fe according to claim 23O4The preparation method of composite drug carried microsphere, Characterized in that, it is -50 DEG C~-10 DEG C that temperature is freeze-dried described in step C, cooling time is 0.5h~6h.
- 8. the magnetic targeted nanometer INH/HBPE-DDSA/Fe obtained by any one of the claim 1-7 preparation methods3O4Compound load Medicine microballoon.
- 9. magnetic targeted nanometer INH/HBPE-DDSA/Fe according to claim 83O4Composite drug carried microsphere, it is characterised in that The magnetic targeted nanometer INH/HBPE-DDSA/Fe3O4The particle diameter of composite drug carried microsphere is 10nm~200nm.
- 10. the magnetic targeted nanometer INH/HBPE-DDSA/Fe obtained by any one of the claim 1-7 preparation methods3O4It is compound Drug bearing microsphere is preparing the application in treating tuberculosis drugs.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104146962A (en) * | 2014-07-26 | 2014-11-19 | 南京师范大学 | Magnetic-targeted isoniazid composite drug carrying microspheres and preparation method thereof |
| CN104490791A (en) * | 2014-12-31 | 2015-04-08 | 南京师范大学 | Magnetic hyperbranched polyester compound drug-carrying microsphere and preparation method thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104146962A (en) * | 2014-07-26 | 2014-11-19 | 南京师范大学 | Magnetic-targeted isoniazid composite drug carrying microspheres and preparation method thereof |
| CN104490791A (en) * | 2014-12-31 | 2015-04-08 | 南京师范大学 | Magnetic hyperbranched polyester compound drug-carrying microsphere and preparation method thereof |
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| Title |
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| CHILI ZHAO ET AL.: "A facile one-step method for preparation of Fe3O4/CS/INH nanoparticles as a targeted drug delivery for tuberculosis", 《MATERIALS SCIENCE AND ENGINEERING C》 * |
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