CN104146962A - Magnetic-targeted isoniazid composite drug carrying microspheres and preparation method thereof - Google Patents

Magnetic-targeted isoniazid composite drug carrying microspheres and preparation method thereof Download PDF

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CN104146962A
CN104146962A CN201410358546.4A CN201410358546A CN104146962A CN 104146962 A CN104146962 A CN 104146962A CN 201410358546 A CN201410358546 A CN 201410358546A CN 104146962 A CN104146962 A CN 104146962A
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isoniazid
magnetic
preparation
composite drug
chitosan
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CN104146962B (en
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马振叶
张侠
秦红
王春梅
张亮
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Nanjing Normal University
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Nanjing Normal University
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Abstract

The invention discloses magnetic-targeted isoniazid composite drug carrying microspheres and a preparation method thereof. The composite drug carrying microspheres comprise the following components: 1-89% of magnetic Fe3O4, 1-80% of isoniazid and 10-19% of chitosan. The preparation method comprises the following steps: (1) preparing the magnetic Fe3O4, namely dissolving a Fe<3+>-containing compound and a Fe<2+>-containing compound in water, introducing inert gas, adding an alkali solution and stirring at a certain temperature to obtain the magnetic Fe3O4; and (2) preparing the composite drug carrying microspheres, namely adding the Fe3O4 and the isoniazid into an acid solution of the chitosan, dripping a sodium tripolyphosphate solution at a certain temperature, and carrying out magnetic separation and freeze drying to obtain the magnetic-targeted isoniazid composite drug carrying microspheres. The magnetic-targeted isoniazid composite drug carrying microspheres disclosed by the invention have the advantages of superparamagnetism, small particle size, dispersion uniformity, good biocompatibility and the like and can be used for magnetic-guided passive targeting therapy.

Description

A kind of magnetic targeting isoniazid composite drug carried microsphere and preparation method thereof
Technical field
The present invention relates to a kind of isoniazid medicine-carried system, particularly relate to a kind of magnetic targeting isoniazid composite drug carried microsphere and preparation method thereof, belong to medical technical field.
Background technology
Magnetic nano-particle has some special natures, as high-coercive force and superparamagnetism, therefore in biomedicine field, can be used as carrier bag medicine carrying thing, makes medicine have targeting, thereby improves the utilization rate of medicine and reduce toxic and side effects.Nanometer Fe 3o 4because particle diameter is little, good biocompatibility, highly sensitive, magnetic response is strong, toxicity is low, stable in properties, raw material are easy to get and extensively adopt.
Isoniazid (INH) is the phthisical first-line drug for the treatment of, is a kind of micromolecular water soluble drug.Isoniazid has high selectivity to tubercule bacillus, and antimicrbial power is strong.The antibacterial mechanism of isoniazid may be by suppressing the synthetic of mycobacteria acid, makes antibacterial lose acid resistance, hydrophobicity and proliferative ability and death.Because curative effect is good, toxicity is little, inexpensive, convenient oral, therefore be listed in first-selected antitubercular agent.But the tulase that some patients infect has produced drug resistance to isoniazid, therefore the targeted therapy of magnetic guiding can effectively solve drug resistance and the toxic and side effects of isoniazid; Under additional the action of a magnetic field, by the MagneticphamaceuticaMicrophere Microphere specific region of leading, and discharge medicine, thereby reach the object of targeting.Thereby a small amount of isoniazid can be assembled and make blood drug level reach desired minimum inhibitory concentration at targeting moiety, and in its hetero-organization, the concentration of isoniazid is little, has reduced its toxic and side effects.
Chitosan (CS) is the product obtaining by chitosan, chitosan, it is a kind of natural macromolecule amylose that extensively has, has amino and oh group at nature, have nontoxic, no antigen, biocompatibility, biodegradability be good, promote the advantages such as Cell uptake.The premium properties such as the biological functionality of this natural polymer and the compatibility, blood compatibility, safety, microbic resolvability are by extensive concern.Chitosan has good biocompatibility and degradability, under the effect of microbial activity enzyme, there is hydrolysis, thereby its macromolecular skeleton structure is ruptured, become little segment, and final fracture becomes stable micromolecule product, be degraded to the 2-Acetamido-2-deoxy-D-glucose nontoxic to human body by lysozyme in vivo, chitosan and catabolite thereof are nontoxic.Meanwhile, chitosan is because containing free amino, can binding hydrogen ions under acid condition, thus make chitosan become positively charged electrolyte, form cationic polymer.
At present, adopt chitosan crosslinked while carried magnetic particle and medicine to make the report of magnet composite drug-carrying microspheres little.Chinese patent CN201010610928.3 discloses a kind of method that adopts chemical coprecipitation to prepare chitosan magnetic micro-sphere, and preparation technology is simple, at preparation Fe 3o 4process in by Chitosan-coated at Fe 3o 4surface, thus chitosan magnetic micro-sphere formed.Chinese patent CN201210470282.2 discloses and has adopted emulsification and cross linked method to prepare a kind of method of thunder mycin/magnetic carboxymethyl chitosan nano drug-carrying microsphere, though the medicine carrying microballoons targeting of the method preparation is strong, slow-releasing good, particle diameter is little, but in preparation process, adopt a large amount of toxic reagents, may produce toxic and side effects.
Summary of the invention
The object of the invention is to make up the deficiencies in the prior art, a kind of magnetic targeting isoniazid composite drug carried microsphere is provided, its structure is a kind of nucleocapsid structure, with Fe 3o 4for core, chitosan and isoniazid are shell, are a kind of chitosan composite drug carried microspheres with superparamagnetism, can be used for the passive target treatment of magnetic guiding.
Another object of the present invention is also the preparation method of the magnetic targeting isoniazid composite drug carried microsphere that provides described, and the present invention adopts ionic gel legal system for Fe 3o 4compound year isoniazid microsphere of/CS/INH.Chitosan is because containing free amino, and under acid condition, energy ionizing, makes it positively charged, is cationic polymer, and sodium tripolyphosphate is anionic polymer, and chitosan can be sent out and answer with the sodium tripolyphosphate generation ionic gel of oppositely charged, NH 3 +and P 3o 10 5-by the electrostatic attraction of physics, chitosan is occurred crosslinked, avoided the toxic reagent in chemical crosslinking, can not produce toxic and side effects, and described preparation method has simply, mild condition, low cost and other advantages.
For achieving the above object, the present invention adopts following technical scheme: a kind of magnetic targeting isoniazid composite drug carried microsphere, it is characterized in that, and described composite drug carried microsphere is nucleocapsid structure, with Fe 3o 4for core, chitosan and isoniazid are shell, crosslinked Chitosan-coated Fe 3o 4, isoniazid is dispersed between crosslinked chitosan long-chain.The composition of described magnetic targeting isoniazid composite drug carried microsphere and content is by mass percentage: magnetic Fe 3o 4be 1% ~ 89%, isoniazid is 1% ~ 80%, and chitosan is 10% ~ 19%.
The particle diameter of described chitosan magnetic composite drug carried microsphere is 10nm ~ 150nm.
The preparation method that the invention still further relates to described magnetic targeting isoniazid composite drug carried microsphere, the technical scheme of employing is ionic gel method, i.e. a kind of preparation method of magnetic targeting isoniazid composite drug carried microsphere, concrete step is:
(1) magnetic Fe 3o 4preparation: will contain Fe 3+compound and contain Fe 2+compound soluble in water, logical noble gas, at a certain temperature, adds aqueous slkali, gets final product to obtain magnetic Fe 3o 4;
(2) preparation of composite drug carried microsphere: by Fe 3o 4add in the acid solution of chitosan with isoniazid, at a certain temperature, drip sodium tripolyphosphate solution, after magnetic separation, lyophilization, can obtain described magnetic targeting isoniazid composite drug carried microsphere.
In step (1), described in contain Fe 3+compound can be Fe 2(SO 4) 3, FeCl 3, Fe (NO 3) 3, NH 4fe (SO 4) 2deng in one or more; The described Fe that contains 2+compound can be FeCl 2, FeSO 4, Fe (NO 3) 2, (NH 4) 2fe (SO 4) 2deng in one or more; Preferably, described Fe 3+and Fe 2+mol ratio be 2:1 ~ 3:2; Described aqueous slkali can be preferably NaOH or NH 3h 2o; Described reaction temperature is 50 DEG C ~ 90 DEG C, response time 10min ~ 60min; Described noble gas is preferably nitrogen or argon.
In step (2), the acid solution of chitosan can be the one in the dilute acid solutions such as acetic acid, citric acid, hydrochloric acid, sulphuric acid, nitric acid; In described acid solution, the mass percent concentration of acid can be 0.5% ~ 2%; The concentration of chitosan can be 1 mg/mL ~ 6mg/mL; The concentration of described sodium tripolyphosphate solution is 1mg/mL ~ 10mg/mL.The mass ratio of described chitosan and sodium tripolyphosphate is 1:3 ~ 6:1; Described reaction temperature is 10 DEG C ~ 40 DEG C; Described response time 10min ~ 60min; Described lyophilization temperature is-50 DEG C ~-45 DEG C, and cooling time is 12h ~ 48h.
The present invention adopts ionic gel legal system for Fe 3o 4compound year isoniazid microsphere (referring to Fig. 1) of/CS/INH, crosslinked by the electrostatic attraction of physics, avoid the toxic reagent in chemical crosslinking, can not produce toxic and side effects.Specifically comprise following advantage:
(1) chemical coprecipitation method is prepared magnetic Fe 3o 4process is simple, preparation condition gentleness, Fe 3o 4good biocompatibility, toxicity is little, and cost is low.
(2) the composite drug carried microsphere particle diameter of preparing is little, good dispersion, and drug loading is high, and sustained release performance is good.
(3) chitosan there is biocompatibility and itself as carrier and catabolite all nontoxic, the slow-releasing that can improve medicine simultaneously chitosan drug-loading microsphere has again targeting.
(4) sodium tripolyphosphate using is nontoxic anion cross-linking agent and has biocompatibility.
(5) the present invention provides efficient, low toxicity, minimizing patient's the advantage such as drug resistance for isoniazid in pulmonary tuberculosis treatment.Described composite drug carried microsphere optionally arrives by intravenous injection approach and is positioned targeting district and discharges medicine under the guiding of externally-applied magnetic field.
Brief description of the drawings
Fig. 1 is that ionic gel legal system is for Fe 3o 4the schematic diagram of/CS/INH composite drug carried microsphere.
Fig. 2 is the Fe of preparation in embodiment 1 3o 4the transmission electron microscope picture of/CS/INH composite drug carried microsphere.
Fig. 3 is the Fe of preparation in embodiment 2 3o 4and Fe 3o 4the hysteresis graph of/CS/INH composite drug carried microsphere.
Fig. 4 is Fe in embodiment 3 3o 4, INH, CS and Fe 3o 4the infrared spectrogram of/CS/INH composite drug carried microsphere.
Detailed description of the invention
Describe the present invention below in conjunction with specific embodiment.
Embodiment 1
Accurately take Iron(III) chloride hexahydrate 2.97g, green vitriol 1.529g is dissolved in 50 mL deionized waters, and stirring and dissolving, adds in there-necked flask, and sealing is stirred, and passes into N 2, be heated to 80 DEG C and then slowly add 10 ml ammonia, continue to stir, after reaction 30min, cool to room temperature, uses washed with de-ionized water three times, and with ethanol cleaning three times, magnetic separates postlyophilization, obtains magnetic Fe 3o 4.Accurately weigh the Fe of 0.03g 3o 4join in the chitosan solution that concentration is 2mg/mL, add isoniazid 0.1g, stir, the sodium tripolyphosphate solution that dropping concentration is 1.5mg/mL, stirring reaction 10min, washes three times with deionized water, and magnetic separates postlyophilization, obtains Fe 3o 4/ CS/INH composite drug carried microsphere.Transmission electron microscope observing (referring to Fig. 2), TEM schemes as shown in Figure 2, and result shows Fe 3o 4the particle diameter of/CS/INH composite drug carried microsphere is 10nm-50nm.
Embodiment 2
Accurately take Fe(NO3)39H2O 4.444g, Iron dichloride tetrahydrate 1.095g is dissolved in 50mL deionized water, stirring and dissolving, add in there-necked flask, sealing, stirs, pass into argon, be heated to 80 DEG C and then slowly add 10 ml ammonia, continue to stir, after reaction 30min, cool to room temperature, uses washed with de-ionized water three times, with ethanol cleaning three times, magnetic separates postlyophilization, obtains magnetic Fe 3o 4.Accurately weigh the Fe of 0.03g 3o 4join in the chitosan solution that concentration is 4mg/mL, add isoniazid 0.1g, stir, the sodium tripolyphosphate solution that dropping concentration is 3mg/mL, stirring reaction 20min, washes three times with deionized water, and magnetic separates postlyophilization, obtains Fe 3o 4/ CS/INH composite drug carried microsphere.Under superconducting quantum magnetometer, survey Fe 3o 4and Fe 3o 4the magnetic size (referring to Fig. 3) of/CS/INH composite drug carried microsphere.As shown in Figure 3, result shows magnetic Fe to B-H loop 3o 4saturation magnetization be 76.462emu/g, Fe 3o 4the saturation magnetization of/CS/INH composite drug carried microsphere is 47.436 emu/g.
Embodiment 3
Accurately take NH 4fe (SO 4) 22.948g, (NH 4) 2fe (SO 4) 21.562 g are dissolved in 50mL deionized water, and stirring and dissolving adds in there-necked flask, sealing, stirs, and passes into argon, be heated to 90 DEG C of NaOH that then slowly add 10 ml, continue to stir, after reaction 60min, cool to room temperature, by washed with de-ionized water three times, with ethanol cleaning 3 times, magnetic separates postlyophilization, obtains magnetic Fe 3o 4.Accurately weigh the Fe of 0.03g 3o 4join in the chitosan solution that concentration is 6mg/mL, add isoniazid 0.1g, stir, the sodium tripolyphosphate solution that dropping concentration is 5mg/mL, stirring reaction 60min, washes three times with deionized water, and magnetic separates postlyophilization, obtains Fe 3o 4/ CS/INH composite drug carried microsphere.Fe 3o 4, INH, CS and Fe 3o 4the infrared spectrogram (referring to Fig. 4) of/CS/INH composite drug carried microsphere.Result shows Fe 3o 4in/CS/INH composite drug carried microsphere at 3425cm -1(OH), 1640cm -1(C=O), 1551cm -1and 1075cm (N-H) -1(C-O-C) spike number is compared all and is moved to lower wave number, Fe with CS, INH 3o 4in/CS/INH composite drug carried microsphere at 589cm -1and Fe (Fe-O) 3o 4compare wave number and move to high wave number, this shows Fe 3o 4, when crosslinked, there is interaction in CS and INH.

Claims (10)

1. a magnetic targeting isoniazid composite drug carried microsphere, is characterized in that, described composite drug carried microsphere is nucleocapsid structure, with Fe 3o 4for core, chitosan and isoniazid are shell, crosslinked Chitosan-coated Fe 3o 4, isoniazid is dispersed between crosslinked chitosan long-chain; Its composition and content are by mass percentage: magnetic Fe 3o 4be 1% ~ 89%, isoniazid is 1% ~ 80%, and chitosan is 10% ~ 19%.
2. magnetic targeting isoniazid composite drug carried microsphere according to claim 1, is characterized in that, the particle diameter of described magnetic targeting isoniazid composite drug carried microsphere is 10nm ~ 150nm.
3. the preparation method of magnetic targeting isoniazid composite drug carried microsphere claimed in claim 1, is characterized in that, described method comprises the following steps:
A. magnetic Fe 3o 4preparation: will contain Fe 3+compound and contain Fe 2+compound soluble in water, logical noble gas, at a certain temperature, adds aqueous slkali, gets final product to obtain magnetic Fe 3o 4;
B. the preparation of composite drug carried microsphere: by Fe 3o 4add in the acid solution of chitosan with isoniazid, at a certain temperature, drip sodium tripolyphosphate solution, after magnetic separation, lyophilization, can obtain described magnetic targeting isoniazid composite drug carried microsphere.
4. preparation method according to claim 3, is characterized in that, in steps A, described in contain Fe 3+compound be Fe 2(SO 4) 3, FeCl 3, Fe (NO 3) 3, NH 4fe (SO 4) 2in one or more; The described Fe that contains 2+compound be FeCl 2, FeSO 4, Fe (NO 3) 2, (NH 4) 2fe (SO 4) 2in one or more; Described Fe 3+and Fe 2+mol ratio be 2:1 ~ 3:2.
5. preparation method according to claim 3, is characterized in that, in steps A, described aqueous slkali is NaOH or NH 3h 2o.
6. preparation method according to claim 3, is characterized in that, in steps A, described reaction temperature is 50 DEG C ~ 90 DEG C, response time 10min ~ 60min.
7. preparation method according to claim 3, is characterized in that, in step B, described acid solution is acetic acid, citric acid, hydrochloric acid, sulphuric acid or nitre aqueous acid; In described acid solution, the mass percent concentration of acid is 0.5% ~ 2%.
8. preparation method according to claim 3, is characterized in that, in step B, the concentration of chitosan is 1 mg/mL ~ 6mg/mL; The concentration of described sodium tripolyphosphate solution is 1mg/mL ~ 10mg/mL; The mass ratio of described chitosan and sodium tripolyphosphate is 1:3 ~ 6:1.
9. preparation method according to claim 3, is characterized in that, in step B, described reaction temperature is 10 DEG C ~ 40 DEG C; The described response time is 10min ~ 60min.
10. preparation method according to claim 3, is characterized in that, in step B, described lyophilization temperature is-50 DEG C ~-45 DEG C, and cooling time is 12h ~ 48h.
CN201410358546.4A 2014-07-26 2014-07-26 A kind of magnetic targeted isoniazid composite drug carried microsphere and preparation method thereof Expired - Fee Related CN104146962B (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
CN104774831A (en) * 2015-04-23 2015-07-15 江南大学 Immobilization method of beta-galactosidase based on immobilized carrier
CN107334746A (en) * 2017-06-14 2017-11-10 南京师范大学 A kind of magnetic targeted nanometer INH/HBPE DDSA/Fe3O4The preparation method of composite drug carried microsphere

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
MUHAMMED RAFEEQ P E ETAL: "Development and characterization of chitosan nanoparticles loaded with isoniazid for the treatment of Tuberculosis", 《RESEARCH JOURNAL OF PHARMACEUTICAL, BIOLOGICAL AND CHEMICAL SCIENCES》 *
李凤生等: "磁响应纳米四氧化三铁/壳聚糖复合微球的制备及特性", 《磁性材料及器件》 *
谢玮玮: "磁性壳聚糖复合材料的制备及性能研究", 《中国优秀硕士学位论文全文数据库工程科技I辑》 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
CN104490791B (en) * 2014-12-31 2017-07-28 南京师范大学 A kind of magnetic hyper-branched polyester composite drug carried microsphere and preparation method thereof
CN104774831A (en) * 2015-04-23 2015-07-15 江南大学 Immobilization method of beta-galactosidase based on immobilized carrier
CN107334746A (en) * 2017-06-14 2017-11-10 南京师范大学 A kind of magnetic targeted nanometer INH/HBPE DDSA/Fe3O4The preparation method of composite drug carried microsphere

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