CN108440684A - A kind of NI-Cys-Alg self-assembled nanometers carrier and its preparation method and application - Google Patents
A kind of NI-Cys-Alg self-assembled nanometers carrier and its preparation method and application Download PDFInfo
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- CN108440684A CN108440684A CN201810242717.5A CN201810242717A CN108440684A CN 108440684 A CN108440684 A CN 108440684A CN 201810242717 A CN201810242717 A CN 201810242717A CN 108440684 A CN108440684 A CN 108440684A
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
- C08B37/0084—Guluromannuronans, e.g. alginic acid, i.e. D-mannuronic acid and D-guluronic acid units linked with alternating alpha- and beta-1,4-glycosidic bonds; Derivatives thereof, e.g. alginates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
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- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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- 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
- A61K9/5161—Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
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Abstract
The invention discloses a kind of NI Cys Alg self-assembled nanometer carriers and its preparation method and application, raw material includes 2 nitroimidazole cysteine alginates.The present invention using through the modified sodium alginate of L cysteines and 2 nitroimidazoles as carrier material, it is prepared with mucosa adhesion, resistance to enzymic degradation and with the nano-carrier of hypoxic sensitivity using the method for ultrasonic self assembly, it solves pharmaceutical carrier to have a single function, the problems such as medicine stability is poor, bioavailability is low, and drug cannot respond to different physiological environment in vivo and be discharged.
Description
Technical field
The invention belongs to nano-carrier technical fields, and in particular to a kind of NI-Cys-Alg self-assembled nanometers carrier and its system
Preparation Method and application.
Background technology
Nano medication delivery systme obtains extensive research and development in recent years.Nano-carrier size and big ratio
Surface area is conducive to reinforce the absorption of drug.The physicochemical properties of nano-carrier can be improved using different carrier materials,
Medicine-releasing performance, such as slow-release controlled-release and triggering release and biological behaviour, such as targeting, bioadhesion, cellular uptake.
Current various biological responding materials, which are used as nano carrier material, can assign carrier a variety of sensibility, such as pH responses,
Temperature sensitivity, oxidation-reduction quality, concentration of glucose response and hypoxic sensitivity etc..Exploitation has intelligent response material
Nano-carrier is prepared, makes drug that can realize intelligent response physiological environment and precisely release the drug as current research trends.
Invention content
The purpose of the present invention is to provide a kind of NI-Cys-Alg self-assembled nanometers carriers.
Another object of the present invention is to provide the preparation methods of above-mentioned NI-Cys-Alg self-assembled nanometers carrier.
It is still another object of the present invention to provide the medicine-carrying methods of above-mentioned NI-Cys-Alg self-assembled nanometers carrier
Technical scheme is as follows：
A kind of NI-Cys-Alg self-assembled nanometers carrier, raw material include 2- nitroimidazoles-cysteine-alginate,
2- nitroimidazoles-cysteine-the alginate includes sodium alginate strand, L-cysteine and 2- nitro miaows
Azoles hexyl amine, above-mentioned L-cysteine graft on and form half Guang on the carboxyl through carbodiimide activation of sodium alginate strand
Propylhomoserin-sodium alginate strand, above-mentioned 2- nitroimidazoles hexyl amine graft on above-mentioned cysteine-sodium alginate strand,
The 2- nitroimidazoles hexyl amine is obtained by 2- nitroimidazoles through alkylation.
In a preferred embodiment of the invention, grain size is 100~300nm.
The preparation method of above-mentioned NI-Cys-Alg self-assembled nanometers carrier, includes the following steps：
(1) the 2- nitroimidazoles-cysteine-alginate is placed in methanol with distilled water with 1: 1~3 volume ratio
In the mixed solution of composition, stirring is protected from light until being completely dissolved, is then ultrasonically treated 2~5min；
(2) step (1) resulting material is placed in bag filter, dialyse under room temperature in distilled water 20~25h；
(3) step (2) resulting material in distilled water is sufficiently stirred 20~25h, is then precipitated by centrifugation, so
By after vacuum freeze drying to get the NI-Cys-Alg self-assembled nanometers carrier.
In a preferred embodiment of the invention, the power of the supersound process is 50~100W.
In a preferred embodiment of the invention, the mixed solution by methanol and distilled water with 1: 2 volume ratio
Composition.
In a preferred embodiment of the invention, the speed of the centrifugation in the step (3) be 8000~
10000rpm。
The medicine-carrying method of above-mentioned NI-Cys-Alg self-assembled nanometers carrier, includes the following steps：
(1) the 2- nitroimidazoles-cysteine-alginate is placed in methanol with distilled water with 1: 1~3 volume ratio
In the mixed solution of composition, the drug to be loaded is added, is protected from light stirring until be completely dissolved, then it is ultrasonically treated 2~
5min；
(2) step (1) resulting material is placed in bag filter, dialyse under room temperature in distilled water 20~25h；
(3) step (2) resulting material in distilled water is sufficiently stirred 20~25h, is then precipitated by centrifugation, so
By after vacuum freeze drying to get having loaded the NI-Cys-Alg self-assembled nanometer carriers of drug.
In a preferred embodiment of the invention, the power of the supersound process is 50~100W.
In a preferred embodiment of the invention, the mixed solution by methanol and distilled water with 1: 2 volume ratio
Composition.
In a preferred embodiment of the invention, the speed of the centrifugation in the step (3) be 8000~
10000rpm。
The beneficial effects of the invention are as follows：
1, the present invention, as carrier material, is utilized using through the modified sodium alginate of L-cysteine and 2- nitroimidazoles
The method of ultrasonic self assembly is prepared with mucosa adhesion, resistance to enzymic degradation and with the nano-carrier of hypoxic sensitivity, solution
Pharmaceutical carrier has a single function, and medicine stability is poor, bioavailability is low, drug cannot respond to different physiological environment in vivo and into
The problems such as row release.
2, preparation method of the present invention utilizes ultrasonic self-assembly method, simple for process, easy to operate.
3, the present invention can enhance adhesion of the drug on biological mucous membrane, extend its residence time at mucous membrane, be convenient for
Drug concentration gradient is formed in absorption-absorption site, drives drug release.
4, the present invention has resistance to enzymic degradation effect, and the drug in nano-carrier can be protected not by enzymatic degradation, solved
The problems such as drug oral administration bioavilability is low.
5, the present invention has different hydrophilic and hydrophobics in different oxygen concentration solution, and carrier is by hydrophobic under low-oxygen environment
Sex reversal is hydrophily, and carrier is swollen, and drug discharges rapidly, and under normal oxygen environment, show as slow release.The nano-carrier
It can the extensive use in the industries such as medicine, food.
Description of the drawings：
Fig. 1 is the transmission electron microscope picture of NI-Cys-Alg self assembly grains in case study on implementation 2 of the present invention；
Fig. 2 is NI-Cys-Alg self-assembled nanometer grain particle sizes and Zeta potential in case study on implementation 2 of the present invention；
Fig. 3 is the outer adhesion evaluation of NI-Cys-Alg self-assembled nanometers plastochondria in case study on implementation 2 of the present invention；
Fig. 4 is that NI-Cys-Alg self-assembled nanometer grain hypoxic sensitivities are evaluated in case study on implementation 3 of the present invention.
Specific implementation mode
Technical scheme of the present invention is further detailed and is described below by way of specific implementation mode combination attached drawing.
Embodiment 1 prepares 2- nitroimidazoles-cysteine-alginate
(1) 2- nitroimidazoles (NI), tertiary butyl (6- hexyl bromides) carbamate and potassium carbonate are dissolved in diformamide
(DMF), 75~82 DEG C of heating 0.8~1.2h of reaction, cooled to room temperature after the completion of reaction, gained reaction solution is through silica gel chromatograph
Column purification, purifying products therefrom is dissolved in hydrochloric acid/methanol solution, 10~13h of magnetic agitation, and rotary evaporation in vacuo removal is organic
Solvent, then washed through dichloromethane, obtain the 2- nitroimidazoles hexyl amine；2- nitroimidazoles and tertiary butyl (6- hexyl bromides) ammonia
The molar ratio of carbamate is 1~2: 1, and the molar ratio of tertiary butyl (6- hexyl bromides) carbamate and potassium carbonate is 0.8~1.2
: 0.8~1.2；Eluant, eluent used in silica gel chromatograph column purification is petrol ether/ethyl acetate, and wash-out concentration is 0~50% acetic acid second
Ester；
(2) 1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride (EDC is added in sodium alginate soln
HCl) and n-hydroxysuccinimide (NHS), stir evenly, it is 5.4~5.6 to adjust pH, is protected from light 40~50min of stirring, is added
L-cysteine hydrochloride (L-CysHCl) adjusts pH to 3.9~4.2, is protected from light 1.5~2.5h of stirring, then pH is adjusted to
6.0, continue 0.8~1.2h of stirring；Sodium alginate and the mass ratio of L-cysteine hydrochloride are 1: 0.5~2；1- ethyls-(3-
Dimethylaminopropyl) a concentration of 48~55mM of carbodiimide hydrochloride and n-hydroxysuccinimide in the reaction system；
(3) material obtained by step (2) is transferred in bag filter, the HCl for being placed in 0.8~1.2mMpH3.9~4.1 is molten
In liquid dialyse 20~25h, be subsequently placed in pH3.9~4.1 0.8~1.2mM and containing 0.8~1.2%NaCl HCl solution in thoroughly
20~25h is analysed, 20~25h of dialysis in the HCl solution of pH3.9~4.1 0.8~1.2mM is finally placed in；After the completion of dialysis, first will
Material in bag filter is placed in -20 DEG C of pre-freezes, then is placed in -80 DEG C of vacuum freeze dryings；
(4) the 2- nitroimidazole hexyl amines obtained by step (1) are dissolved in diformamide, it is molten obtains 2- nitroimidazole hexyl amines
Liquid；First that material obtained by step (3) is dissolved in that formamide and distilled water are formed with 0.8~1.2: 0.8~1.2 volume ratio
In mixed solution, fully it is swollen, is subsequently added into 1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride (EDCHCl)
With n-hydroxysuccinimide (NHS), 0.4~0.6h is stirred, above-mentioned 2- nitroimidazoles hexyl amine aqueous solution is then added, is protected from light and fills
Divide stirring 20~25h；1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride and n-hydroxysuccinimide are reacting
A concentration of 48~55mM in system；
(5) material obtained by step (4) is placed in the second mixing that methanol and distilled water are formed with 1: 1~3 volume ratio
In solution, dialyse 20~25h, is subsequently placed in distilled water, and dialyse 45~50h；After the completion of dialysis, first by the material in bag filter
- 20 DEG C of pre-freezes are placed in, then are placed in -80 DEG C of vacuum freeze dryings to get the 2- nitroimidazoles-cysteine-alginate material
Expect (NI-Cys-Alg polymer).
Embodiment 2
(1) use electronic balance weighing embodiment 1 prepared by NI-Cys-Alg polymer 20mg, be dissolved in 10mL methanol/
In distilled water (1/2, v/v), it is placed on magnetic stirring apparatus to be protected from light and stirs to polymer dissolving completely.
(2) material obtained by step (1) is placed in probe cell Ultrasonic Cell Disruptor, 2~5min of ultrasound, work(is carried out under ice bath
Rate is 50~100w.
(3) material obtained by step (2) is fitted into bag filter, is dialysed for 24 hours in distilled water under room temperature.
(4) solution after the completion of dialysing pours into magnetic agitation in 100mL distilled water and for 24 hours, is placed in centrifuge and centrifuges, and turns
Speed is 8000~10000rpm.
(5) supernatant is detached after centrifuging, collects precipitation, and grain size is 100~300nm to obtain the final product after vacuum freeze drying
NI-Cys-Alg self-assembled nanometer carriers.
(6) the NI-Cys-Alg self-assembled nanometer carrier 10mg through vacuum freeze drying obtained by step (5) are weighed, are dissolved in
In 10mL distilled water, fully dissolving is allowed to a concentration of 1mg/mL, takes 10-20 μ L solution to drop on copper mesh after ultrasonic disperse, in
Its pattern is observed under transmission electron microscope (transmission electron microscope picture of NI-Cys-Alg self assembly grains is as shown in Figure 1)；
(7) the NI-Cys-Alg self-assembled nanometers solution for measuring the 1mg/mL that 1mL steps (6) are prepared in Zeta potential and is received
Rice/submicron particle size analyzer measure its grain size and Zeta potential value (NI-Cys-Alg self-assembled nanometer grain particle sizes and
Zeta potential figure is as shown in Figure 2)；
(8) it takes commercially available pig stomach mucous membrane protein powder to be dissolved in PBS (pH6.8) solution, is configured to a concentration of 1% suspension,
It is stirred overnight, later the Probe Ultrasonic Searching 10min in ice-water bath, 15min is centrifuged with 5000rpm/min, takes supernatant to be diluted to dense
Degree is 0.5%, obtains submicron order mucoprotein suspension；
(8) the self assembly NI-Cys-Alg nanoparticles for taking different cysteine contents, are configured to a concentration of 0.5% solution
Its Zeta potential value is measured using mucoprotein particle method, evaluates its external adhesion (outside NI-Cys-Alg self-assembled nanometer plastochondrias
Adhesion evaluation figure is as shown in Figure 3).
Embodiment 3
(1) use electronic balance weighing embodiment 1 prepared by NI-Cys-Alg polymer 20mg, be dissolved in 10mL methanol/
In distilled water (1/2, v/v), certain density drug is added into the solution, is placed on magnetic stirring apparatus and is protected from light stirring to polymerization
Object dissolving is complete.
(2) step (1) resulting material is placed in probe cell Ultrasonic Cell Disruptor, 2~5min of ultrasound, power is carried out under ice bath
For 50~100w.
(3) material obtained by step (2) is fitted into bag filter, is dialysed for 24 hours in distilled water under room temperature.
(4) material obtained by step (3) is poured into 100mL distilled water magnetic agitation for 24 hours, be placed in centrifuge from
The heart, rotating speed 8000-10000rpm.
(5) it detaches supernatant after centrifuging, measures carrier encapsulation rate, collect precipitation, after vacuum freeze drying to obtain the final product
The grain size for carrying medicine is the NI-Cys-Alg self-assembled nanometer grains of 100~300nm.
(6) nanoparticle obtained by step (5) is taken to be configured to 1mg/mL solution, in equivalent difference concentration of glucose content (0mg/
DL, 100mg/mL, 400mg/mL) solution in, impregnate take after the different time (1h, 2h, 3h, 4h, 6h, 8h) 2mL solution in
UV detector measures its absorbance, sets absorbing wavelength as 330nm, according to the Assessment of Changes nanoparticle of its absorbance
Hypoxic sensitivity (NI-Cys-Alg self-assembled nanometer grain hypoxic sensitivities evaluation figure is as shown in Figure 4).
The foregoing is only a preferred embodiment of the present invention, therefore cannot limit the scope of implementation of the present invention according to this, i.e.,
According to equivalent changes and modifications made by the scope of the claims of the present invention and description, all should still belong in the range of the present invention covers.
Claims (10)
1. a kind of NI-Cys-Alg self-assembled nanometers carrier, it is characterised in that：Its raw material includes 2- nitroimidazoles-cysteine-
Alginate,
2- nitroimidazoles-cysteine-the alginate include sodium alginate strand, L-cysteine and 2- nitroimidazoles oneself
Base amine, above-mentioned L-cysteine graft on and form half Guang ammonia on the carboxyl through carbodiimide activation of sodium alginate strand
Acid-sodium alginate strand, above-mentioned 2- nitroimidazoles hexyl amine graft on above-mentioned cysteine-sodium alginate strand, should
2- nitroimidazoles hexyl amine is obtained by 2- nitroimidazoles through alkylation.
2. a kind of NI-Cys-Alg self-assembled nanometers carrier as described in claim 1, it is characterised in that：Its grain size be 100~
300nm。
3. the preparation method of NI-Cys-Alg self-assembled nanometers carrier as claimed in claim 1 or 2, it is characterised in that：Including such as
Lower step：
(1) the 2- nitroimidazoles-cysteine-alginate methanol is placed in form with 1: 1~3 volume ratio with distilled water
Mixed solution in, be protected from light stirring until be completely dissolved, be then ultrasonically treated 2~5min；
(2) step (1) resulting material is placed in bag filter, dialyse under room temperature in distilled water 20~25h；
(3) step (2) resulting material in distilled water is sufficiently stirred 20~25h, is then precipitated by centrifugation, is then passed through
To get the NI-Cys-Alg self-assembled nanometers carrier after vacuum freeze drying.
4. preparation method as claimed in claim 3, it is characterised in that：The power of the supersound process is 50~100W.
5. preparation method as claimed in claim 3, it is characterised in that：The mixed solution is by methanol and distilled water with 1: 2
Volume ratio forms.
6. preparation method as claimed in claim 3, it is characterised in that：The speed of centrifugation in the step (3) be 8000~
10000rpm。
7. the medicine-carrying method of NI-Cys-Alg self-assembled nanometers carrier as claimed in claim 1 or 2, it is characterised in that：Including such as
Lower step：
(1) the 2- nitroimidazoles-cysteine-alginate methanol is placed in form with 1: 1~3 volume ratio with distilled water
Mixed solution in, add the drug to be loaded, be protected from light stirring until be completely dissolved, be then ultrasonically treated 2~5min；
(2) step (1) resulting material is placed in bag filter, dialyse under room temperature in distilled water 20~25h；
(3) step (2) resulting material in distilled water is sufficiently stirred 20~25h, is then precipitated by centrifugation, is then passed through
To get having loaded the NI-Cys-Alg self-assembled nanometer carriers of drug after vacuum freeze drying.
8. medicine-carrying method as claimed in claim 7, it is characterised in that：The power of the supersound process is 50~100W.
9. medicine-carrying method as claimed in claim 7, it is characterised in that：The mixed solution is by methanol and distilled water with 1: 2
Volume ratio forms.
10. medicine-carrying method as claimed in claim 7, it is characterised in that：The speed of centrifugation in the step (3) be 8000~
10000rpm。
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001060412A3 (en) * | 2000-02-15 | 2002-01-24 | Genzyme Corp | Modification of biopolymers for improved drug delivery |
| CN103830738A (en) * | 2014-03-20 | 2014-06-04 | 华侨大学 | Lysine-grafted alginate carrier and preparation method for same |
| CN103848925A (en) * | 2014-03-20 | 2014-06-11 | 华侨大学 | Lysine grafted alginate (ALG-g-Lys) material and synthesis method thereof |
| CN107530296A (en) * | 2015-04-21 | 2018-01-02 | 北卡罗来纳州立大学 | Use the glucose responding insulin delivery system of hypoxia sensitivity nano composite material |
-
2018
- 2018-03-22 CN CN201810242717.5A patent/CN108440684A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001060412A3 (en) * | 2000-02-15 | 2002-01-24 | Genzyme Corp | Modification of biopolymers for improved drug delivery |
| CN103830738A (en) * | 2014-03-20 | 2014-06-04 | 华侨大学 | Lysine-grafted alginate carrier and preparation method for same |
| CN103848925A (en) * | 2014-03-20 | 2014-06-11 | 华侨大学 | Lysine grafted alginate (ALG-g-Lys) material and synthesis method thereof |
| CN107530296A (en) * | 2015-04-21 | 2018-01-02 | 北卡罗来纳州立大学 | Use the glucose responding insulin delivery system of hypoxia sensitivity nano composite material |
Non-Patent Citations (3)
| Title |
|---|
| ANDREAS BERNKOP-SCHNÜRCH ET AL: "Improvement in the mucoadhesive properties of alginate by the covalent attachment of cysteine", 《JOURNAL OF CONTROLLED RELEASE》 * |
| TAHA MO ET AL: "Synthesis of zinc-crosslinked thiolated alginic acid beads and their in vitro evaluation as potential enteric delivery system with folic acid as model drug", 《PHARMAZIE》 * |
| THOMAS F.PALMBERGER ET AL: "In vivo evaluation of anionic thiolated polymers as oral delivery systems for efflux pump inhibition", 《INTERNATIONAL JOURNAL OF PHARMACEUTICS》 * |
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Application publication date: 20180824 |