CN102198098A - Temperature-sensitive core-shell vesicle controlled-release drug carrier, preparation method and application thereof - Google Patents
Temperature-sensitive core-shell vesicle controlled-release drug carrier, preparation method and application thereof Download PDFInfo
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Abstract
The invention provides a temperature-sensitive core-shell vesicle controlled-release drug carrier which consists of liposome at the inner core and temperature-sensitive polymer composite gel at the outer layer. The stability of vesicle can be improved by core-shell configuration, and both the liposome at the inner core and the temperature-sensitive biological polymer composite gel at the outer layer can be used as drug carriers for carrying drugs. As the temperature raises, the gel at the outer layer varies so as to shrink, the drugs covered by the gel at the outer layer can be quickly released by means of temperature control, and the content of the liposome at the inner core can be slowly released owing to the presence of the gel at the outer layer, therefore, the effect of multidimensional release is achieved. The drug release carrier provided by the invention has outstanding biocompatibility and quick temperature response, can be used not only in the field of cosmetics, but also as the carrier for an embedded drug, and is applied to implantation in open operation, injection in minimally invasive surgery and implantation by means of an endoscope.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, be specifically related to nucleocapsid structure type controlled release drug carrier, more specifically relate to the macromolecule modified preparation method in vesicle surface and as the application of pharmaceutical carrier.
Background technology
Surfactant has amphipathic molecular structure, be usually used in strengthening interfacial activity, reduce interfacial tension, or self assembly forms micelle, the liquid crystal of different shape, play crucial effect aspect rheological properties that determines the interface and the biphase material Transfer, in cosmetics, pharmaceuticals and various emulsifying dispersion technology, having important use to be worth.
The natural biological surfactant is that a class has surface-active native compound, it is except having the effect identical with general chemical surfactant, also with its safe, nontoxic, the good biodegradability and the compatibility, advantages such as good heat and chemical stability are extremely paid attention in fields such as biological medicine, environmental protection and petroleum industries.The hydrophilic group of biosurfactant can be monosaccharide, disaccharide, polysaccharide, carboxyl, amino or the peptide chain of ion or non-ionic form; Hydrophobic group then is made up of satisfied fatty acid, unsaturated fatty acid or hydroxyl fatty acid.Its kind is a lot, according to their chemical composition and microbe-derived phospholipid, glycolipid, lipopeptid and the lipoprotein etc. of being divided into.Wherein, phospholipid, glycolipid are the important compositions of vital tissues cell membrane skeleton, also are one of hot research in recent years.
When amphipathic phospholipid was scattered in water, the hydrophobic tail of molecule was tended to flock together, and avoids water, and hydrophilic head is exposed to water, formed the vesicle with bilayer structure, was called liposome.Since nineteen sixty-five Britain scientist Bangham finds liposome, because its similar biomembrane, when using as pharmaceutical carrier, the hydrophilic area at vesicle center can be sealed water soluble drug and can seal fat-soluble medicine in the interlayer of the hydrophobic group of vesicle, and can improve medicine stability and targeting, reduce drug toxicity, delay to discharge, therefore obtain extensive and deep research.But, liposome vesicle still exists document D.R.Khan, E.M.Rezler, J.L.-Fields and G.B.Fields:Chem.Biol.Drug Des.71 (2008), 3 and S.Sriwongsitanont and M.Ueno:Colloid Polym.Sci.282 (2004), the easy gathering of 753 reports, sedimentation, problems such as structural stability difference, and document S.K.E.Messerschmidt, A.Musyanovych, M.Altvater, P.Scheurich, K.Pfizenmaier, K.Landfester and R.E.Kontermann:J.Controlled Release 137 (2009), 69, document S.Sriwongsitanont and M.Ueno:Chem.Pharm.Bull.50 (9) (2002), easily being absorbed of 1238 and S.Sriwongsitanont and M.Ueno:Colloid Polym.Sci.282 (2004), 753 reports by reticuloendothelial system, the defective that the body-internal-circulation cycle is short etc., therefore, need further the liposome vesicle structure to be modified and processed.At present, though there is the people to increase its body-internal-circulation time and stability of structure, be not prepared into nucleocapsid structure, and effect is all not ideal enough by modification to liposome vesicle.
The present inventor is core with the liposome vesicle, rely on effects such as chemical bond, electrostatic force to make biomacromolecule and temperature sensitive macromolecule form " pluralgel shell " in the vesicle appearance, with stability that increases vesicle and the effect that reaches multiple release medicine, thereby finished the present invention.
Summary of the invention
An object of the present invention is to provide a kind of temperature sensitive type nucleocapsid structure controlled release drug carrier.
Temperature sensitive type nucleocapsid structure controlled release drug carrier provided by the invention is made of kernel vesicle and outer macromolecule pluralgel.
The vesicle that kernel adopts in the pharmaceutical carrier of the present invention is the liposome vesicle that biosurfactant constitutes, outer temperature-sensitive macromolecular gel for natural biological macromole formation.
The biosurfactant that constitutes the kernel liposome vesicle can be selected from phospholipid and glycolipid, preferred phospholipid.
Natural biological macromole in the pharmaceutical carrier skin of the present invention is the acidic polysaccharose Biodegradable material, for example, and hyaluronic acid (HA), chrondroitin, chitosan etc., preferred HA; Temperature sensitive macromolecule can adopt biocompatibility and temperature sensitive polymer, is preferably poly-N-isopropyl acrylamide (PNIPAM).
Link by chemical bond between kernel liposome vesicle in the pharmaceutical carrier of the present invention and polysaccharide Biodegradable material.
In a preferred implementation, the present invention selects hyaluronic acid (HA) Biodegradable material, hyaluronic acid (HA) and glycidyl methacrylate (GMA) are connected into HA-GMA, GMA intramolecularly on this chain contains carbon-carbon double bond, can carry out radical reaction, have very high reaction motility, can with kernel liposome vesicle generation radical reaction, and form outer macromolecule pluralgel.
In a preferred implementation, temperature sensitive macromolecule in the outer macromolecule pluralgel is poly-N-isopropyl acrylamide (PNIPAM), by N-N-isopropylacrylamide (NIPAM) at cross-linking agent N, there is following cross-linking reaction in N-methylene-bisacrylamide (MBA) and forms, and with acidic polysaccharose strand generation cross-linking reaction, the outside of liposome can be fixed and be wrapped in to formed network-like pluralgel structure.
Preparation of drug carriers method provided by the invention may further comprise the steps:
1) biosurfactant is dissolved in the organic solvent, the rotary container evaporating solvent is to doing under the vacuum, and the lipid film uniform deposition is on the bottle wall, and vacuum drying adds phosphate buffer solution aquation lipid film behind the 30-60 ℃ of ultrasonic preheating 10-30min of water-bath;
2) acidic polysaccharose is dissolved in the ultra-pure water, adds equal-volume triethylamine and tetrabutyl ammonium bromide, carry out lyophilization behind the reaction 10-20h, add water, dialyse 5-10 days, then with 1) the ultrasonic 10-60min that mixes of liposome solutions of acquisition;
3) 2) add cross-linking agent 1 weight portion and temperature sensitive high polymer monomer 15 weight portions in the gained dispersion liquid, drip catalyst solution down in nitrogen protection, 50-80 ℃ of reaction 2-5 hour.
Organic solvent used in the inventive method can be selected from anhydrous chloroform, dichloromethane and ethanol.
The preferred NIPAM of described temperature sensitive high polymer monomer, the preferred MBA of described cross-linking agent.
In the inventive method, step 1) can be dissolved in first kind of medicine and biosurfactant in the organic solvent simultaneously, obtains wrapping up the liposome of first kind of medicine.
The inventive method also can comprise step 4): with the product lyophilizing of step 3), immerse and dissolved in the aqueous solution of second kind of medicine, behind the 20-40 ℃ of maintenance 10-20min, leave standstill half a day, obtain sealing the carrier of second kind of medicine.
As required, pharmaceutical carrier of the present invention is first kind of medicine of parcel in liposome vesicle only, and non-encapsulated medicine separates by dextran microgel column to be removed; Pharmaceutical carrier of the present invention also can only be sealed second kind of medicine at the temperature sensitive macromolecule pluralgel of skin, this second kind of medicine is adsorbed by the outer field phase change of thermosensitive hydrogel and penetrates into gel layer inside, the absorption that reaches capacity after leaving standstill, non-encapsulated medicine separates by dextran microgel column; More preferably, first kind of medicine of parcel sealed second kind of medicine in the temperature sensitive macromolecule pluralgel of skin in liposome vesicle, second kind of medicine discharged earlier, and then discharge first kind of medicine.
In a preferred version, pharmaceutical carrier preparation method of the present invention may further comprise the steps:
1) thin-film ultrasonic aquation legal system is equipped with nanometer liposome
Biosurfactant or biosurfactant and hydrophobicity medicine are dissolved in organic solvent; Rotary evaporation is removed organic solvent in 30-60 ℃ the water bath with thermostatic control, continues to drain behind the lipidosis bottle wall.After removing vacuum, from drying baker, take out bottle, in bottle, fill with nitrogen, put into the ultrasonic preheating 10-30min of water-bath of 30-60 degree, in bottle, add buffer solution aquation lipid, last, separate non-encapsulated medicine by dextran microgel column.
2) synthetic HA-GMA complex
It is soluble in water to get HA (hyaluronic acid), and the concentration of sample is 1-4mg/mL, adds the triethylamine of equivalent, GMA (glycidyl methacrylate), and tetrabutyl ammonium bromide behind the reaction 10-20h, is hatched 2-5h down at 40-60 ℃.Reacted sample lyophilization 1-5 days is dispersed in the water, puts into bag filter dialysis 5-10 days.
3) coating of acidic polysaccharose
Getting 2) dialyzed sample HA-GMA adds in the entry and dilutes, and dropwise adds vesicle solution in HA-GMA, and ultrasonic 30-60min, and this moment, solution was called GHA-lip.
4) the synthetic HA-PNIPAM gel of shell
Add MBA (N among the GHA-lip; the N-methylene-bisacrylamide); NIPAM (N-N-isopropylacrylamide) wiring solution-forming; again the water-soluble back of APS (Ammonium persulfate .) is added in the normal pressure funnel in addition; evacuation leads to nitrogen protection; slowly be added drop-wise in the solution, dropwise, 50-80 ℃ was reacted 2-5 hour down.
5) the outer medicine carrying of core-shell particle
Hydrophilic medicament is represented uranine yellow: with 4) gained microgranule lyophilizing processing, the weighing uranine yellow is put in the phosphate buffer solution (pH7.4) that has dissolved liposome.Sample heats up (20-40 ℃) maintenance 10-20min postcooling to room temperature (25 ℃), uranine yellow is adsorbed by the outer field phase change of thermosensitive hydrogel and penetrates into gel layer inside, the absorption so that gel reaches capacity of leaving standstill half a day separates non-encapsulated medicine by dextran microgel column at last.
The present invention is core with the liposome vesicle, relies on the effect of chemical bond, electrostatic force etc., makes biomacromolecule form " gel shell " in the absorption of vesicle appearance, thereby a kind of temperature sensitive type nucleocapsid structure liposome controlled release drug carrier is provided.This core-shell configuration not only can increase the stability of vesicle, reaches high envelop rate, has the fast-response of thermosensitive hydrogel simultaneously.The present invention selects acidic polysaccharose with excellent biological compatibility and the N-N-isopropylacrylamide (NIPAM) with temperature sensitive property for use, prepare temperature sensitive property mixed gel, make the shell of gel not only keep the superiority of the good biocompatibility of acidic polysaccharose like this, the fast temperature response that also has poly-N-isopropyl acrylamide PNIPAM, and the mechanical strength of gel shell also is greatly improved.
The present invention modifies the thermo-responsive hydro gel layer in the liposome outside first, prepared nucleocapsid microgel with temperature-sensing property, the lipid bilayer somatocyst bubble and the outer field temperature sensitive property biopolymer gel of this microgranule kernel can be as the pharmaceutical carrier medicine carryings, rising along with temperature, outer field gel can undergoing phase transition and shrinkage, outer gel packaging medicine can come out by rapid release by homoiothermic, the container of internal layer liposome then can slowly discharge because of the existence of outer gel, thereby reaches the effect that multidimensional discharges.
Temperature sensitive type nucleocapsid structure liposome controlled release drug carrier of the present invention has excellent biological compatibility and fast temperature response, is the injectable type preparation in room temperature, and undergoing phase transition postprecipitation is attached to the surface of solids, can reach the directed purpose that discharges.Product of the present invention can be used for cosmetic field, also can be used as the carrier of heeling-in medicine, is applied to opening operation and implants, and Minimally Invasive Surgery is injected or implanted by endoscope.
Description of drawings
Fig. 1 is the shape appearance figure that the liposome particles of shell gelation arrives with atomic force microscope observation, and sweep limits is 5 * 5 μ m.
Fig. 2 is the liposome particles structure that arrives through microscopic examination of shell gelation.
Fig. 3, Fig. 4 are respectively that different molecular weight HA makes behind the core-shell structure particles particle diameter and permeability with variation of temperature.HA molecular weight: ■: 3604g mol
-1●: 1.1 * 10
4G mol
-1▲: 3.0 * 10
5G mol
-1 
8.0 * 10
5Gmol
-1
Fig. 5 and Fig. 6 are respectively that skin and internal layer drug release effect compare.Curve is 37 ℃ of following release conditions among the figure, and drug level detects on spectrofluorophotometer.
The specific embodiment
Below for a more detailed description with embodiment to the present invention.These embodiment only are the descriptions to best mode for carrying out the invention, scope of the present invention are not had any restriction.
Embodiment 1
1. get hyaluronic acid and be dissolved in the ultra-pure water, concentration is 2mg/mL, and the adding weight ratio is 1: 1: 1 a triethylamine, tetrabutyl ammonium bromide and GMA (glycidyl methacrylate) behind the room temperature reaction 10h, are hatched 2h down at 40 ℃, lyophilization is 2 days then, dialyses 5 days.
2. will add the 1mg rhodamine 6G in the phospholipid solution, solution moves in the round-bottomed flask, evaporating solvent, and vacuum drying 2-4h under the room temperature, preparation contains the immobilized artificial membrane of rhodamine 6G.After removing vacuum, put into the water-bath preheating 20min of 50 degree; Liposome with preparing the parcel rhodamine 6G after the buffer aquation makes it separate non-encapsulated part by dextran microgel column, can obtain to have wrapped up the liposome of rhodamine 6G.
3. the reactant liquor with step 1 gained adds the ultra-pure water dilution, dropwise adds the solution of step 2 gained liposome, ultrasonic 30min.
4. the reactant liquor with step 3 gained adds 1 weight portion MBA (N; the N-methylene-bisacrylamide); 10 parts of NIPAM (N-N-isopropylacrylamide); again with 1 weight portion APS (Ammonium persulfate .); water-soluble the inside is put in the normal pressure funnel, and evacuation leads to nitrogen protection, and the APS that slowly drips 10mL is in solution; dropwise, 50 ℃ were reacted 5 hours down.
5. the lyophilizing of the temperature sensitive property of step 4 gained granule is handled, got uranine yellow (solid) and put in the phosphate buffer solution that has dissolved the temperature sensitive liposome of solid, the ultimate density of uranine yellow is 0.027mg/ml.Uranine yellow is adsorbed by the outer field phase change of thermosensitive hydrogel and penetrates into gel layer inside, makes the gel absorption that reaches capacity, and makes it separate non-encapsulated part by dextran microgel column.
6. the release of aids drug in the granule
Outer: get eluent 0.5mL and put into the dialysis band, will dialyse to be with again and put into the phosphate buffer that 30mL pH7.4 is housed, 37 ℃ of constant temperature are changed the blank buffer of preheating and the fluorescence intensity level of assay buffer again every the 20min periphery.
Internal layer: continue dialysis, change the blank buffer of preheating and the fluorescence intensity level of assay buffer again every the 2-3h periphery.
Embodiment 2
1. get chrondroitin and be dissolved in the ultra-pure water, concentration is 4mg/mL, adds the 0.6mL triethylamine, and 0.6g tetrabutyl ammonium bromide and 0.6mLGMA, room temperature reaction were hatched 2h down at 60 ℃ after 20 hours, and lyophilization is 5 days then, dialyses 8 days.
2. will add the 0.5mg rhodamine 6G in the phospholipid solution, the lyophilization preparation contains the adipose membrane of rhodamine 6G.Liposome with preparing the parcel rhodamine 6G after the buffer aquation makes it separate non-encapsulated part by dextran microgel column, obtains to have wrapped up the liposome of rhodamine 6G.
3. the reactant liquor with step 1 gained adds the ultra-pure water dilution, dropwise adds the solution of step 2 gained liposome, ultrasonic 30min.
4. the reactant liquor with step 3 gained adds 1 part of MBA (N; the N-methylene-bisacrylamide); 10 parts of NIPAM (N-N-isopropylacrylamide); again the water-soluble the inside of 1 weight portion APS (Ammonium persulfate .) is put in the normal pressure funnel; evacuation leads to nitrogen protection; slowly drip APS in solution, dropwise, 70 ℃ were reacted 3 hours down.
5. the lyophilizing of the temperature sensitive property of step 4 gained granule is handled, an amount of uranine yellow (solid) of weighing is put in the phosphate buffer solution that has dissolved the temperature sensitive liposome of solid.Uranine yellow is adsorbed by the outer field phase change of thermosensitive hydrogel and penetrates into gel layer inside, makes the gel absorption that reaches capacity.Make it separate non-encapsulated part by dextran microgel column.
Result of study shows: temperature sensitive property nucleocapsid structure microgranule is investigated its temperature sensitive property with dynamic light scattering DLS and ultraviolet photometer UV, lowest critical solution temperature is all near 34 ℃, outer field gel layer wraps up a kind of hydrophilic aids drug uranine yellow, envelop rate 72.96%, cumulative release time 1h, cumulative release rate 81.16%; A kind of hydrophobic aids drug rhodamine 6G of kernel liposome, because the crosslinked covering effect of outer gel, the aids drug of internal package can reach the effect of slow release, its envelop rate 52.64%, cumulative release time 40h, cumulative release rate 82.28%.Two kinds of different release modes, thus the release time of different pharmaceutical, difference reached two dimension release.
Claims (11)
1. a temperature sensitive type nucleocapsid structure liposome controlled release drug carrier is made of kernel liposome and outer temperature sensitive macromolecule pluralgel.
2. controlled release drug carrier as claimed in claim 1, wherein said kernel are the liposome vesicle that biosurfactant constitutes, and the temperature sensitive macromolecule pluralgel of described skin is made of natural biological macromole and temperature sensitive macromolecule.
3. controlled release drug carrier as claimed in claim 2, wherein said biosurfactant is selected from phospholipid.
4. controlled release drug carrier as claimed in claim 2, wherein said natural biological macromole is selected from acidic polysaccharose hyaluronic acid, chrondroitin, chitosan.
5. controlled release drug carrier as claimed in claim 2, wherein said temperature sensitive macromolecule is PNIPAM, is carried out cross-linking reaction and formed in the presence of cross-linking agent MBA by NIPAM.
6. the preparation method of the described controlled release drug carrier of claim 1 may further comprise the steps:
1) biosurfactant is dissolved in the organic solvent, the rotary container evaporating solvent is to doing under the vacuum, and the lipid film uniform deposition is on the bottle wall, and vacuum drying adds phosphate buffer solution aquation lipid film behind the 30-60 ℃ of ultrasonic preheating 10-30min of water-bath;
2) acidic polysaccharose is dissolved in the ultra-pure water, adds equal-volume triethylamine and tetrabutyl ammonium bromide, carry out lyophilization behind the reaction 10-20h, add water, dialyse 5-10 days, then with 1) the ultrasonic 10-60min that mixes of liposome solutions of acquisition;
3) 2) add cross-linking agent 1 weight portion and temperature sensitive high polymer monomer 15 weight portions in the gained dispersion liquid, drip catalyst solution down in nitrogen protection, 50-80 ℃ of reaction 2-5 hour.
7. preparation method as claimed in claim 6, wherein said organic solvent is selected from anhydrous chloroform, dichloromethane and ethanol.
8. preparation method as claimed in claim 6, wherein said temperature sensitive high polymer monomer is NIPAM, described cross-linking agent is MBA.
9. preparation method as claimed in claim 6, wherein said step 1) is dissolved in first kind of medicine and biosurfactant in the organic solvent simultaneously, obtains wrapping up the liposome of first kind of medicine.
10. as claim 6 or 9 described preparation methoies, wherein also comprise step 4): with the product lyophilizing of step 3), immerse and dissolved in the aqueous solution of second kind of medicine, behind the 20-40 ℃ of maintenance 10-20min, leave standstill half a day, obtain sealing the carrier of second kind of medicine.
11. the described controlled release drug carrier of claim 1 is in the purposes of preparation controlled release drug or cosmetic field.
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| CN103479568A (en) * | 2013-10-22 | 2014-01-01 | 中国药科大学 | Novel hydrochloric acid topotecan intratumor injection preparation composition and preparation method thereof |
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| CN104840415B (en) * | 2014-02-19 | 2019-03-15 | 香港浸会大学 | Long-acting controlled release lipidosome gel composition containing blood-sugar decreasing active and preparation method thereof |
| CN104840415A (en) * | 2014-02-19 | 2015-08-19 | 香港浸会大学 | Long-acting controlled release liposome gel combination containing blood sugar reducing active component, and preparation method thereof |
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