CN102579343A - Method for improving target effect of receptor targeting preparation based on folic acid compounds - Google Patents
Method for improving target effect of receptor targeting preparation based on folic acid compounds Download PDFInfo
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Abstract
The invention relates to the field of medicinal preparations and particularly relates to a method for improving an active targeting effect of an active targeting preparation based on folic acid compounds by increasing distribution of targeting groups, namely folic acid compound groups, of the active targeting preparation in external water phase. The method is characterized in that the key difference between the method and the conventional preparation method is that normal water, osmotic-pressure regulator solution or neutral buffer saline solution does not serve as the water phase, but alkalescence solution with pH being 7.5-10.0 serves as the water phase. The active targeting effect of the receptor targeting preparation prepared by the method can be improved.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, being specifically related to a kind of increase is the distribution of water outside of folacin compound group based on targeting group in the active target preparation of folacin compound, and then improves the initiatively method of targeting effect of preparation.
Background technology
Folic acid (FA) is reducible to be tetrahydrofolic acid, and the latter is the coenzyme of one carbon unit transferring enzyme, participates in the de novo synthesis of one carbon unit metabolism and purine, thymus pyrimidine.The expression high conservative of folacin receptor in normal structure; Only in lung, kidney, choroid and Placenta Hominis, there is the medium level of being low to moderate to express; And with the β hypotype is main; But in most of malignant tumor, as all highly expressing in ovarian cancer, carcinoma of endometrium, carcinoma of prostate, renal carcinoma, breast carcinoma, pulmonary carcinoma, colon cancer and the nasopharyngeal carcinoma, comparable sometimes normal structure exceeds 100～300 times; And folacin receptor mainly is positioned the epithelium tip end surface that polarizes in the normal structure, and folic acid composite can't be in contact with it in the blood circulation.Result of study up to now shows; After folic acid is connected to form folic acid composite through its carboxyl and medicament carrier system; Itself and cell surface receptor affinity remain unchanged basically; Overcome delivery system is difficult to permeates cell membranes under physiological status problem, guaranteed delivery system to be delivered in the tumor cell through folate-mediated.Folic acid is as the targeting molecule of tumor cell, has no immunogenicity, is easy to modify and advantage such as cheap and easy to get, become the mediation delivery system initiatively target tumor the research focus it
Yuan H etc. has prepared folacin coupled Paclitaxel liposome; Improved the cellular uptake of preparation; But it directly is connected folic acid with fatty acid, the centre does not have polyglycol chain, and the liposome of processing is tachytrophism in vivo; Do not possess the characteristics that long circulating liposomes delays drug metabolism, increases the body-internal-circulation time, influenced the performance of drug effect largely.
Based on the targeting preparation of folic acid through for many years improvement; Generally folate molecule is connected dosage surface indirectly and obtains the receptor type targeting preparation at present through the hydrophilic straight chain polymer; This method has remedied ordinary preparation targeting property deficiency, has been prone to by macrophage membrane surface Fc receptor identification in the reticuloendothelial system and by the rapid shortcoming of removing from blood circulation, for medicine is imported at high proportion a kind of comparatively practical antitumor drug targeting vector is provided in the tumor cell.Robert J.Lee etc. is connected on folic acid and the bonded PEG molecule of lipoid far-end, it is stretched from liposome neatly, and then the FA-PEG-liposome complex is imported target cell.Said preparation can be used as the effective carrier that transmits chemotherapeutics, but this method prepares liposome, and the folic acid group can be embedded between the liposome phospholipid bilayer because of the hydrophobicity of self in the preparation process, and then reduces the active targeting ability of preparation.
Pedro M has prepared the nanoparticle that PLGA-PEG-FA modifies; Discovery has only 20% folic acid group to be positioned at the outer aqueous phase of nanoparticle; In the hydrophobic inner core that other 80% is coated on nanoparticle, prove that the hydrophobicity of folic acid group itself has influenced its application on active target preparation greatly.Though can increase the absolute number of the folic acid target head that is exposed to water in the formulation preparation process through the inventory that increases the targeting material; But the targeting material cost is higher on the one hand; In addition; Can be because insert the targeting material of preparation main body early stage through the sterically hindered insertion that hinders later stage targeting material of its PEG chain or other hydrophilic chains, so the modification amount of targeting material can not arbitrarily increase.Therefore, how the raising folic acid group of the convenient and efficient distribution proportion of water has outside become at present both at home and abroad and has demanded problem anxious to be solved urgently in the active target preparation research based on folic acid.
Chinese patent (application number 201110114306.6) at first prepares micelle with PHOSPHATIDYL ETHANOLAMINE-Macrogol 2000-folic acid; Prepare conventional liposome then and both are hatched jointly; Making micellar PHOSPHATIDYL ETHANOLAMINE group is the outer phospholipid layer that the phospholipid group inserts liposome; This fusion process can make the folic acid group be distributed in outside the liposome, and then better brings into play the targeting ability of folic acid.This patent preferably resolves the classical method of modifying middle period acid groups major part of folacin receptor targeting preparation and is coated on the preparation hydrophobic inner core, can't exposes and then influence with the target cell surface receptor interactional problem takes place, but this patent exist preparation technology loaded down with trivial details when hatching the limited problem of PHOSPHATIDYL ETHANOLAMINE group phospholipid group insertion liposome efficient of PHOSPHATIDYL ETHANOLAMINE-Macrogol 2000-folic acid.It is very limited to hatch the method versatility simultaneously; It is hydrophilic and semisolid that the method for hatching requires preparation body surfaces to be finished; And the targeting material must contain group identical with the dosage surface material structure or that have a high affinity could make things convenient for its insertion, fusion; With this patent is example, and polyglycol chain or other hydrophilic chain other end of folic acid group connect is not phospholipid but other amphipathic nature materials or hydrophobic material if be used to connect, and the affinity that then has this material and a liposome phospholipid layer is not by force even the problem that can't insert; If dosage surface is a hydrophobicity; Formulation system only keeps physically stable through charge repulsion between the preparation individuality or other active force, and perhaps the preparation body surfaces is solid-state, does not possess appropriate flowability; The method of then hatching can not be used for the modification of active target preparation at all, can't realize because this critical process is inserted in the back at all.
Summary of the invention
The invention discloses a kind of increase based on the distribution of water outside of targeting group in the active target preparation of folic acid, and then improve the initiatively method of targeting effect of preparation.
Main feature of the present invention is for to prepare in the process at the active target preparation based on folacin compound; The targeting material that contains the folic acid group feeds intake with the lipid or the macromolecular material that form the preparation main body simultaneously; The spontaneous formation of fellowship preparation main body; With the alkalescence aqueous slkali as outer water, from significantly increasing the hydrophilic of folacin compound group in essence, so make its in the spontaneous forming process of preparation main body active distributed in outer water; Avoid its hydrophobicity to be embedded in the hydrophobic position of preparation main body, finally reach the effect that strengthens folate-mediated active targeting effect because of self.
Classical method for preparing based on the active target preparation of folic acid is: matrix material and the targeting material that contains the folic acid group are dissolved in organic solvent, and the rotary evaporation film forming adds the water hydration, and it is ultrasonic to pop one's head in, filtration sterilization.
The key difference of the present invention and common method for preparing is not for to use water commonly used, osmotic pressure regulator solution or neutral buffered saline solution as water, and the weakly alkaline solution of employing pH7.5～10.0.
The method for preparing of receptor type targeting preparation of the present invention comprises: matrix material or macromolecular material are dissolved in organic solvent with the targeting material that contains the folacin compound group, are scattered in water through thin film elution method, alcohol injection, reverse evaporation, dialysis, emulsifying-solvent evaporation method or microemulsion method; The degerming of granulate after-filtration promptly gets, and before the preparation carrying medicine, is fat-soluble like medicine; Then medicine and matrix material or macromolecular material together are dissolved in organic solvent; Like medicine is water solublity, then medicine is soluble in the aqueous phase, in above-mentioned preparation; Key is: water contains lewis base, and aqueous pH values remains in 7.5～10.0 scopes.More preferably pH value is 7.8～8.2.The receptor type targeting preparation of the inventive method preparation can improve initiatively targeting effect of preparation.
Infer that principle of the present invention is following: it is fundamentally to solve the folic acid group by the embedding key of problem that targeting material middle period acid groups is carried out the polar transformation.Under the prerequisite that keeps folic acid group space conformation and steady chemical structure, it is the most simple and feasible method that its unsubstituted α free carboxy is transformed.The alkalescence hydration medium of pH7.5～10.0 can make this α free carboxy ionizing, makes the folic acid group by the nonpolar polarity that transfers to, significantly strengthens folic acid group self hydrophilic.Above theory is proposed by the present invention first.Targeting material and lipid or the macromolecular material that will contain the folic acid group feed intake simultaneously; The spontaneous formation of fellowship preparation main body; The hydrophobic group of targeting material can cross that hydrophobic interaction power attracts each other, spontaneous gathering with the hydrophobic segment of other matrix materials or macromolecular material in water; And hydrophilic chains such as PEG and hydrophilic modification folic acid group squeezed outer water, fundamentally stop of the embedding of folic acid group in the hydrophobic main body of preparation.More than imagination is practical through K562 cellular uptake experiment proof.Selection about outer aqueous pH values scope; The ratio of folic acid α carboxylic ions type number and free type number can increase with the increase of outer aqueous pH values in the preparation system; But the speed that this ratio increases can reduce rapidly with the increase of outer aqueous pH values, promptly through increase the Ionized efficient of outer aqueous pH values promotion α free carboxy can be along with the increase of outer aqueous pH values rapid variation, so in order to make the α free carboxy ionizing more fully of folic acid; Outer water should possess pH value higher, meta-alkalescence; But needn't be too high, and the too high meeting of pH value causes the hydrolysis of part matrix material such as phospholipid, during in conjunction with the preparation intravenous drip to the requirement of blood vessel irritation; The scope that our test is illustrated in pH7.5～10.0 can obtain this effect, more preferably pH7.8～8.2.For the outer water of pH value 9.0～10.0, can adopt the macromolecular material that chemical property is more stable under the alkali condition to prepare preparation.
The present invention is with respect to the active targeting vector assemble method of classics; The outer water of realization folic acid group that can be easy distributes; Because preparation process middle period acid groups is a hydrophilic; Fundamentally prevented the distribution of folic acid in the carrier hydrophobic inner core, and weakly alkaline hydration medium can not influence the chemical stability of folic acid group itself and the binding ability of folic acid and its target cell surface receptor, can not influence the physico-chemical property of matrix material and the physical stability and the envelop rate of preparation itself yet; The final pH value of preparation also meets the injection requirement, and safety is good.
The present invention is with respect to the existing i.e. patented technology (CN201110114306.6) of back insertion of hatching of China; Possess easy and simple to handle; The targeting material inserts the high characteristics of efficient; The more important thing is that this method possesses good versatility from having changed the hydrophobic property of folic acid group in essence; The group that no matter needs to insert the preparation main body in the targeting material is still hydrophobic alkyl short chain or a macromolecular material fully of amphipathic phospholipid material; Because the targeting material has been participated in early stage spontaneous forming process rather than the insertion again after the preparation main body forms of formulation system, this method can both be anchored on the preparation main body securely with most targeting materials, and not having above-mentioned hatching is the restriction that requires targeting material anchoring group to be necessary for phospholipid in the back insertion technology or must possess the attach structure similarity with the dosage surface material.Simultaneously; Active target preparation is for strengthening the physical stability of preparation itself at present; Mostly adopt the assemble method of hydrophobic inner core outsourcing hydrophilic surface layer,, destroyed and impelled folic acid to transfer hydrophilic outer water weakly alkaline environment to even adopt dilution such as glucose injection in the clinical use; Because the surface of preparation own is coated with hydrophilic layer, the folic acid group that hydrophilic weakens still can be stablized and is distributed in aqueous phase and can not insert the preparation hydrophobic cores again because of its hydrophobicity.
The preferred lewis base of described alkali; Can provide in the material of electron pair one or more; More preferably one or more in carbonate, acid carbonate, hydroxide, phosphate, sulphite, ammonia, the amine, one or more in further preferred sodium carbonate, sodium bicarbonate, sodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium hydroxide, potassium hydroxide, the sodium sulfite.
The preferred folic acid of described folacin compound, folinic acid, dihydrofoilic acid, tetrahydrofolic acid, 5-formyl tetrahydrofolic acid, 10-formyl tetrahydrofolic acid, 5-methyl tetrahydrofolate, 5; 10-methylene tetrahydrofolate, 5,10-anhydroleucovorin, methotrexate, the many glutamic acid of the acyl of talking endlessly, 2-deaminize-and hydroxyl folic acid, 1-deaminizes-hydroxyl folic acid, 1-denitrification folic acid, 3-denitrification folic acid or 8-denitrification folic acid.
Said targeting material be folic acid and other medically to allow the covalent conjunct agent of materials used be the folic acid-molecular complex of modified with folic acid, preferred stearic bicine diester PHOSPHATIDYL ETHANOLAMINE-Polyethylene Glycol-folic acid (DSPE-PEG-FA), PHOSPHATIDYL ETHANOLAMINE-Polyethylene Glycol-folic acid (PE-PEG-FA), polylactic acid-glycolic guanidine-acetic acid copolymer-Polyethylene Glycol-folic acid (PLGA-PEG-FA), CPEG-folic acid (Chol-PEG-FA), gather cetyl cyanoacrylate-Polyethylene Glycol-folic acid (PHDCA-PEG-FA) or monostearate polyoxyethylene ester-folic acid (S100-FA).
Said active target preparation is common dosage forms such as liposome, micelle, solid lipid nanoparticle, nano structured lipid carrier or butterfat body.
The preferred 5nm-10 μ of said active target preparation particle size range m.
In the preferred glyceryl tristearate of described matrix material, tripalmitin, LAURIN DYNASAN 112, glyceryl monostearate, Compritol 888 ATO, caprylic/capric triglyceride, propylene glycol dicaprylate, propylene glycol dicaprate, myristin, cholesterol, stearic acid, microcrystalline wax, whale ester type waxes, soybean phospholipid, lecithin, egg yolk lecithin, the hydrogenated phospholipid one or more.
In used macromolecular material preferred starch, arabic gum, gelatin, guar gum, chitin, chitosan, tragakanta, sodium alginate, albumin, polyacrylic acid, acrylic resin, ethylene/vinyl acetate copolymer, polylactic acid, polyglycolic acid, the lactic acid/co-glycolic acid one or more.
Preparation aqueous phase of the present invention can add osmotic pressure regulator in addition, like sodium chloride, glucose, mannitol.
Method for preparing of the present invention also is suitable for nanoparticle is processed lyophilized formulations; Nano particle preparations adds freeze drying protectant such as glucose, mannitol, lactose, sucrose, trehalose, sorbitol, dextran, glycerol or glycine; The filtration sterilization postlyophilization can make the nanoparticle lyophilized formulations.
Can also add antioxidant in the formulation preparation process of the present invention, preferred ascorbic acid, Tocopheryl derivatives such as vitamin E.
Preparation aqueous phase of the present invention can also add surfactant to reduce the nanoparticle particle diameter, preferred poloxamer 188, polyoxyethylene sorbitan monoleate, polyoxyethylene castor oil, sodium deoxycholate.
During the preparation nanoparticle, institute's medicament and raw material are generally chosen by following parts by weight: medicine 1-3 part, lipid 0-150 part; Macromolecular material 0-300 part, targeting material 1-300 part, antioxidant 0-2 part; Freeze drying protectant 0-1000 part; Osmotic pressure regulator 0-600 part, lewis base 1-300 part, surfactant 0-500 part.
Be effect comparison below with common targeting preparation with the targeting preparation of the improvement of the inventive method preparation of conventional method preparation:
Ordinary target is to formulation preparation: take by weighing soybean phospholipid 8g, LAURIN DYNASAN 112 1g, S100-FA (monostearate polyoxyethylene ester and folic acid are with covalent bonds) 0.3g, coumarin-6 storing solution an amount of (making the final formulation concentrations of coumarin-6 is 10 μ g/mL), add ethanol/methylene (1: 1, v/v) mixed solvent 200mL dissolving; The rotary evaporation film forming; 37 ℃ of hydration 30min of 300mL deionized water, it is ultrasonic to pop one's head in, and crosses 0.22 μ m microporous filter membrane; Promptly get common targeting preparation, particle diameter 54.5nm.
The targeting preparation preparation of the present invention's improvement:
Improvement targeting preparation one: take by weighing soybean phospholipid 8g, LAURIN DYNASAN 112 1g, S100-FA0.3g, coumarin-6 storing solution an amount of (making the final formulation concentrations of coumarin-6 is 10 μ g/mL), the adding ethanol/methylene (1: 1, v/v) mixed solvent 200mL dissolving; Rotary evaporation film forming, adding 300mLpH value are 7.8 sodium bicarbonate aqueous solution, 37 ℃ of hydration 30min; It is ultrasonic to pop one's head in; Cross 0.22 μ m microporous filter membrane, promptly get particle diameter 58.3nm.
Improvement targeting preparation two: take by weighing soybean phospholipid 8g, LAURIN DYNASAN 112 1g, S100-FA0.3g, coumarin-6 storing solution an amount of (making the final formulation concentrations of coumarin-6 is 10 μ g/mL), the adding ethanol/methylene (1: 1, v/v) mixed solvent 200mL dissolving; Rotary evaporation film forming, adding 300mLpH value are 8.4 aqueous sodium carbonate, 37 ℃ of hydration 30min; It is ultrasonic to pop one's head in; Cross 0.22 μ m microporous filter membrane, promptly get particle diameter 54.8nm.
Improvement targeting preparation three: take by weighing soybean phospholipid 8g, LAURIN DYNASAN 112 1g, S100-FA0.3g, coumarin-6 storing solution an amount of (making the final formulation concentrations of coumarin-6 is 10 μ g/mL), the adding ethanol/methylene (1: 1, v/v) mixed solvent 200mL dissolving; Rotary evaporation film forming, adding 300mLpH value are 9.0 sodium hydrate aqueous solution, 37 ℃ of hydration 30min; It is ultrasonic to pop one's head in; Cross 0.22 μ m microporous filter membrane, promptly get particle diameter 55.1nm.
Take the logarithm the people source K562 cell of trophophase with 1 * 10
5Individual/hole is inoculated in 24 orifice plates; Complete medium is cultivated 24h for 37 ℃, removes culture fluid, cleans three times with not containing the folic acid culture medium; Reuse does not contain the folic acid culture medium and cultivates 24h for 37 ℃; Remove culture medium, every hole adds the common active target preparation and improvement active target preparation (n=6) of 0.5mL with the above-mentioned year coumarin-6 that does not contain 100 times of folic acid culture medium dilutions, hatches 4h respectively at 37 ℃.Discard the culture fluid that contains preparation,, adopt fluorescence-HPLC method and BCA test kit method to measure coumarin-6 and proteic concentration in the cell with ice-cold PBS washing three times.Experimental result shows that cellular uptake amount that the present invention improves targeting preparation one, two, three is respectively 1.82,1.89,1.73 times of common targeting preparation.Experimental result is seen Fig. 1.
Description of drawings
Fig. 1 is that the common and of the present invention improved target of coumarin-6 is to Formulation K 562 cellular uptakes (n=6)
The specific embodiment
Embodiment 1
Take by weighing soybean phospholipid 8g, LAURIN DYNASAN 112 1g, DSPE-PEG-FA 0.2g, amycin 300mg, and the adding ethanol/methylene (1: 1, v/v) mixed solvent 200mL dissolving; Rotary evaporation film forming, adding 300mLpH value are 8.0 sodium bicarbonate aqueous solution, 37 ℃ of hydration 30min; It is ultrasonic to pop one's head in; Cross 0.22 μ m microporous filter membrane, promptly get and improve active target preparation, particle diameter 80.6nm.
Embodiment 2
Take by weighing soybean phospholipid 8g, LAURIN DYNASAN 112 1g, DSPE-PEG-FA 0.2g, mitoxantrone 200mg, and the adding ethanol/methylene (1: 1, v/v) mixed solvent 200mL dissolving; Rotary evaporation film forming, adding 300mLpH value are 8.2 aqueous sodium carbonate, 37 ℃ of hydration 30min; It is ultrasonic to pop one's head in; Cross 0.22 μ m microporous filter membrane, promptly get and improve active target preparation, particle diameter 85.3nm.
Embodiment 3
Take by weighing soybean phospholipid 8g, LAURIN DYNASAN 112 1g, Chol-PEG-FA 0.2g, camptothecine 100mg, and the adding ethanol/methylene (1: 1, v/v) mixed solvent 200mL dissolving; Rotary evaporation film forming, adding 300mLpH value are 8.6 aqueous sodium carbonate, 37 ℃ of hydration 30min; It is ultrasonic to pop one's head in; Cross 0.22 μ m microporous filter membrane, promptly get and improve active target preparation, particle diameter 75.4nm.
Embodiment 4
Take by weighing PLGA-PEG 0.1g, PLGA-PEG-FA 0.01g; Pipette coumarin-6 mother solution an amount of (making the final formulation concentrations of coumarin-6 is 1 μ g/mL); Add acetonitrile 10mL dissolving, dropwise add 100mLpH value and be in 8.6 the aqueous sodium carbonate also vigorous stirring, put the 24h that dialyses in the 8000-12000 molecular cut off bag filter; Promptly get and improve active target preparation, particle diameter 300.3nm.
Embodiment 5
Take by weighing soybean phospholipid 8g, LAURIN DYNASAN 112 1g, PE-PEG-FA 0.2g, dexamethasone acetate 100mg, and the adding ethanol/methylene (1: 1, v/v) mixed solvent 200mL dissolving; Rotary evaporation film forming, adding 300mLpH value are 8.0 sodium hydrogen phosphate aqueous solution, 37 ℃ of hydration 30min; It is ultrasonic to pop one's head in; Cross 0.22 μ m microporous filter membrane, promptly get and improve active target preparation, particle diameter 77.4nm.
Embodiment 6
Take by weighing soybean phospholipid 8g, LAURIN DYNASAN 112 1g, PE-PEG-FA 0.2g, ibuprofen 100mg, and the adding ethanol/methylene (1: 1, v/v) mixed solvent 200mL dissolving; Rotary evaporation film forming, adding 300mLpH value are 8.0 sodium bicarbonate aqueous solution, 37 ℃ of hydration 30min; It is ultrasonic to pop one's head in; Cross 0.22 μ m microporous filter membrane, promptly get and improve active target preparation, particle diameter 72.3nm.
Claims (7)
1. the method for preparing of a receptor type targeting preparation comprises: matrix material or macromolecular material are dissolved in organic solvent with the targeting material that contains the folacin compound group, are scattered in water through thin film elution method, alcohol injection, reverse evaporation, dialysis, emulsifying-solvent evaporation method or microemulsion method; The degerming of granulate after-filtration promptly gets; Before the preparation carrying medicine, be fat-soluble, then medicine and matrix material or macromolecular material together be dissolved in organic solvent like medicine; Like medicine is water solublity; Then medicine is soluble in the aqueous phase, it is characterized in that: water contains lewis base, and aqueous pH values is 7.5～10.0.
2. the method for preparing of claim 1, wherein aqueous pH values is 7.8～8.2.
3. the method for preparing of claim 1, wherein lewis base is selected from one or more in sodium carbonate, sodium bicarbonate, sodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium hydroxide, potassium hydroxide, the sodium sulfite.
4. the method for preparing of claim 1; Wherein folacin compound is folic acid, folinic acid, dihydrofoilic acid, tetrahydrofolic acid, 5-formyl tetrahydrofolic acid, 10-formyl tetrahydrofolic acid, 5-methyl tetrahydrofolate, 5; 10-methylene tetrahydrofolate, 5,10-anhydroleucovorin, methotrexate, the many glutamic acid of the acyl of talking endlessly, 2-deaminize-and hydroxyl folic acid, 1-deaminizes-hydroxyl folic acid, 1-denitrification folic acid, 3-denitrification folic acid or 8-denitrification folic acid.
5. the method for preparing of claim 1, wherein the receptor type targeting preparation is liposome, micelle, solid lipid nanoparticle, nano structured lipid carrier or butterfat body.
6. the method for preparing of claim 1, wherein matrix material is selected from one or more in glyceryl tristearate, tripalmitin, LAURIN DYNASAN 112, glyceryl monostearate, Compritol 888 ATO, caprylic/capric triglyceride, propylene glycol dicaprylate, propylene glycol dicaprate, myristin, cholesterol, stearic acid, microcrystalline wax, whale ester type waxes, soybean phospholipid, lecithin, egg yolk lecithin, the hydrogenated phospholipid.
7. the method for preparing of claim 1, wherein macromolecular material is selected from one or more in starch, arabic gum, gelatin, guar gum, chitin, chitosan, tragakanta, sodium alginate, albumin, polyacrylic acid, acrylic resin, ethylene/vinyl acetate copolymer, polylactic acid, polyglycolic acid, the lactic acid/co-glycolic acid.
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| CN109122684A (en) * | 2018-08-14 | 2019-01-04 | 武汉轻工大学 | Carvacrol solid lipid nano granule dispersion liquid with bacteriostatic activity and its preparation method and application |
| CN109122684B (en) * | 2018-08-14 | 2021-03-26 | 武汉轻工大学 | Carvacrol solid lipid nanoparticle dispersion liquid with antibacterial activity and preparation method and application thereof |
| CN110227065A (en) * | 2019-03-22 | 2019-09-13 | 中山大学孙逸仙纪念医院 | Folate-targeted carries NaHCO3Liposome and its application in terms of enhancing immunotherapy of tumors effect |
| CN110227065B (en) * | 2019-03-22 | 2021-07-27 | 中山大学孙逸仙纪念医院 | Folic acid targeting NaHCO3Liposome and application thereof in enhancing tumor immunotherapy effect |
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