CN105617389A - Positively charged nano microsphere medicine carrier for eye and preparation method of positively charged nano microsphere medicine - Google Patents
Positively charged nano microsphere medicine carrier for eye and preparation method of positively charged nano microsphere medicine Download PDFInfo
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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- 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
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- A61K9/00—Medicinal preparations characterised by special physical form
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Abstract
The invention provides a positively charged nano microsphere medicine carrier for eyes and a preparation method the positively charged nano microsphere medicine. The positively charged nano microsphere medicine carrier is positively charged, the particle size ranges from 1 nm to 10 [mu]m, and preferably, from 10 nm to 500 nm; the charge range is 0.1-200 mv, and preferably, is 5-50 mv. After being injected into a vitreous cavity, the positively charged nano microsphere medicine carrier can be enriched at a fundus under the action of a micro electric field inside an eye; by adjustment of the charge amount of the carrier, different subshells permeating into the fundus from the carrier can be further regulated and controlled. Therefore, the carrier has a multi-stage targeting function to a fundus subshell diseased region, the problems that a medicine is low in bioavailability, large in toxic and side effect and the like can be solved, and the treatment effect can be remarkably improved. Raw materials which can be used in the medicine carrier provided by the invention are wide in source, different medicines can be carried for different fundus diseases, universality is achieved, and orientated transfer of the medicines in eyes can be achieved.
Description
Technical field
The invention belongs to pharmaceutical carrier field, it is specifically related to a kind of the eye positive susceptance microsphere drug carrier of lotus and its preparation method, it is achieved eye interior orientation transhipment medicine.
Technical background
Fundus oculi disease is the Eye disease having impaired vision He causing blind risk, and sick kind is various, both comprise the common retina/choroidal artery diseases such as age-related macular degeneration, diabetic retinopathy, retinal vein occlusion, retinopathy of prematurity change, also comprise the infectious diseases such as cytomegaloviral retinitis, acute retinal necrosis. Due to the multiple factor such as rescue level lifting of the propagation of aging population, acquired immune deficiency syndrome (AIDS), not healthy living custom and premature infant, the sickness rate of fundus oculi disease constantly rises in recent years, according to the epidemiological investigation data display that Beijing is up-to-date, the total incidence of all kinds of fundus oculi disease is more than 1.4%, it is necessary to by the fundus oculi disease conservative estimation of pharmacological agent more than 1.2%.
Vitreous space injectable drug is the important way of clinical treatment fundus oculi disease, and however, intravitreal injection administration still exists many defects in clinical application: (1) transformation period is short, it is necessary to duplicate injection frequently; (2) medicine free disperse within the eye, without specificity; (3) the different subgrades of retina cannot be entered by regulating medicine.
There is physiological potential difference in eyeball, just like natural battery, front end is positive pole, and rear end is negative pole. as shown in Figure 1, comparing with neutral or electronegative particle, positively charged particle will more trend towards by the retina surface adsorption of section after eye, meanwhile, the polymer of positively charged as chitosan be also proved to be can compact siro spinning technology between reversibly opening cell, be convenient to enter retina deep layer further. therefore, if this physiological property of electric microfield in ingenious utilization eye, by preparing grain size and the regulatable microballoon of receiving of surface charge, the research charged particle motor behavior in electric microfield within the eye, it is directed and enter the impact of retina different levels that the lotus of microballoon/matter comparison retina is received in system evaluation, just likely filter out and can be used in vitreous space injection, can directed retina, and can regulate and control to enter the microballoon of receiving of the different subgrade of retina, further embedding medicinal on this basis, realize the slow releasing for medicine, solve a series of problems that intraocular drug injection exists. therefore, develop frequency and side effect that the medicament carrier system having multistage orientation and slow-release function concurrently can reduce vitreous space injectable drug undoubtedly to a great extent, promote result for the treatment of, no matter in medical value, social benefit or market application, all have a extensive future.
Summary of the invention
For the deficiencies in the prior art, the present invention provide a kind of can the pharmaceutical carrier of eye interior orientation transhipment medicine, this carrier need to have certain positive charge, can be enriched in eyeground after vitreous space is injected under the effect of electric microfield within the eye; Further by regulating the quantity of electric charge, it is possible to regulation and control carrier penetrates into the different subgrades on eyeground further, thus realizes the multistage targeting to eyeground subgrade diseased region, solves drug bioavailability low, and the problems such as toxic side effect is big, significantly improve result for the treatment of.
For reaching this goal of the invention, the present invention adopts following technical scheme:
The preparation method of the positive susceptance microsphere drug carrier of a kind of lotus, it is characterised in that, comprise the steps:
Step one, take a certain amount of oil soluble macromolecule dissolution in organic solvent as oil phase, after mixed with water, prepare emulsion oil-in-water;
Step 2, the emulsion oil-in-water of step one is at room temperature stirred spend the night to organic solvent volatilization complete, with distilled water centrifuge washing several times, obtain receiving microballoon;
Step 3, above-mentioned obtained microballoon of receiving is suspended in the wetting ability charged macromolecular solution of different concns, vertical mixed outstanding instrument is hatched, carries out positive charge modification;
The quantity of electric charge of step 4, microballoon can be regulated by the substitution value of the concentration of polymer or electric charge group;
So far, the preparation of the positive susceptance microsphere drug carrier of lotus completes.
Wherein, when carrying out medicine embedding, if medicine is hydrophobic drug, then in step one, medicine is dissolved in oil phase together with oil soluble polymer and embeds; If medicine is hydrophilic medicament, then first it is dissolved as interior aqueous phase, then the form adopting multiple breast carries out load, or it is adsorbed on together with charged polymer in step 3 or step 5 and receives on microballoon.
As the preferred technical solution of the present invention, in described step one, the preparation method of emulsion oil-in-water is paddling process, ultrasonic method, the precipitator method, homogenizing emulsifying or porous membrane emulsiilcation method, it is preferable that can prepare the porous membrane emulsiilcation technology of an equal emulsion.
Preferably, in described step 3, the electric charge modifying method of employing is absorption method or chemical coupling method.
In described step one, oil soluble polymer can be polylactic acid-based polymer or polyester polymer.
The particle size range of microballoon received obtained in described step 2 is 1nm��10 ��m, it is preferable that the nanometer ball of 10��500nm.
In described step 3, wherein the polymer of positive charge can be chitosan, n-trimethyl chitosan chloride, polymine or polylysine.
The present invention also protects a kind of positive susceptance microsphere drug carrier of lotus, it is characterised in that: it utilizes the preparation of the method described in claim 1��5 any one to be formed, and particle size range is 1nm��10 ��m, it is preferable that 10nm��500nm; Ranges of charge is 0.1��200mv, it is preferable that 5��50mv.
In addition, also protect the positive susceptance microsphere drug carrier of above-mentioned lotus as the application of the directed transport vehicle of ophthalmic disease medicine for treatment thing. Wherein, described ophthalmic disease is age-related macular degeneration, diabetic retinopathy, retinal vein occlusion, retinopathy of prematurity change, cytomegaloviral retinitis or acute retinal necrosis.
Described ophthalmic disease medicine for treatment thing is one or more couplings wherein such as small-molecule chemical medicine, protein and peptide class medicine, antibody drug or genomic medicine.
Compared with prior art, the technical superiority of the present invention is:
1, pharmaceutical carrier of the present invention is positively charged, it is possible to realizes directed transhipment within the eye, after vitreous space is injected, is enriched in eyeground within the eye under electric microfield effect; By regulating the carrying capacity of carrier, it is possible to regulation and control carrier penetrates into the different subgrades on eyeground further, thus realizes the multistage targeting to eyeground subgrade diseased region, solves drug bioavailability low, and the problems such as toxic side effect is big, significantly improve result for the treatment of;
2, the raw material sources that pharmaceutical carrier of the present invention can use are extensive, can load different medicines for different fundus oculi disease, have universality.
Accompanying drawing explanation
Fig. 1 is the different positive susceptance microsphere drug carrier of the lotus motion under electric microfield effect and distribution schematic diagram within the eye;
Fig. 2 be different charged NP prepare schematic diagram;
Fig. 3 is the scanning electron microscope (SEM) photograph of NP++;
Fig. 4 is the motion conditions under electric microfield effect simulated in vitro by the gel that the charged NP that NP--, NP-, NP0, NP+, NP++ are different is placed in dilution;
Fig. 5 a is body outer osmotic simulator schematic diagram;
Fig. 5 b is the quantitative data that different charged NP permeates individual layer RF/6A retinal endothelial cell;
Fig. 5 c is the laser co-focusing photo that different charged NP permeates individual layer RF/6A cell;
Fig. 5 d is that different charged NP is to the infiltration situation of isolated pig eyes retina;
Fig. 6 a be injection different charged NP(fluorescent mark) after in-vitro eyeball fluorescence imaging;
Fig. 6 b be different charged NP eye in the residence time;
The infiltration situation of the different charged NP of Fig. 6 c on eyeground;
Fig. 7 a is Fundus angiography picture;
Fig. 7 b choroidal neovascularization paving sheet;
Fig. 7 c choroidal neovascularization areal analysis;
Fig. 7 d treats rear intraocular pressure data.
Embodiment
The technical scheme of the present invention is described further below by way of embodiment, and described embodiment is only help to understand the present invention, it should not be considered as the concrete restriction to the present invention. As shown in Figure 1, be the different positive susceptance microsphere drug carrier of lotus within the eye the motion under electric microfield effect and distribution schematic diagram in theory, pharmaceutical carrier of the present invention is positively charged, it is possible to realize directed transhipment within the eye, after vitreous space is injected, it is enriched in eyeground under electric microfield effect within the eye; By regulating the carrying capacity of carrier, it is possible to regulation and control carrier penetrates into the different subgrades on eyeground further, thus realizes the multistage targeting to eyeground subgrade diseased region, solves drug bioavailability low, and the problems such as toxic side effect is big, significantly improve result for the treatment of. In theory, as long as the pharmaceutical carrier of positive charge all possess above-mentioned multistage target to potentiality, preparation method and material therefor are not limited to foregoing.
(1) a certain amount of oil soluble macromolecule dissolution is taken in methylene dichloride as oil phase, 1wt% polyvinyl alcohol (polyvinylalcohol, PVA) it is aqueous phase, O/W(oil-in-water is prepared after mixing) type emulsion, after stirred overnight at room temperature to methylene dichloride volatilizees, with distilled water centrifuge washing 5 times, can obtain receiving microballoon. Its oil-soluble polymer can be polylactic acid-based polymer, polyester polymer etc.; The method wherein preparing emulsion can be the technology by stirring, ultrasonic, homogenizing emulsifying or porous membrane emulsiilcation, it is preferable that can prepare the porous membrane emulsiilcation technology of an equal emulsion; Wherein receive the particle size range of microballoon in 1nm��10 ��m, it is contemplated that to small particle size, there is higher specific charge, be conducive to the motion in electric microfield, it is preferable that the nanometer ball (Nanoparticle, NP) of 10��500nm.
(2) above-mentioned obtained NP is suspended in the hydrophilic charged macromolecular solution of different concns, after vertical mixed outstanding instrument is hatched, polymer will be adsorbed on the NP of negative charge by electrostatic interaction, both must the NP of band positive charge in various degree with deionized water centrifuge washing. Wherein the polymer of positive charge can be chitosan, n-trimethyl chitosan chloride, polymine, polylysine etc.; Wherein carrier ranges of charge is at 0.1��200mv, it is preferable that 5-50mv, to take into account carrying capacity and biological safety.
(3) as a control group, (2) NP in can be suspended in the hydrophilic load electricity macromolecular solution of different concns further, after vertical mixed outstanding instrument is hatched, polymer is received on microballoon by what be adsorbed in positive charge by electrostatic interaction, namely obtains the NP of band negative charge in various degree with deionized water centrifuge washing. Negative charge polymer wherein can be using carboxyl chitosan, hyaluronic acid, polyglutamic acid etc.
(4) if medicine is hydrophobic drug, it is possible to directly in (1) step, medicine is dissolved in oil phase together with hydrophobic polymer and embeds; If medicine is hydrophilic medicament, it is possible to as interior aqueous phase after first dissolving, the form of multiple breast is adopted to carry out load, it is also possible to adsorb together with charged polymer in (2) or (3) step.
As shown in Figure 2, in order to prepare different charged NP, first electronegative NP is prepared with PLGA (PLGA), NP++ and NP+ of positive charge can be turned into by follow-up absorption n-trimethyl chitosan chloride (HTCC), can be turned into NP--and NP-of negative charge further by the Carboxymethyl chitosan (CMC) of absorption negative charge, carrying capacity can be regulated by the concentration of HTCC and CMC and substitution value.
As shown in Figure 3, for the charged NP++ prepared, scanning electron microscope display granule-morphology is complete, and particle diameter is about 150nm, and electric charge is+36.4mv after measured.
It is illustrated in figure 4 the gel that different charged NP is placed in dilution, simulate the motion conditions under electric microfield effect in vitro, wherein NP--, NP-, NP0, NP+, NP++ represent different charged situation, different charged NP motion conditions in electric microfield in simulated eye is investigated by agarose gel electrophoresis, positive charge NP can tend to negative pole motion in gel, negative charge NP then tends to positive polar motion, and migration distance and carried charge positive correlation. To present different motor behaviors under these results suggest that the effect of different charged NP electric microfield within the eye, positive charge NP more trend will be enriched in the eyeground of negative polarization.
Fig. 5 is the eyeground infiltration situation of different charged NP, as shown in Figure 5 a, for verifying the infiltration situation of different charged NP, establish body outer osmotic detection model: RF/6A is cultured on Transwell individual layer, then different charged NP(fluorescent marks is added), cell accesses 100mV voltage stabilizing electrode, cell upper strata insertion positive pole, lower floor's insertion negative pole, draw lower floor's nutrient solution in different time points and detect wherein fluorescent signal, calculate accumulation fluorescence intensity, thus react corresponding accumulation infiltration situation.
Being the quantitative data that different charged NP permeates individual layer RF/6A retinal endothelial cell as shown in Figure 5 b, after Ge Zu cell lower floor self administration of medication 1h, fluorescence intensity starts to produce difference, and along with time lengthening, difference increases gradually. Positively charged NP transmitance is far longer than the NP of band neutral charge and negative charge, and positive charge amount is more many, and osmotic effect is more good.
If Fig. 5 c is the laser co-focusing photo that different charged NP permeates individual layer RF/6A cell, in figure, light color is cytolemma, and further laser co-focusing picture display, can observe a large amount of positive charge NP in RF/6A cellular layer. Except being permeated by intracellular transport, these positive charges NP can also permeate through intercellular pathways. In order to distinguish obviously, in figure, NP indicates with arrow.
As fig 5d, different charged NP is to the infiltration situation of isolated pig eyes retina, wherein the Dark grey of ash color part is nucleus, light gray is NP, when electric microfield, the fresh pig retina peeled off is given and different charged NP, after 24h, copolymerization Jiao adopts XZY Mode scans retina, observes NP to the penetrating power of retina. Positively charged NP depth of penetration is far longer than the NP of band neutral charge and negative charge, and positive charge amount is more many, permeates more dark. In order to distinguish obviously, in figure, NP indicates with arrow.
Fig. 6 be different charged NP eye in distribution situation, such as Fig. 6 a and 6b, be respectively the different charged NP(fluorescent mark of injection) after in-vitro eyeball fluorescence imaging and residence time in the eye of difference charged NP charged for difference NP is entered in the big rathole of SD through vitreous space injection, utilize multifunctional active small animal imaging system, get different time and observe NP distribution situation within the eye, and fluorescence is carried out quantitatively. After free fluorescence molecule injection, signal is decayed fast, illustrates that eye intracellular metabolite is very fast; And NP preparation can stop the longer time within the eye, signal attenuation is slower. It is that different charged NP(arrow indicates as fig. 6 c) infiltration situation on eyeground, with laser co-focusing, the frozen section of eyeground layer is scanned further, positive charge NP group can more be enriched in eyeground; The NP+ that wherein carrying capacity is less can enter the neural retina internal layer in shallow portion, eyeground, is suitable for the treatment of the diseases such as retinal vein occlusion after load medicine; And the more NP++ of carrying capacity can enter that darker neural retina is outer and choroid layer, after load medicine, it is suitable for the treatment of the chorioido-retinal disorders such as polypoid choroidal artery sample pathology, age-related macular degeneration.
For evaluating the actual delivery medicine of NP and corresponding result for the treatment of, laser is utilized to avoid blood vessel slap shot retina apart from optic disk 1��2PD place around optic disk, every experimental eye slap shot 6��8 light condensation points, set up choroidal neovascularization (choroidalneovascularization, CNV) model. Based on different charged NP carrying medicament dexamethasone (DEX), CNV rat is carried out vitreous space injection, after two weeks, observe eyeground radiography. If Fig. 7 is that different charged NP loads dexamethasone and contrasts for the treatment situation of choroidal neovascularization model, as shown in Figure 7a, NP--, NP-and NP0 group light coagulates spot (arrow sign) obvious fluorescence seepage, in disk shape hyperfluorescenceZeng Yongminggaoyingguang; And the solidifying spot (arrow sign) of the light of NP+ and NP++ group is without obvious fluorescence seepage, in hypofluorescence. Choroid spreads sheet further observe (Fig. 7 b) and carry out accordingly quantitatively (Fig. 7 c), with NP--, NP-and NP0, the vessel density of positive charge group significantly reduces, and NP++ group owing to can be delivered to the CNV diseased region in deep, eyeground more accurately by medicine, and effect is also ideal; After treatment, rat intraocular pressure is also in normal level, illustrates that security is higher.
The foregoing is only the better embodiment of the present invention, not in order to limit the present invention, within the spirit and principles in the present invention all, any amendment of doing, equivalent replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (10)
1. the preparation method of the positive susceptance microsphere drug carrier of lotus, it is characterised in that, comprise the steps:
Step one, take a certain amount of oil soluble macromolecule dissolution in organic solvent as oil phase, after mixed with water, prepare emulsion oil-in-water;
Step 2, the emulsion oil-in-water of step one is at room temperature stirred spend the night to organic solvent volatilization complete, with distilled water centrifuge washing several times, obtain receiving microballoon;
Step 3, above-mentioned obtained microballoon of receiving is suspended in the wetting ability charged macromolecular solution of different concns, vertical mixed outstanding instrument is hatched, carries out positive charge modification;
Step 4, regulated the quantity of electric charge of microballoon by the substitution value of the concentration of polymer or electric charge group,
So far, the preparation of the positive susceptance microsphere drug carrier of lotus completes.
2. the preparation method of the positive susceptance microsphere drug carrier of lotus according to claim 1, it is characterised in that: when carrying out medicine embedding, if medicine is hydrophobic drug, then in step one, medicine is dissolved in oil phase together with oil soluble polymer and embeds; If medicine is hydrophilic medicament, then first it is dissolved as interior aqueous phase, then the form adopting multiple breast carries out load, or it is adsorbed on together with wetting ability charged polymer in step 3 and receives on microballoon.
3. the preparation method of the positive susceptance microsphere drug carrier of lotus according to claim 1, it is characterized in that, in described step one, the preparation method of emulsion oil-in-water is paddling process, ultrasonic method, the precipitator method, homogenizing emulsifying or porous membrane emulsiilcation method, it is preferable that can prepare the porous membrane emulsiilcation method of an equal emulsion.
4. the preparation method of the positive susceptance microsphere drug carrier of lotus according to claim 1, it is characterised in that, in described step 3, the electric charge modifying method of employing is absorption method or chemical coupling method.
5. the preparation method of the positive susceptance microsphere drug carrier of lotus according to claim 1, it is characterised in that: in described step one, oil soluble polymer is polylactic acid-based or polyester polymer.
6. the preparation method of the positive susceptance microsphere drug carrier of lotus according to claim 1, it is characterised in that: in described step 3, wetting ability charged polymer is chitosan, n-trimethyl chitosan chloride, polymine or polylysine.
7. the positive susceptance microsphere drug carrier of lotus, it is characterised in that: it utilizes the preparation of the method described in claim 1��6 any one to be formed, and particle size range is 1nm��10 ��m, it is preferable that 10nm��500nm; Ranges of charge is 0.1��200mv, it is preferable that 5��50mv.
8. the positive susceptance microsphere drug carrier of lotus according to right 7 is as the application of the directed transport vehicle of ophthalmic disease medicine for treatment thing.
9. the positive susceptance microsphere drug carrier of lotus according to claim 7 is as the application of the directed transport vehicle of ophthalmic disease medicine for treatment thing, it is characterised in that: described ophthalmic disease is age-related macular degeneration, diabetic retinopathy, retinal vein occlusion, retinopathy of prematurity change, cytomegaloviral retinitis or acute retinal necrosis.
10. the positive susceptance microsphere drug carrier of lotus according to claim 8 or claim 9 is as the application of the directed transport vehicle of ophthalmic disease medicine for treatment thing, it is characterised in that: described ophthalmic disease medicine for treatment thing is one or more couplings wherein such as small-molecule chemical medicine, protein and peptide class medicine, antibody drug or genomic medicine.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112353752A (en) * | 2020-09-29 | 2021-02-12 | 丽水学院 | Light-driven drug delivery system for optic nerve recovery and preparation method and application thereof |
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| CN1903365A (en) * | 2005-07-28 | 2007-01-31 | 中国医学科学院生物医学工程研究所 | Drug-carried nanometer particles, and its preparing process for preparing medicien prepn. for anti-restenosis of blood-vessel |
| CN104001178A (en) * | 2014-05-19 | 2014-08-27 | 中山大学 | Polylactic acid-hydroxyacetic acid copolymer nano-drug carrier as well as preparation method and application thereof |
| CN104548210A (en) * | 2014-12-13 | 2015-04-29 | 浙江大学 | Controlled-release PLGA microsphere containing dexamethasone transforming growth factor and preparation method of controlled-release PLGA microsphere |
| CN104739783A (en) * | 2015-04-14 | 2015-07-01 | 南京林业大学 | Preparation method and product of biodegradable polylactic acid-hydroxyacetic acid copolymer/chitosan drug carrying microsphere |
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| CN1903365A (en) * | 2005-07-28 | 2007-01-31 | 中国医学科学院生物医学工程研究所 | Drug-carried nanometer particles, and its preparing process for preparing medicien prepn. for anti-restenosis of blood-vessel |
| CN104001178A (en) * | 2014-05-19 | 2014-08-27 | 中山大学 | Polylactic acid-hydroxyacetic acid copolymer nano-drug carrier as well as preparation method and application thereof |
| CN104548210A (en) * | 2014-12-13 | 2015-04-29 | 浙江大学 | Controlled-release PLGA microsphere containing dexamethasone transforming growth factor and preparation method of controlled-release PLGA microsphere |
| CN104739783A (en) * | 2015-04-14 | 2015-07-01 | 南京林业大学 | Preparation method and product of biodegradable polylactic acid-hydroxyacetic acid copolymer/chitosan drug carrying microsphere |
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| CN112353752A (en) * | 2020-09-29 | 2021-02-12 | 丽水学院 | Light-driven drug delivery system for optic nerve recovery and preparation method and application thereof |
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