CN103550223A - Novel application of eye medicine wrapped with erythrocyte membrane - Google Patents
Novel application of eye medicine wrapped with erythrocyte membrane Download PDFInfo
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- CN103550223A CN103550223A CN201310520788.4A CN201310520788A CN103550223A CN 103550223 A CN103550223 A CN 103550223A CN 201310520788 A CN201310520788 A CN 201310520788A CN 103550223 A CN103550223 A CN 103550223A
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Abstract
The invention provides application of an eye medicine wrapped with an erythrocyte membrane in preparation of an eye preparation, and also provides the eye preparation. The preparation is in a form of biodegradable nano particles wrapped with the erythrocyte membrane. The preparation has the advantages that the shortcomings of the traditional eye drops that partial removal is quickly realized, the bioavailability is low, the eye drops are absorbed by the whole body, and the side effect is difficult to avoid, are overcome; the time of the medicine standing in eyes is obviously prolonged; the controlled-released administration of the medicine is realized. Therefore, the bioavailability of the medicine is improved, the side effect on the whole body is reduced, and a new hope is brought to clinical ophthalmology on treatment of intraocular diseases.
Description
Technical field
The purposes of the eye medicinal that the present invention relates to erythrocyte membrane parcel in preparing ophthalmic preparation.
Background technology
Latanoprost, is the alternative propyl diester prostatitis element F2a of a kind of novel phenyl, is selectivity F2a receptor stimulating agent.Latanoprost is hydrolyzed to free acid in cornea, and this free acid diffuses out and enters room from cornea, and about 2h can reach blood medicine peak value.After 3～4h, intraocular pressure starts to decline, and 8～12h reaches maximum fall, has good intraocular pressure lowering effect, can maintain 24h intraocular pressure and not raise, and needs put drops in one's eyes once every day.
Bimatoprost, also for reducing not tolerating other ocular hypotensive agents or the open angle glaucoma of responsive not (repeatedly medication cannot reach target intraocular pressure value) and the intraocular pressure of ocular hypertension, this medicine still need every day eye drip once.
As can be seen here, above-mentioned each medicine all needs medication every day, and for the patient who needs long-term prescription, it is convenient not to use.In at present known slow releasing preparation, drug treating time is the longest only can be maintained about 10 days.If can prepare the slow-releasing prolonged action drug of slow release ingredient, can alleviate the inconvenience of this successive administration.
Summary of the invention
The object of the present invention is to provide eye medicinal of a kind of erythrocyte membrane parcel and uses thereof.
The purposes of the eye medicinal that the invention provides erythrocyte membrane parcel in preparing ophthalmic preparation.
Further, the preparation method of the eye medicinal of described erythrocyte membrane parcel is as follows:
(1) get eye medicinal, add macromolecular material, prepare nanoparticle;
(2) get erythrocyte membrane and nanoparticle and mix, then be pressed through nano-porous films, obtain the eye medicinal of erythrocyte membrane parcel.
Further, described macromolecular material is selected from a kind of in PCL, PLGA, PLA, PLA-PEG, chitosan, gelatin; Described macromolecular material can be preferably PCL or PLGA.
Further, in step (1), adopt coacervation, emulsion polymerization method, intra-liquid desiccation method, automatic emulsified method or polymer micelle legal system for nanoparticle; Can preferably adopt automatic emulsified legal system for nanoparticle.
Further, in step (2), the aperture of described nano-porous films is 300～500nm, is preferably 400nm.
Further, described eye medicinal is that latanoprost is or/and Bimatoprost.
Further, described ophthalmic preparation is eye injection.
Further, described eye is intravitreal injection liquid with injection.
Further, described ophthalmic preparation is the ophthalmic preparation for the treatment of glaucoma or reduction intraocular pressure.
The present invention also provides a kind of long-acting ophthalmic preparation, and it is to take latanoprost or/and Bimatoprost is active component, adopts with the following method and prepares:
(1) get latanoprost or/and Bimatoprost adds macromolecular material, prepare nanoparticle;
(2) get erythrocyte membrane and nanoparticle and mix, then be pressed through nano-porous films, obtain long-acting ophthalmic preparation.
Described macromolecular material is selected from a kind of in PCL, PLGA, PLA, PLA-PEG, chitosan, gelatin; Described macromolecular material can be preferably PCL or PLGA.
Further, described macromolecular material is PCL, and the mass ratio of latanoprost or Bimatoprost and PCL is 0.4～0.5:4;
Or described macromolecular material is PLGA, the mass ratio of latanoprost or Bimatoprost and PLGA is 0.4～0.5:1.
The present invention is surprised to find that, adopt the medicament nano granule of erythrocyte membrane parcel, be injected in sustainable reducing iop in vitreous body and be 4 weeks, obviously be longer than existing various slow release or controlled release preparation its action time within the eye, and other use position, illustrate that the present invention is used for ophthalmic preparation by the medicament nano granule of erythrocyte membrane parcel, has played unexpected technique effect.
Preparation of the present invention, with erythrocyte membrane, wrap up biodegradable nano-particle, overcome the shortcoming that the local removing of traditional eye drop is fast, bioavailability is low and systemic Absorption side effect is difficult to avoid, significant prolongation the medicine time of staying within the eye, realized target controlling and releasing administration, and then improve the bioavailability of medicine, reduce systemic side effects, for the treatment of ophthalmic in clinical ophthalmology provides new hope.
Accompanying drawing explanation
The transmission electron microscope picture of Fig. 1 ophthalmic preparation is the PCL nanoparticle being wrapped up by erythrocyte membrane of a 200nm left and right size shown in figure; This particle is osmic acid negative staining, observes (TEM) under transmission electron microscope
Fig. 2 latanoprost eye drop and normal saline matched group comparison diagram
Fig. 3 medicine of the present invention and blank PCL nano-carrier intraocular pressure lowering comparison diagram (in 192 hours), A-medicine of the present invention, the blank PCL nano-carrier of B-;
Fig. 4 medicine of the present invention and blank PCL nano-carrier intraocular pressure lowering comparison diagram (7 to 30 days), A-medicine of the present invention, the blank PCL nano-carrier of B-;
Fig. 5 latanoprost nanoparticle and blank PCL nano-carrier intraocular pressure lowering comparison diagram, A-latanoprost nanoparticle, the blank PCL nano-carrier of B-
The specific embodiment
Latanoprost-PCL nanoparticle of embodiment 1 erythrocyte membrane parcel
Adopt emulsion process to prepare latanoprost-polycaprolactone (PCL) nanoparticle
Concrete grammar is: the latanoprost of 440ug is dissolved in containing in the chloroform of 4 milligrams of PCL alcoholic solution.After mixture supersound process, be emulsified in the water of 2 milliliters of polyvinyl alcohol (PVA) that contain 0.25% (wt/wt).In organic solvent, spend the night after evaporation, residue cleans in Amicon100k MWCO wave filter, removes after PVA, obtains PCL nanoparticle, and dynamic light scattering detects size and the dispersibility of PCL particle.
The nanoparticle of getting erythrocyte membrane and above-mentioned preparation is mixed; again mixture is pressed through to the perforated membrane of 400 nanometers; consequent granule is latanoprost-PCL nanoparticle of erythrocyte membrane parcel, its average diameter 350 nanosizeds (transmission electron microscope picture is shown in Fig. 1).
The preparation method of nanoparticle in the present invention, also can adopt coacervation, emulsion polymerization method, intra-liquid desiccation method or polymer micelle method.Its concrete operation method can be referring to existing document or books, as < < pharmaceutics > Cui > Ford, 2008 the 6th edition, P414～416.Certainly, the preparation method of nanoparticle is not limited to above-mentioned several method, and all use known methods are prepared nanoparticle, are all applicable to the present invention.Erythrocyte membrane can adopt prior art to prepare.
Latanoprost-PLGA nanoparticle of embodiment 2 erythrocyte membrane parcels
Adopt emulsion process to prepare latanoprost-polycaprolactone (PLGA) nanoparticle
Concrete grammar is:
First PLGA polymer is dissolved in to acetone with 1 mg/ml concentration, getting latanoprost is dissolved in PLGA solution with 1mM, again 1 ml soln is dropwise added in 3 ml waters, gained mixture is exposed in air and stirs 2 hours, centrifugal or filter after, get final product to obtain latanoprost PLGA nanoparticle.
The nanoparticle of getting erythrocyte membrane and above-mentioned preparation is mixed, then mixture is pressed through to the perforated membrane of 400 nanometers, and consequent granule is latanoprost-PLGA nanoparticle of erythrocyte membrane parcel.
By test example, illustrate beneficial effect of the present invention below.
Test example 1
1, trial drug
(1) medicine of the present invention
Latanoprost-PCL nanoparticle of the erythrocyte membrane parcel of the embodiment of the present invention 1 preparation, by emulsifying technology, estimate at 50% drug pack efficiency, the nanoparticle of making is pressed to every part of latanoprost portioning that loads 8.3ug, then press sucrose concentration 5% (wt/ weight) interpolation sucrose, subsequently lyophilizing for every part.By the latanoprost drug level of every part of 8.3ug, 100uL solution can reach 200uM, and during preparation 50uM concentration solution, every part of need are diluted in 400uL.
(2) blank group, the blank PCL nanoparticulate carriers identical with drug level of the present invention
(3) latanoprost eye drop, purchased from commercially available prod
(4) latanoprost PLGA nanoparticle, with reference to embodiment 2 method preparations, and presses (1) below legal system for the test liquid of same concentrations
2, test method
Adult SD rats is accepted Local eye drop medicine by training, and tonometry is carried out in adaptation under waking state.Experiment adopts anterior chamber's perfusion to set up chmice acute Ocular hypertensive model, adopts TONO-LAB tonometer, measures for three days on end bilateral intraocular pressure every day, averages as basic intraocular pressure.Normal SD rats is divided into 4 groups: (1) first group, and 200uM latanoprost eye drip, 1 times/day, after measure dripping 24h before medicine and dripping medicine 1,2,4,6,8, the intraocular pressure of 24h; (2) second groups, normal saline eye drip in contrast, after measure dripping 24h before medicine and dripping medicine 1,2,4,6,8, the intraocular pressure of 24h; (3) the 3rd groups, intravitreal medicine of the present invention, injects and measures 3 times intraocular pressure rear every day; (4) the 4th groups, the blank PCL nano-carrier (200uM) of intravitreal same concentrations is as blank group, and after injection, measure intraocular pressure every day 3 times, to bilateral intraocular pressure, recovers normal, and observe local response and the general reaction of eye.(5) the 5th groups, the latanoprost PLGA nanoparticle (200uM) of intravitreal same concentrations, measures intraocular pressure every day 3 times, observes its action time.
3, experimental result
3.1 latanoprost eye drips and the contrast of normal saline group
After latanoprost 200uM partial points ocular administration, a hour intraocular pressure starts to decline, slightly lower than normal saline matched group.After administration four hour, record obvious decrease of IOP, △ IOP=2.42 ± 0.65mmHg, some ocular administration intraocular pressure lowering effect probably may persist to about 24 hours and (refers to Fig. 2).
3.2 intravitreal medicine of the present invention and the contrast of blank PCL nano-carrier
After latanoprost-PCL nanoparticle of intravitreal 200uM erythrocyte membrane parcel, within 20 hours, occur minimum, recording intraocular pressure is 9.53 ± 0.56mmHg, reduces by 3.57 ± 0.45mmHg, observes 192 hours, keeps continuing to reduce (referring to Fig. 3).
Extend test period to January, still have good reducing iop (referring to Fig. 4), show the latanoprost nanoparticle of erythrocyte membrane parcel, reduce intraocular pressure and be 4 weeks.
3.3 latanoprost PLGA nanoparticles
When only using PLGA nanoparticle load latanoprost, do not adopt erythrocyte membrane when parcel, only can extend about intraocular pressure lowering effect to 7 day (referring to Fig. 5).
Brief summary:
From above-mentioned test, adopt the latanoprost nanoparticle of erythrocyte membrane parcel, can the significant prolongation time of staying within the eye, duration of efficacy is unexpectedly increased to 4 weeks, be more better than nanoparticle and ordinary eye drops.
Preparation of the present invention, with erythrocyte membrane, wrap up biodegradable nanoparticle, overcome the shortcoming that the local removing of traditional eye drop is fast, bioavailability is low and systemic Absorption side effect is difficult to avoid, significant prolongation the medicine time of staying within the eye, realized target controlling and releasing administration, and then improve the bioavailability of medicine, reduce systemic side effects, for the treatment of ophthalmic in clinical ophthalmology provides new hope.
Claims (10)
1. the purposes of the eye medicinal that erythrocyte membrane wraps up in preparing ophthalmic preparation.
2. purposes according to claim 1, is characterized in that: the preparation method of the eye medicinal of described erythrocyte membrane parcel is as follows:
(1) get eye medicinal, add macromolecular material, prepare nanoparticle;
(2) get erythrocyte membrane and nanoparticle and mix, then be pressed through nano-porous films, obtain the eye medicinal of erythrocyte membrane parcel.
3. purposes according to claim 2, is characterized in that: described macromolecular material is selected from a kind of in PCL, PLGA, PLA, PLA-PEG, chitosan, gelatin; Be preferably PCL or PLGA.
4. purposes according to claim 2, is characterized in that: in step (1), adopt coacervation, emulsion polymerization method, intra-liquid desiccation method, automatic emulsified method or polymer micelle legal system for nanoparticle; Preferably adopt automatic emulsified method.
5. purposes according to claim 2, is characterized in that: in step (2), the aperture of described nano-porous films is 300～500nm, is preferably 400nm.
6. according to the purposes described in claim 1～5 any one, it is characterized in that: described eye medicinal is that latanoprost is or/and Bimatoprost.
7. according to the purposes described in claim 1～5 any one, it is characterized in that: described ophthalmic preparation is eye injection; Preferably, eye is intravitreal injection liquid with injection.
8. according to the purposes described in claim 1～7 any one, it is characterized in that: described ophthalmic preparation is the ophthalmic preparation for the treatment of glaucoma or reduction intraocular pressure.
9. a long-acting ophthalmic preparation, is characterized in that: it is to take latanoprost or/and Bimatoprost is active component, adopts with the following method and prepares:
(1) get latanoprost or/and Bimatoprost adds macromolecular material, prepare nanoparticle;
(2) get erythrocyte membrane and nanoparticle and mix, then be pressed through nano-porous films, obtain long-acting ophthalmic preparation.
10. long-acting ophthalmic preparation according to claim 9, is characterized in that: described macromolecular material is PCL, and the mass ratio of latanoprost or Bimatoprost and PCL is 0.4～0.5:4;
Or described macromolecular material is PLGA, the mass ratio of latanoprost or Bimatoprost and PLGA is 0.4～0.5:1.
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Cited By (11)
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| CN105769818A (en) * | 2016-03-16 | 2016-07-20 | 华东师范大学 | Antibody nanoparticles coated by red cell membranes for antibody drug delivery and preparation method |
| CN106924755A (en) * | 2015-12-31 | 2017-07-07 | 复旦大学 | The bionic nano particle and preparation method of a kind of Polymorphonuclear Leukocytes Membrane cladding of activation |
| CN106943378A (en) * | 2017-02-16 | 2017-07-14 | 上海交通大学 | Erythrocyte membrane encapsulating polyesters carry arsenic trioxide nanoparticle and preparation method thereof |
| CN107014931A (en) * | 2017-03-07 | 2017-08-04 | 浙江省立同德医院 | A kind of film modified nano carbon microsphere material of cell and its preparation method and application |
| CN108113977A (en) * | 2018-01-25 | 2018-06-05 | 上海交通大学 | A kind of gelatin of erythrocyte membrane encapsulating carries the preparation method and applications of Berberine hydrochloride nanoparticle |
| CN108355139A (en) * | 2018-03-28 | 2018-08-03 | 河南大学 | A kind of bionical acid-sensitive Nano medication and its preparation and application method |
| CN108836949A (en) * | 2018-07-23 | 2018-11-20 | 西南大学 | The preparation method of Ce6 embedded type erythrocyte membrane package prussian blue nano particle |
| CN109394733A (en) * | 2018-12-14 | 2019-03-01 | 上海交通大学 | Tetrandrine PLGA nanoparticle of a kind of erythrocyte membrane encapsulating and preparation method thereof and its application |
| CN111228520A (en) * | 2020-01-19 | 2020-06-05 | 东华大学 | Cell membrane coated ultra-small ferroferric oxide nanocluster and preparation and application thereof |
| CN112656763A (en) * | 2020-12-29 | 2021-04-16 | 吉林大学 | Preparation method of drug-loaded nano-micelle based on shear force response |
| CN113133988A (en) * | 2021-04-26 | 2021-07-20 | 西南医科大学附属医院 | Novel kidney-targeted nano drug delivery system subjected to biomimetic modification of erythrocyte membrane, preparation method and application |
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| CN106924755A (en) * | 2015-12-31 | 2017-07-07 | 复旦大学 | The bionic nano particle and preparation method of a kind of Polymorphonuclear Leukocytes Membrane cladding of activation |
| CN106924755B (en) * | 2015-12-31 | 2020-06-09 | 复旦大学 | Activated neutral particle cell membrane coated bionic nano particle and preparation method thereof |
| CN105769818B (en) * | 2016-03-16 | 2019-03-01 | 华东师范大学 | The antibody nanoparticle and preparation method of erythrocyte membrane package for antibody drug delivering |
| CN105769818A (en) * | 2016-03-16 | 2016-07-20 | 华东师范大学 | Antibody nanoparticles coated by red cell membranes for antibody drug delivery and preparation method |
| CN106943378A (en) * | 2017-02-16 | 2017-07-14 | 上海交通大学 | Erythrocyte membrane encapsulating polyesters carry arsenic trioxide nanoparticle and preparation method thereof |
| CN106943378B (en) * | 2017-02-16 | 2020-09-15 | 上海交通大学 | Erythrocyte membrane encapsulated polyester arsenic trioxide-loaded nanoparticle and preparation method thereof |
| CN107014931A (en) * | 2017-03-07 | 2017-08-04 | 浙江省立同德医院 | A kind of film modified nano carbon microsphere material of cell and its preparation method and application |
| CN108113977A (en) * | 2018-01-25 | 2018-06-05 | 上海交通大学 | A kind of gelatin of erythrocyte membrane encapsulating carries the preparation method and applications of Berberine hydrochloride nanoparticle |
| CN108355139A (en) * | 2018-03-28 | 2018-08-03 | 河南大学 | A kind of bionical acid-sensitive Nano medication and its preparation and application method |
| CN108355139B (en) * | 2018-03-28 | 2020-12-18 | 河南大学 | Bionic acid-sensitive nano-drug and preparation and application method thereof |
| CN108836949A (en) * | 2018-07-23 | 2018-11-20 | 西南大学 | The preparation method of Ce6 embedded type erythrocyte membrane package prussian blue nano particle |
| CN108836949B (en) * | 2018-07-23 | 2020-07-24 | 西南大学 | Preparation method of Prussian blue nano-particles wrapped by Ce6 embedded red cell membranes |
| CN109394733A (en) * | 2018-12-14 | 2019-03-01 | 上海交通大学 | Tetrandrine PLGA nanoparticle of a kind of erythrocyte membrane encapsulating and preparation method thereof and its application |
| CN111228520A (en) * | 2020-01-19 | 2020-06-05 | 东华大学 | Cell membrane coated ultra-small ferroferric oxide nanocluster and preparation and application thereof |
| CN111228520B (en) * | 2020-01-19 | 2021-04-02 | 东华大学 | Cell membrane coated ultra-small ferroferric oxide nanocluster and preparation and application thereof |
| CN112656763A (en) * | 2020-12-29 | 2021-04-16 | 吉林大学 | Preparation method of drug-loaded nano-micelle based on shear force response |
| CN112656763B (en) * | 2020-12-29 | 2022-07-15 | 吉林大学 | Preparation method of drug-loaded nano-micelle based on shear force response |
| CN113133988A (en) * | 2021-04-26 | 2021-07-20 | 西南医科大学附属医院 | Novel kidney-targeted nano drug delivery system subjected to biomimetic modification of erythrocyte membrane, preparation method and application |
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