CN103550223B - The purposes of the eye medicinal of erythrocyte membrane parcel - Google Patents
The purposes of the eye medicinal of erythrocyte membrane parcel Download PDFInfo
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- CN103550223B CN103550223B CN201310520788.4A CN201310520788A CN103550223B CN 103550223 B CN103550223 B CN 103550223B CN 201310520788 A CN201310520788 A CN 201310520788A CN 103550223 B CN103550223 B CN 103550223B
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- latanoprost
- erythrocyte membrane
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Abstract
The eye medicinal that the invention provides erythrocyte membrane parcel is preparing the purposes in ophthalmic preparation.Present invention also offers a kind of ophthalmic preparation.Invention formulation, that erythrocyte membrane wraps up biodegradable nano-particle, said preparation overcome traditional eye drop local remove fast, bioavailability is low and systemic Absorption side effect is difficult to the shortcoming avoided, significant prolongation medicine time of staying within the eye, achieve target controlling and releasing administration, and then improve the bioavailability of medicine, reduce systemic side effects, in clinical ophthalmology, the treatment of ophthalmic provides new hope.
Description
Technical field
The eye medicinal that the present invention relates to erythrocyte membrane parcel is preparing the purposes in ophthalmic preparation.
Background technology
Latanoprost, being the propyl diester prostatitis element F2a that a kind of novel phenyl substitutes, is selectivity F2a receptor stimulating agent.Latanoprost is hydrolyzed to free acid in cornea, and this free acid diffuses out from cornea and enters room, 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, need put drops in one's eyes once every day.
Bimatoprost, also for reducing not tolerating other ocular hypotensive agents or the responsive not open angle glaucoma of (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 needing long-term prescription, it is convenient not to use.In slow releasing preparation known at present, drug treating time is the longest only can maintain about 10 days.If the slow-releasing prolonged action drug of slow releasing ingredient can be prepared, then can alleviate the inconvenience of this successive administration.
Summary of the invention
Eye medicinal that the object of the present invention is to provide a kind of erythrocyte membrane to wrap up and uses thereof.
The eye medicinal that the invention provides erythrocyte membrane parcel is preparing the purposes in 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 mixing, then be pressed through nano-porous films, obtain the eye medicinal of erythrocyte membrane parcel.
Further, described macromolecular material is selected from the one 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 injection is intravitreal injection liquid.
Further, described ophthalmic preparation is treatment glaucoma or the ophthalmic preparation reducing intraocular pressure.
Present invention also offers a kind of long-acting ophthalmic preparation, it is with latanoprost or/and Bimatoprost is active component, adopts and prepares with the following method:
(1) get latanoprost or/and Bimatoprost, add macromolecular material, prepare nanoparticle;
(2) get erythrocyte membrane and nanoparticle mixing, then be pressed through nano-porous films, obtain long-acting ophthalmic preparation.
Described macromolecular material is selected from the one 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, its action time within the eye is obviously longer than existing various slow release or controlled release preparation, and other use position, illustrate that the medicament nano granule that erythrocyte membrane wraps up is used for ophthalmic preparation by the present invention, serve unexpected technique effect.
Invention formulation, biodegradable nano-particle is wrapped up with erythrocyte membrane, overcome traditional eye drop local remove fast, bioavailability is low and systemic Absorption side effect is difficult to the shortcoming avoided, significant prolongation medicine time of staying within the eye, achieve target controlling and releasing administration, and then improve the bioavailability of medicine, reduce systemic side effects, in clinical ophthalmology, the treatment of ophthalmic provides new hope.
Accompanying drawing explanation
The transmission electron microscope picture of Fig. 1 ophthalmic preparation is the PCL nanoparticle wrapped up by erythrocyte membrane of about a 200nm size shown in figure; This particle is osmic acid negative staining, under transmission electron microscope, observe (TEM)
Fig. 2 latanoprost eye drops and saline control 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-
Detailed description of the invention
Latanoprost-PCL the nanoparticle of embodiment 1 erythrocyte membrane parcel
Emulsion process is adopted to prepare latanoprost-polycaprolactone (PCL) nanoparticle
Concrete grammar is: the latanoprost of 440ug is dissolved in the chloroform containing 4 milligrams of PCL alcoholic solution.Be emulsified in after mixture supersound process in the water of the polyvinyl alcohol (PVA) 2 milliliters containing 0.25% (wt/wt).Spend the night in organic solvent after evaporation, residue cleans in Amicon100k MWCO wave filter, after removing PVA, obtains PCL nanoparticle, and dynamic light scattering detects size and the dispersibility of PCL particle.
The nanoparticle getting erythrocyte membrane and above-mentioned preparation mixes; again mixture is pressed through the perforated membrane of 400 nanometers; consequent granule is the latanoprost-PCL nanoparticle of erythrocyte membrane parcel, its average diameter 350 nanosized (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 see existing document or books, as " pharmaceutics " Cui Fude, 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 prepare nanoparticle, are all applicable to the present invention.Erythrocyte membrane can adopt prior art to prepare.
Latanoprost-PLGA the nanoparticle of embodiment 2 erythrocyte membrane parcel
Emulsion process is adopted to prepare latanoprost-polycaprolactone (PLGA) nanoparticle
Concrete grammar is:
First PLGA polymer is dissolved in 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, latanoprost PLGA nanoparticle.
The nanoparticle getting erythrocyte membrane and above-mentioned preparation mixes, then mixture is pressed through the perforated membrane of 400 nanometers, and consequent granule is the latanoprost-PLGA nanoparticle of erythrocyte membrane parcel.
Beneficial effect of the present invention is illustrated below by way of test example.
Test example 1
1, trial drug
(1) medicine of the present invention
Latanoprost-PCL the nanoparticle of erythrocyte membrane parcel prepared by the embodiment of the present invention 1,50% drug encapsulation efficacy is estimated at by emulsifying technology, the nanoparticle made is loaded the latanoprost portioning of 8.3ug by every part, then every part is added sucrose, lyophilizing subsequently by sucrose concentration 5% (wt/ weight).By the latanoprost drug level of every part of 8.3ug, 100uL solution can reach 200uM, and during preparation 50uM strength 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 drops, purchased from commercially available prod
(4) latanoprost PLGA nanoparticle, with reference to the preparation of embodiment 2 method, and by the test liquid of legal system below (1) item for same concentrations
2, test method
Adult SD rats is accepted Local eye drop medicine by training, and adapts to carry out tonometry under waking state.Experiment adopts reverse headgear method to set up chmice acute Ocular hypertensive model, adopts TONO-LAB tonometer, measures bilateral intraocular pressure every day for three days on end, intraocular pressure based on averaging.Normal SD rats is divided into 4 groups: (1) first group, 200uM latanoprost eye drip, 1 times/day, measure drip 24h before medicine and after dripping medicine 1,2,4,6,8, the intraocular pressure of 24h; (2) second groups, normal saline eye drip in contrast, measure drip 24h before medicine and after dripping medicine 1,2,4,6,8, the intraocular pressure of 24h; (3) the 3rd groups, intravitreal medicine of the present invention, after injection, every day measures 3 intraocular pressures; (4) the 4th groups, the blank PCL nano-carrier (200uM) of intravitreal same concentrations is as blank group, and after injection, every day measures 3 intraocular pressures, recovers normal, and observe local response and the general reaction of eye to bilateral intraocular pressure.(5) the 5th groups, the latanoprost PLGA nanoparticle (200uM) of intravitreal same concentrations, measures 3 intraocular pressures every day, 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 saline control 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 24 hours (referring to Fig. 2).
3.2 intravitreal medicine of the present invention and the contrast of blank PCL nano-carrier
After the 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 that erythrocyte membrane wraps up, reduce intraocular pressure and be 4 weeks.
3.3 latanoprost PLGA nanoparticles
When only using PLGA nanoparticle load latanoprost, when not adopting erythrocyte membrane to wrap up, only can extend (referring to Fig. 5) about intraocular pressure lowering effect to 7 day.
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, is more better than nanoparticle and ordinary eye drops.
Invention formulation, biodegradable nanoparticle is wrapped up with erythrocyte membrane, overcome traditional eye drop local remove fast, bioavailability is low and systemic Absorption side effect is difficult to the shortcoming avoided, significant prolongation medicine time of staying within the eye, achieve target controlling and releasing administration, and then improve the bioavailability of medicine, reduce systemic side effects, in clinical ophthalmology, the treatment of ophthalmic provides new hope.
Claims (1)
1. a long-acting ophthalmic preparation, is characterized in that: it is with latanoprost or/and Bimatoprost is active component, adopts and prepares with the following method:
(1) get latanoprost or/and Bimatoprost, add macromolecular material, prepare nanoparticle;
(2) get erythrocyte membrane and nanoparticle mixing, then be pressed through nano-porous films; The aperture of described nano-porous films is 300 ~ 500nm, obtains long-acting ophthalmic preparation;
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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| 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 |
| 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 |
| CN107014931B (en) * | 2017-03-07 | 2019-11-08 | 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 |
| CN108113977B (en) * | 2018-01-25 | 2020-06-16 | 上海交通大学 | Preparation method and application of gelatin-loaded berberine hydrochloride nanoparticles encapsulated by erythrocyte membranes |
| CN108355139B (en) * | 2018-03-28 | 2020-12-18 | 河南大学 | Bionic acid-sensitive nano-drug and preparation and application method thereof |
| 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 |
| 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 |
| CN112656763B (en) * | 2020-12-29 | 2022-07-15 | 吉林大学 | Preparation method of drug-loaded nano-micelle based on shear force response |
| CN113133988B (en) * | 2021-04-26 | 2023-04-07 | 西南医科大学附属医院 | Erythrocyte membrane biomimetic-modified kidney-targeted nano drug-loading system, preparation method and application |
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Address after: Moon Road, Science City high tech Industrial Development Zone of Guangzhou City, Guangdong province 510730 No. 3 Guangzhou international business incubator F F616. Patentee after: GUANGZHOU KANGRUI BIOLOGICAL PHARMACEUTICAL TECHNOLOGY Co.,Ltd. Address before: 510663 Guangdong city of Guangzhou province high tech Industrial Development Zone of Guangzhou city science and technology innovation base on Road No. 80 A District second floor Patentee before: GUANGZHOU KANG RUI BIOLOGICAL PHARMACEUTICAL TECHNOLOGY Co.,Ltd. |
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