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Ophthalmic liposome capable of penetrating cornea and targeting retina, preparation method and application thereof

An ophthalmic liposome and liposome technology, which is applied in the field of medicine, can solve the problems of not being able to effectively improve the fluidity of the vitreous body and targeting the retina, poor fluidity of the unimproved carrier, and large eye irritation, etc., to achieve Strengthen the corneal penetration effect, improve medication compliance, and increase the penetration effect

Active Publication Date: 2021-07-27
GUANGZHOU OCUSUN OPHTHALMIC BIOTECHNOLOGY CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Patent CN201510749931.6, literature (Yongchao C, Ning C, Huajun Y, et al. Topical ocular delivery to laser-induced choroidal neovascularization by dual internalizing RGD and TAT peptide-modified nanoparticles[J]. International Journal of Nanomedicine, 2017, 12: 1353-1368.doi:10.2147 / IJN.S126865), (Yang X, Wang L, Li L, et al. A novel dendrimer-based complex co-modified with cyclic RGD hexapeptide and penetratin for noninvasive targeting and penetration of the ocular posterior segment [J].DrugDelivery,2019,26(1):989-1001.doi:10.1080 / 10717544.2019.1667455)(Liu C,JiangK,Tai L,et al.Facile Noninvasive Retinal Gene Delivery Enabled byPenetratin.ACS Appl Mater Interfaces. 2016; 8(30):19256-19267.doi:10.1021 / acsami.6b04551) Co-modification of RGD and cell-penetrating peptide CPP on dendrimers PAMAM and PLGA nanoparticles to treat posterior ocular neovascularization, but dendritic polymerization The drug PAMAM has high eye irritation and high toxicity, and is not suitable for ocular administration, and the drug delivery system has not improved the problem of poor fluidity of the carrier in the vitreous. Compared with the free drug solution, the double-modified drug-loaded nanoparticles only improved about 4 times the drug concentration
[0009] In addition, literature (Tai L, Liu C, Jiang K, et al.A novel penetratin-modified complex for noninvasive intraocular delivery of antisense oligonucleotides[J].International Journal of Pharmaceutics,2017:347-356.doi:10.1016 / j.ijpharm .2017.06.090) successively coated hyaluronic acid and Penetratin on the surface of PAMAM through electrostatic adsorption to improve the ocular biocompatibility and permeability of PAMAM, and found that the distribution and retention time of the complex in the posterior segment of the eye increased, but the hyaluronic Acid is encapsulated inside Penetratin, which cannot effectively improve vitreous fluidity and retinal targeting
[0010] At present, there is no report of a liposome loaded with anti-VEGF drug and connected with cell-penetrating peptide CPP and hyaluronic acid HA on the surface for topical eye drops to treat posterior eye diseases

Method used

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  • Ophthalmic liposome capable of penetrating cornea and targeting retina, preparation method and application thereof
  • Ophthalmic liposome capable of penetrating cornea and targeting retina, preparation method and application thereof
  • Ophthalmic liposome capable of penetrating cornea and targeting retina, preparation method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] 1. Preparation of liposomes

[0048] (1) Link DSPE-PEG-Mal with cell penetrating peptide CPP by addition reaction.

[0049] The cell penetrating peptide CPP was synthesized by Shanghai Qiangyao Biotechnology Co., Ltd., and CPP was thiolated. CPP is specifically

[0050] Penetratin: RQIKIWFQNRRMKWKK (SEQ ID NO: 1), wherein C is an amino acid-cysteine ​​C added during the sequence synthesis, and this amino acid contains a sulfhydryl group, that is, the sulfhydrylation of CPP is completed.

[0051] DSPE-PEG-CPP is obtained by 1,4 addition reaction between the maleimide group of DSPE-PEG-Mal and the sulfhydryl group on the cysteine ​​residue of the cell penetrating peptide CPP. DSPE-PEG-Mal (11.6 mg) and thiolated Penetratin (16.8 mg) were dissolved in chloroform solution, triethylamine was added dropwise as a catalyst, and shaken gently. The mixed solution was reacted at room temperature and protected from light for 24 h under the condition of nitrogen filling. The org...

Embodiment 2

[0076] During the research process, our research group investigated the influence of multiple factors on the therapeutic effect of liposomes, including the following CPP and HA ratio screening experiments.

[0077] Human corneal epithelial cells HCEC were divided into 5 × 10 per well 6 The density of cells was seeded into the upper chamber of the collagen-coated Transwell chamber to construct a simulated in vitro corneal barrier. Retinal pigment epithelial cells ARPE-19 per well 2 × 10 5 The density of cells was plated in the lower chamber of the Transwell to simulate the fundus retinal environment. In order to investigate the efficiency of liposomes modified with different ratios of CPP and HA (the preparation method is the same as in Example 1) to penetrate the corneal barrier and be taken up by retinal cells, the fluorescently labeled drug-loaded liposomes modified with different ratios of CPP and HA were added to Go to the upper chamber of the Transwell chamber. After b...

Embodiment 3

[0083] Comparison of intraocular fluorescence intensity of different vectors.

[0084] PenHA-Lip: Penetratin, HA double modified liposome set; prepared according to the method of Example 1.

[0085] PenHA-PAMAM: Penetratin, HA double-modified PAMAM group; the preparation method is: first thiolate Penetratin, then take the thiolated Penetratin (16.8mg) and NHS-PEG-Mal (8.7mg) and dissolve them in 3mL of phosphate buffer and vortex After spinning for 1 min, it was added dropwise to 6 mL of PAMAM (10 mg) in phosphate buffer, and Pen-PAMAM was obtained after reaction. HA (22mg), EDC (22mg), and NHS (22mg) were dissolved in acetate buffer, and preactivated at 37°C for 2h. The activated HA was then added to Pen-PAMAM (35.5mg), adjusted to a final pH of 8 with borate buffer, and incubated at 37°C for 12h, stirring with a magnetic stirrer to couple HA to the liposome surface , forming PenHA-PAMAM.

[0086] PenHA-PLGA: Penetratin, HA double-modified PLGA group; the preparation metho...

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Abstract

The invention relates to an ophthalmic liposome capable of penetrating the cornea and targeting the retina, its preparation method and application. The ophthalmic liposome is a kind of liposome composed of lipid material with good biocompatibility, loaded with anti-VEGF drug and connected with cell penetrating peptide CPP and hyaluronic acid HA on the surface. The present invention loads the anti-VEGF drug inside the liposome, which effectively improves the shortcoming of the poor stability of the anti-VEGF drug. At the same time, the amphiphilicity of the liposome is used to enhance the corneal penetration effect, and the surface is covalently connected with a cell-penetrating liposome. Penetrant CPP and retina-targeted hyaluronic acid HA, found that the prepared liposomes can significantly increase the corneal penetration and accumulation of the drug to the fundus through eye drops, thereby increasing the concentration of the drug in the lesion , significantly improving the healing effect.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to an ophthalmic liposome co-modified with a cell penetrating peptide CPP and hyaluronic acid HA capable of penetrating the cornea and targeting the retina, and a preparation method and application thereof. Background technique [0002] The eye is an extremely complex and precise organ, anatomically divided into two parts: the anterior segment and the posterior segment. The anterior segment mainly includes the cornea, conjunctiva, aqueous humor, and lens, and the posterior segment mainly includes the vitreous, sclera, choroid, and retina. Intraocular neovascular diseases are mainly located in the posterior segment of the eye, such as retinopathy of prematurity (ROP), diabetic retinopathy (Diabetic retinopathy, DR) and age-related macular degeneration (Age-related macular degeneration, AMD), It is a serious blinding eye disease. Fundus neovascular diseases include chor...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K47/61A61K47/62A61K47/69A61K9/00A61K45/00A61K39/395A61P9/10A61P27/02
CPCA61K47/62A61K47/61A61K47/6911A61K9/0048A61K45/00C07K16/22A61P27/02A61P9/10
Inventor 丁雪鹰徐楠张姝月高申丁宝月何美台宗光王卓
Owner GUANGZHOU OCUSUN OPHTHALMIC BIOTECHNOLOGY CO LTD
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