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CN119746039A - Composition, eye drops and use thereof - Google Patents

Composition, eye drops and use thereof Download PDF

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Publication number
CN119746039A
CN119746039A CN202411758516.2A CN202411758516A CN119746039A CN 119746039 A CN119746039 A CN 119746039A CN 202411758516 A CN202411758516 A CN 202411758516A CN 119746039 A CN119746039 A CN 119746039A
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CN
China
Prior art keywords
inhibiting
poloxamer
composition
eye drops
recombinant human
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202411758516.2A
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Chinese (zh)
Inventor
赵洪礼
张朔
冯铃
殷莉莉
刘畅
宋满满
刘辉
何伟
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Liaoning He's Medical College
Shenyang Eye Industry Technology Research Institute Co ltd
Shenyang Baifa Technology Co ltd
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Liaoning He's Medical College
Shenyang Eye Industry Technology Research Institute Co ltd
Shenyang Baifa Technology Co ltd
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Priority to CN202411758516.2A priority Critical patent/CN119746039A/en
Publication of CN119746039A publication Critical patent/CN119746039A/en
Pending legal-status Critical Current

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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

The invention relates to the field of biotechnology, in particular to a composition, eye drops and application thereof. The invention provides a composition, an eye drop and application thereof in preparing a product for inhibiting the growth of cornea neovascularization. The eye drops containing recombinant human IL-18 and having the inhibition effect on the new blood vessels of the cornea are characterized by effective use, convenient use and large-scale mass production. Not only has social benefits, but also can generate great economic benefits.

Description

Composition, eye drops and application thereof
Technical Field
The invention relates to the field of biotechnology, in particular to a composition, eye drops and application thereof.
Background
Cornea tissue is an important component of the refractive matrix of the eye, and transparent cornea is important for vision of the eye. Normal corneal tissue is avascular to maintain its transparent state. However, when the ocular surface tissue is stimulated by external factors such as infection, trauma and immune reaction, the new blood capillary grows from the limbus to the cornea, and when the new blood capillary enters the periphery of the cornea for more than 1 millimeter, the new blood capillary is the pathological cornea new blood vessel. Cornea neovascularization not only seriously affects vision, but also is a high risk factor for rejection reaction after allogeneic cornea transplantation, leading to surgical failure. Therefore, developing an eye drop for inhibiting the development of corneal neovascularization has been a hotspot and difficulty in ophthalmology.
The factors causing the corneal neovascularization are many, and the main reasons are (1) microbial infection, such as various viruses, bacteria, chlamydia and other pathogenic microorganisms, and corneal neovascularization can occur when the pathogenic infection enters a chronic stage. (2) Corneal physical trauma such as surgery, mechanical injury, etc. can occur. (3) Chemical damage to the cornea, such as acid-base burns, is often accompanied by a large number of corneal neovascularization and even granulomatous vascular tissue. (4) Other factors, such as immune allergic reactions, corneal dystrophy, advanced diabetes, contact lens wear, etc., can cause corneal neovascularization.
Corneal neovascularization is a complex physiological or pathological process that includes three phases (1) increased secretion of cytokines that promote angiogenesis under the stimulation of external factors (hypoxia, inflammation, trauma, etc.), localized vascular basement membrane degradation, and space for migration and proliferation of endothelial cells, and (2) migration and division proliferation of endothelial cells to the site of existence of inducement constitute hollow, primitive blood vessels composed only of endothelial cells. (3) The primitive blood vessels interact with smooth muscle cells, peripheral cells and extracellular matrix and mature gradually. This reaction is mediated by a number of cytokines, including (1) the vascular endothelial growth factor (vascular endothelial growth factor, VEGF) family and the pro-angiogenic (Ang) family, which specifically act on vascular endothelial cells, (2) certain growth factors and chemokines, such as FGF-2, PDGF, GM-CGF, etc., which act not only on endothelial cells but also on other cell types, and (3) cytokines which act indirectly on endothelial cells, such as TNFα, TGFβ, etc. The former can induce expression of VEGF and its receptor, and the latter can induce expression of TNF alpha, VEGF and FGF-2. Inhibiting the action of various cytokines during corneal neovascularization is a therapeutic target.
The research proves that the whole body injection of interleukin 18 (IL-18) into tumor-bearing mice has an inhibiting effect on tumor neovascularization and has a remarkable inhibiting effect on corneal capillary angiogenesis induced by FGF. Compared with wild mice, the IL-18 gene knockout mice have obvious vascular proliferation, disorder and exudation of fundus blood vessels within 7 days after the birth, the vascular morphology abnormality and exudation are confirmed by the histopathology within 14 days after the birth, and the RT-PCR shows that cytokines closely related to the new blood vessels are over-expressed, namely VEGF, bFGF, PDGF and PEDF, which indicate that the IL-18 has a regulating effect on the growth of the new blood vessels of the mice. Wild-type mice (C57 BL/6) were continuously expressing IL-18, 7 days postnatal wild-type mice were exposed to 75% oxygen for 5 days (between 7-12 days), and a momentary decrease in IL-18 expression was seen on day 17, accompanied by a decrease in IL-18, VEGF expression was seen on the retina, and an oxygen-induced retinopathy (oxygen induced retinopathy, OIR) was seen, but retinal neovascular disease had been contracted to normal levels by day 24, in contrast, IL-18 knockout mice were able to develop severe OIRs on day 17 and continued to bottom 24 days even in higher oxygen concentration environments, indicating that IL-18 inhibited retinal neovascular (CNV). Although the subcutaneous injection of recombinant IL-18 into mice during OIR development did not significantly inhibit the development of ocular fundus lesions, OIR was evident for 24 days when IL-18BP was injected subcutaneously to neutralize endogenous IL-18, suggesting that IL-18 regulates retinal pathological CNV by promoting its recoil rather than inhibiting its production, and that hypoxia or laser-induced experimental CNV can be prevented from developing when murine IL-18 is injected either in the eye or systemically.
Animal experiments prove that obvious eyeground blood vessel exudation appears in a CNV mouse model and an intraocular injection VEGF and VEGF transgenic mouse, and the intraocular injection of recombinant IL-18 into the mice obviously reduces the area of a new blood vessel and the blood exudation area at the same time, which proves that the IL-18 has an inhibition effect on the new blood vessel and the blood vessel exudation caused by VEGF. The vascular endothelial cells are fused with each other through specific transmembrane proteins to form tight connection, wherein the closed protein (Claudin-5) is the structural basis of normal tight connection among the cells, and the tight connection structure and function are destroyed due to the reduced or missing expression of Claudin-5, so that leakage among the cells occurs. Claudin-5 expression in retinal vascular cells of ischemic fundus lesions and VEGF transgenic mice is significantly reduced, and when IL-18 is injected into eyes of the mice, claudin-5 expression in retinal vascular cells is significantly increased and significantly different from that of a control group, which shows that IL-18 has a plurality of regulation targets in inhibiting angiogenesis and blood leakage.
In recent years, research on new blood vessels of IL-18 has been focused on new blood vessels of retina and choroid, and the dosage forms are liquid dosage forms and the modes of use are injection, and no research and application report on the aspect of new blood vessels of cornea exists.
The corneal neovascularization is often accompanied by hypopsia caused by stromal edema, fat precipitation, scar formation and the like, is one of the most common blinding eye diseases and is also the most troublesome medical problem in treatment. Thus, methods for effectively treating corneal neovascularization have been developed over the years. The ideal anti-corneal neovascularization treatment should be effective in inhibiting the growth of new blood vessels, inexpensive and without adverse effects. Current methods of treating corneal neovascularization include (1) removal of the etiology, treatment based on different causes of the disease, such as anti-infective treatment. (2) Drug therapy is mainly directed to inhibitors of angiogenic factor expression. Many studies have demonstrated that Vascular Endothelial Growth Factor (VEGF), basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF) and the like are associated with corneal neovascularization and thus also become new targets for the treatment of corneal neovascularization. (3) Antibodies, which block the actions of endogenous cytokines such as anti-VEGF mab and anti-bFGF mab, by neutralization of monoclonal antibodies are currently under basic research. (4) Anbody relaxation works by inhibiting VEGF and bFGF. (5) curcumin acts by inhibiting bFGF. (6) Heparin sulfate acts by inhibiting bFGF and receptors. All these therapeutic agents have a certain therapeutic effect on corneal neovascularization, but the problem of corneal neovascularization treatment cannot be thoroughly solved, so that development of a novel and effective anti-corneal neovascularization preparation is very necessary.
Disclosure of Invention
In view of this, the present invention provides compositions, eye drops and uses thereof. The invention provides a composition, an eye drop and application thereof in preparing a product for inhibiting the growth of cornea neovascularization. The eye drops containing recombinant human IL-18 and having the inhibition effect on the new blood vessels of the cornea are characterized by effective use, convenient use and large-scale mass production. Not only has social benefits, but also can generate great economic benefits.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a composition, which comprises 1 mug/mL-5 mg/mL of recombinant human IL-18, a viscosity lubricant with the mass volume fraction of 0.1-5%, a Zeta potential regulator with the mass volume fraction of 0.01-3%, a viscosity increasing matrix with the mass volume fraction of 1-8%, a drug carrier with the mass volume fraction of 0.1-4% and an osmotic pressure regulator with the mass volume fraction of 0.1-0.9%;
The viscosity lubricant is at least one selected from hyaluronic acid, gelatin, HPMC, polyethylene glycol or propylene glycol;
the Zeta potential regulator is at least one selected from chitosan, modified chitosan, polylactic acid or povidone K;
the viscosity-increasing matrix is selected from at least one of poloxamer 407, poloxamer 124, poloxamer 188, poloxamer 237 or poloxamer 338;
the pharmaceutical carrier comprises cyclodextrin;
the osmotic pressure regulator comprises sodium chloride or mannitol;
In some embodiments of the invention, the Zeta potential of the composition comprises +20 to 55 mV.
In some embodiments of the invention, the composition comprises the following components:
。
in some embodiments of the invention, the composition comprises the following components:
。
in some embodiments of the invention, the composition comprises the following components:
。
in some embodiments of the invention, the composition comprises the following components:
。
in some embodiments of the invention, the composition comprises the following components:
。
in some embodiments of the invention, the composition comprises the following components:
。
the invention also provides application of the composition in preparing a product for inhibiting the growth of cornea neovascularization.
In some embodiments of the invention, the inhibiting corneal neovascularization comprises any of:
(I) Inhibiting microtubule formation in human vascular endothelial cells, and/or
(II) inhibiting VEGF expression, and/or
(III) inhibiting the area of neovascularization.
The invention also provides eye drops, comprising the composition.
The invention also provides application of the eye drops in preparing medicines for treating and/or improving vision deterioration.
The invention also provides application of the eye drops in preparation of medicines for weakening rejection reaction after allogeneic cornea transplantation.
The invention provides the following beneficial effects:
The eye drops containing recombinant human IL-18 and having the inhibition effect on the new blood vessels of the cornea are characterized by effective use, convenient use and large-scale mass production. Not only has social benefits, but also can generate great economic benefits. Yield values are expected to be over several hundred million yuan.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below.
FIG. 1 shows the purification results of recombinant human IL-18 protein;
FIG. 2 shows the inhibition of microtubule formation by recombinant human IL-18 eye drops on human vascular endothelial cells;
FIG. 3 shows the inhibition of VEGF expression by recombinant human IL-18 eye drops;
Fig. 4 shows corneal neovascular area on the twenty-first day.
Detailed Description
The invention discloses a composition, eye drops and application thereof, and a person skilled in the art can properly improve the technological parameters by referring to the content of the invention. It is expressly noted that all such similar substitutions and modifications will be apparent to those skilled in the art, and are deemed to be included in the present invention. While the methods and applications of this invention have been described in terms of preferred embodiments, it will be apparent to those skilled in the relevant art that variations and modifications can be made in the methods and applications described herein, and in the practice and application of the techniques of this invention, without departing from the spirit or scope of the invention.
In view of the special physiological and pathological characteristics of eyes, macromolecular drugs penetrate through the cornea more, and the permeability of corneal epithelial cells is increased. The method has the advantages that the molecular shape is precisely controlled through the proportion of auxiliary materials, the efficacy of functional groups is improved, and the precise size, potential and morphological characteristics of the nano delivery system are endowed, so that the sustained and controlled release of the medicine is realized, and a novel protein sustained release drug delivery system with good biocompatibility, low toxicity and high bioavailability is formed.
The recombinant human IL-18 is prepared into the eye drops, is used for inhibiting cornea neovascularization, provides a novel preparation for treating cornea neovascularization, and has the characteristics of effectiveness, convenient use and large-scale mass production.
In some embodiments of the invention, the eye drops are comprised of components in concentrations,
Recombinant human IL-18. Mu.g/mL
Gelatin 1mg/mL
Modified chitosan 0.1mg/mL
Poloxamer 407, 10mg/mL
Lubricating cyclodextrin 1mg/mL
Sodium chloride 9mg/mL.
In some embodiments of the invention, the eye drops are comprised of components in concentrations,
Recombinant human IL-18 100 μg/mL
Hyaluronic acid 1mg/mL
Polylactic acid 0.1mg/mL
Poloxamer 124:10 mg/mL
Lubricating cyclodextrin 1mg/mL
Sodium chloride 9mg/mL.
In some embodiments of the invention, the eye drops are comprised of components in concentrations,
Recombinant human IL-18 100 μg/mL
Gelatin 2mg/mL
Modified chitosan 0.2mg/mL
Poloxamer 188:20 mg/mL
Lubricating cyclodextrin 1mg/mL
Sodium chloride 9mg/mL.
In some embodiments of the invention, the eye drops are comprised of components in concentrations,
Recombinant human IL-18 0.5mg/mL
Hyaluronic acid 2mg/mL
Polylactic acid 0.2mg/mL
Poloxamer 407, 20mg/mL
Lubricating cyclodextrin 1mg/mL
Sodium chloride 9mg/mL.
In some embodiments of the invention, the eye drops are comprised of components in concentrations,
Recombinant human IL-18 0.5mg/mL
Polyethylene glycol 1mg/mL
Chitosan 0.1mg/mL
Poloxamer 407, 10mg/mL
Lubricating cyclodextrin 1mg/mL
Sodium chloride 9mg/mL.
In some embodiments of the invention, the eye drops are comprised of components in concentrations,
Recombinant human IL-18 100 μg/mL
Hyaluronic acid 5mg/mL
Polylactic acid 0.1mg/mL
Poloxamer 188:10 mg/mL
Lubricating cyclodextrin 1mg/mL
Sodium chloride 9mg/mL.
In some embodiments of the invention, the eye drops are comprised of components in concentrations,
Recombinant human IL-18 1mg/mL
Hyaluronic acid 2mg/mL
Modified chitosan 0.2mg/mL
Poloxamer 407, 10mg/mL
Lubricating cyclodextrin 1mg/mL
Sodium chloride 9mg/mL.
In some embodiments of the invention, the eye drops are comprised of components in concentrations,
Recombinant human IL-18 1mg/mL
Hyaluronic acid 1mg/mL
Povidone K0.2 mg/mL
Poloxamer 338:10 mg/mL
Lubricating cyclodextrin 1mg/mL
Sodium chloride 9mg/mL.
The raw material information adopted by the invention is as follows:
the compositions, eye drops and raw materials and reagents used in the application of the compositions, eye drops provided by the invention can be purchased from the market unless otherwise specified.
The invention is further illustrated by the following examples:
EXAMPLE 1 determination of purity of recombinant human IL-18
The purity of the recombinant human IL-18 protein raw material is detected by adopting SDS-PAGE method to concentrate the gel concentration to be 5%, separating the gel concentration to be 12% and constant current 25mA electrophoresis for 90 minutes, and the purity of the recombinant human IL-18 can reach more than 95% (figure 1).
The amino acid sequence of the recombinant human IL-18 protein is shown as SEQ ID NO. 1 ：YFGKLESKLPVIRNLNDQVLFIDQGNRPLFEDMTDSDCRDNAPRTIFIISMYKDSQPRGMAVTISVKCEKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRSVPGHDNKMQFESSSYEGYFLACEKERDLPKLILKKEDELGDRSIMFTVQNED
EXAMPLE 2 preparation of recombinant human IL-18 eye drops
Recombinant human IL-18 eye drops were prepared according to the recombinant human IL-18 eye drop formulations shown in Table 1.
TABLE 1 recombinant human IL-18 eye drop formulations
EXAMPLE 3 preparation of recombinant human IL-18 eye drops
Recombinant human IL-18 eye drops were prepared according to the recombinant human IL-18 eye drop formulations shown in Table 2.
TABLE 2 recombinant human IL-18 eye drop formulations
EXAMPLE 4 preparation of recombinant human IL-18 eye drops
Recombinant human IL-18 eye drops were prepared according to the recombinant human IL-18 eye drop formulations shown in Table 3.
TABLE 3 recombinant human IL-18 eye drop formulations
Effect example 1 recombinant IL-18 eye drops inhibiting formation of human vascular endothelial cell microtubules
Taking HUVEC cells which are normally cultured, sucking out an original culture solution, adding PBS for washing, adding pancreatin for digestion for 3-5 min, stopping digestion, blowing into single cells by a pipetting gun, taking 20 mu L of cell suspension, adding 20 mu L of trypan blue for counting, centrifuging the rest cell suspension at 1000rpm for 5min, re-suspending by using a culture medium, plating at 3X 10 5/hole (6 hole plate), culturing at 5% CO 2 and 37 ℃ overnight, adding the recombinant human IL-18 eye drops prepared in examples 2-4 into a 6 hole plate according to the culture medium: eye drops (volume ratio) =9:1, and culturing for 48 hours by taking PBS instead of the eye drops as blank control. The treated human vascular endothelial cells were inoculated into 24-well plates with Matrigel artificial Matrigel spread thereon at a concentration of 1.2X10- 5/mL adjusted with serum-free 1640 medium, 1mL per well was routinely cultured for 16 h, microtube-like structure formation was observed every 4h, and 5 visual fields were randomly taken under an optical microscope (100X) and photographed. Images were analyzed using Microvision Saisam software, and microtubule-like structures were counted for 5 fields per well for statistical analysis. Statistical analysis was performed on the number of microtubules formed, and the experimental group was significantly reduced compared to the control group.
Effect example 2 inhibition of VEGF by recombinant human IL-18 eye drops
Human vascular endothelial cell suspensions were inoculated into 6-well plates (2×10 5/well), and incubated overnight in a 37 ℃ 5% co 2 incubator. The recombinant human IL-18 eye drops prepared in examples 2-4 and a culture medium were added into a 6-well plate according to the culture medium: eye drops (volume ratio) =9:1, and PBS was used as a blank control instead of eye drops, and cultured for 24 hours. The culture supernatants of the control and experimental groups were collected, and the expression of VEGF protein in the cell culture supernatant was detected using VEGF cytokine ELISA detection kit (MLBIO, cat# M1023364-2). The results show (fig. 3) that the expression of VEGF was significantly reduced in the experimental group compared to the control group.
Effect example 3 inhibition of recombinant human IL-18 eye drops on neovascular after alkali burn of rabbit eye cornea
Selecting New Zealand white rabbits as experimental objects, adopting a filter paper sheet with the diameter of 6mm soaked in 1mol/L NaOH to carry out molding, washing the ocular surface of each eye with physiological saline after molding for 30s, and dripping the levofloxacin into the eyes. The round white center of the cornea indicates successful burn. Rabbits with successful modeling were randomly divided into model control and experimental groups. The recombinant human IL-18 eye drops prepared in examples 2 to 4 were administered 2 times a day, 50. Mu.L each time, for 21 days. Statistical analysis of corneal neovascularization area on day 21. The results show (figure 4) that the eye drops of examples 2-4 have obvious inhibition effect on corneal neovascularization caused by alkali burn.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.

Claims (10)

1. The composition is characterized by comprising 1 mug/ml-5 mg/ml of recombinant human IL-18, a viscosity lubricant with the mass volume fraction of 0.1-5%, a Zeta potential regulator with the mass volume fraction of 0.01-3%, a viscosity increasing matrix with the mass volume fraction of 1-8%, a drug carrier with the mass volume fraction of 0.1-4% and an osmotic pressure regulator with the mass volume fraction of 0.1-0.9%;
The viscosity lubricant is at least one selected from hyaluronic acid, gelatin, HPMC, polyethylene glycol or propylene glycol;
the Zeta potential regulator is at least one selected from chitosan, modified chitosan, polylactic acid or povidone K;
the viscosity-increasing matrix is selected from at least one of poloxamer 407, poloxamer 124, poloxamer 188, poloxamer 237 or poloxamer 338;
the pharmaceutical carrier comprises cyclodextrin;
the osmotic pressure regulator comprises sodium chloride or mannitol.
2. The composition of claim 1, wherein the Zeta potential in the composition comprises +20 to 55 mV.
3. A composition according to claim 1 or 2, comprising the following components:
4. a composition according to any one of claims 1 to 3, comprising the following components:
5. a composition according to any one of claims 1 to 4, comprising the following components:
6. Use of a composition according to any one of claims 1 to 5 for the preparation of a product for inhibiting the growth of corneal neovascularization.
7. The use of claim 6, wherein inhibiting corneal neovascularization comprises any of:
(I) Inhibiting microtubule formation in human vascular endothelial cells, and/or
(II) inhibiting VEGF expression, and/or
(III) inhibiting the area of neovascularization.
8. An ophthalmic solution comprising a composition according to any one of claims 1 to 5.
9. Use of an eye drop as claimed in claim 8 for the preparation of a medicament for the treatment and/or amelioration of vision loss.
10. The use of the eye drop as defined in claim 8 for the preparation of a medicament for reducing rejection after allogeneic keratoplasty.
CN202411758516.2A 2024-12-02 2024-12-02 Composition, eye drops and use thereof Pending CN119746039A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202411758516.2A CN119746039A (en) 2024-12-02 2024-12-02 Composition, eye drops and use thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202411758516.2A CN119746039A (en) 2024-12-02 2024-12-02 Composition, eye drops and use thereof

Publications (1)

Publication Number Publication Date
CN119746039A true CN119746039A (en) 2025-04-04

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
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Country Status (1)

Country Link
CN (1) CN119746039A (en)

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