KR20210036288A - Contact Lens Releasing Drug for Treating Retinopathy and Manufacturing Method Thereof - Google Patents

Abstract

The present invention relates to a drug-releasing contact lens with a drug for treating retinopathy and a manufacturing method thereof. The drug-releasing contact lens has the drug on a biodegradable film, the film is decomposed by tears and enzymes secreted from the eye, and the drug is released. Therefore, efficient drug treatment and reduced side effects can be expected.

Description

Contact Lens Releasing Drug for Treating Retinopathy and Manufacturing Method Thereof}

The present invention relates to a drug-releasing contact lens mounted with a drug for treatment of retinopathy and a method of manufacturing the same.

Angiogenesis does not occur in the body except during development and wound healing. However, angiogenesis occurs among a number of pathological conditions. In particular, the prevalence of angiogenic retinopathy due to senile and diabetic complications is increasing significantly with the aging of the population. When new blood vessels form in the eye, bleeding with rapid and permanent vision loss, rapid photoreceptor degeneration, and eventual fibrotic scarring can occur.

This angiogenesis is activated by vascular endothelial growth factor (VEGF), which is VEGFR1 (fms-like tyrosine kinase-1, Flt1) and VEGFR2 (kinase insert domain-containing receptor, Flk-) in the cell membrane. 1/KDR) binds to two types of VEGF receptors (VEGF receptors, VEGFRs). Through the binding (reaction) of VEGFR and VEGF, growth signals are transmitted to vascular endothelial cells, thereby generating new blood vessels (angiogenesis).

In order to suppress angiogenesis, various strategies for anti-angiogenesis have been applied. In particular, the treatment of ocular angiogenesis involves initiating anti-angiogenic signals using angiogenic inhibitors such as pigment epithelial-derived factor (PEDF) and caffeic acid (CA). , As an antagonist with high affinity for VEGFR, a biomacromolecule, a targeting peptide, or an antibody that competitively binds to VEGFR is used to block the binding between VEGF and VEGFR, thereby preventing the formation of new blood vessels. .

Currently, in clinical trials, anti-angiogenic substances are injected directly into the patient's vitreous body to treat retinopathy. Such an injection method is painful for the patient, and complications or side effects such as retinal detachment and endophthalmitis may be caused by injection, and thus there is a problem in that there is a limitation in improving the treatment efficiency by increasing the injection frequency. In order to compensate for these problems, there is a need to develop an improved treatment method with continuous drug delivery and efficiency.

Korean Patent Registration No. 10-1511787 Korean Patent Publication No. 10-2018-0034518

One aspect of the present invention is a film mounted with a drug for treating retinopathy; And it is an object to provide a drug-releasing contact lens for the treatment of retinopathy comprising a hydrogel contact lens base.

Here, the drug for treating retinopathy may be an anti-vascular endothelial growth factor (anti-VEGF).

The film is polylactide, polyglycolide, polycaprolactone, polylactide-co-glycolide, polylactide-co-caprolactone, polyglycolide-co-caprolactone, polydioxanone, polytrimethylene carbonate , Polyglycolide-co-dioxanone, polyamide ester, polypeptide, polymaleic acid, polyanhydride, polysebazoanhydride, polyhydroxyalkanoate, polyhydroxybutyrate and polycyanoacrylate It may be one or more biodegradable polymer films selected from.

The hydrogel contact lens substrate may have pores having a size of 100 to 200 nm.

The hydrogel contact lens substrate is 3-[tris(trimethylsiloxy)silyl]propyl methacrylate or glycidyl methacrylate as a hydrophobic monomer; 2-hydroxyethyl methacrylate as a hydrophilic monomer; And 2-(2-(3-(1,1,1,3,5,5,5-heptamethyltrisiloxane-3-l)propoxy)ethoxy)ethylacrylate or PEO-R- as a surfactant MA-40(ω-methoxy poly(ethylene oxide)n undecyl-α-methacrylate may be included.

The drug-releasing contact lens may include a film on which a drug is mounted between two hydrogel contact lens substrates.

In addition, an aspect of the present invention a) preparing a film containing a drug for treating retinopathy; b) preparing a hydrogel contact lens substrate; And c) a method of manufacturing a drug-releasing contact lens for treatment of retinopathy comprising the step of stacking and disposing a film containing the drug and a hydrogel contact lens substrate.

Here, step a) may be to mix 100 parts by weight of the film composition and 0.01 to 10 parts by weight of a drug for treating retinopathy.

In the step c), a film containing one drug and two hydrogel contact lens substrates are stacked, and a film containing the drug is placed on the first hydrogel contact lens substrate, and a second hydrogel contact lens substrate is placed on the first hydrogel contact lens substrate. It may be to position the gel contact lens substrate.

<Drug-releasing contact lenses>

According to one embodiment of the present invention, the present invention, with reference to Figures 1 to 3, a film 10 mounted with a drug for treating retinopathy; And it provides a drug-releasing contact lens for treatment of retinopathy comprising a hydrogel contact lens substrate 20.

As used in the present invention, "retinopathy" refers to persistent or severe damage to the retina of the eye, and intraretinal bleeding, decreased vision, and the like, may eventually lead to blindness. Such retinopathy may appear mainly as a complication or side effect of a disease such as diabetic retinopathy, hypertensive retinopathy, etc., and may also be caused by external stimuli such as physical shock, radiation, and ultraviolet rays.

As used herein, "hydrogel" refers to a polymeric material capable of absorbing at least 10% by weight of water when fully hydrated, and "contact lens" is on or in the eye (cornea) of the wearer. It refers to a structure that can be positioned, and includes a contact lens capable of correcting, improving, or changing a user's field of view. The "hydrogel contact lens" used in the present invention means a contact lens including a hydrogel material, and may be, for example, a hydrogel contact lens made of a silicone material.

The film on which the drug for treating retinopathy is mounted may be a film containing a drug capable of treating retinopathy caused by angiogenesis.

The drug for treating retinopathy is an anti-vascular endothelial growth factor (anti-VEGF) that inhibits angiogenesis, and for example, may be an angiogenesis inhibitor, a VEGFR antagonist, or the like. For example, pigment epithelial factor (PEDF), caffeic acid (CA), VEGF antibody, a peptide that binds to VEGFR, a protein kinase inhibitor of VEGFR, and the like, but are not limited thereto.

The film serves as a drug delivery vehicle so that the drug can be released by being decomposed by tears or enzymes secreted from the eye. Therefore, the film is preferably biodegradable that is degraded by the action of microorganisms or enzymes under natural conditions, and the decomposition product may be made of a polymer material that is harmless to the living body. Such a film can be used without limitation as long as it is a biodegradable polymer film known in the art. For example, polylactide, polyglycolide, polycaprolactone, polylactide-co-glycolide ( poly(lactide-co-glycolide)), polylactide-co-caprolactone), polyglycolide-co-caprolactone), polydioxane Polydioxanone, poly(trimethylene carbonate), polyglycolide-co-dioxanone), poly(amide ester), polypeptide ), polymaleic acid, polyanhydride, poly(sebacic anhydride), polyhydroxyalkanoate, polyhydroxybutylate, It may be made of a polymer such as polycyanoacrylate. Preferably, it may be a polylactide-co-glycolide film capable of easily adjusting the time of biodegradation by adjusting the copolymerization composition of lactide and glycolide.

The hydrogel contact lens substrate may have a larger pore size than that of a conventional contact lens having several nano-sized pores so that the drug for retinopathy treatment can be efficiently transmitted and absorbed into the eye or retina, and preferably 100 to 200 It may have pores having a size of nm, more preferably pores having a size of 100 to 140 nm. The hydrogel contact lens substrate may be polymerized through a bicontinuous microemulsion (BME) system using a hydrophilic monomer, a hydrophobic monomer, a surfactant, or the like. Here, the hydrophobic monomer may be 3-[tris(trimethylsiloxy)silyl]propylmethacrylate (3-tris(trimethylsiloxy)sily]propylmethacrylate) or glycidyl methacrylate (GMA), and a hydrophilic monomer May be 2-hydroxyethyl methacrylate (HEMA), and the surfactant is 2-(2-(3-(1,1,1,3,5,5,5-heptamethyltri Siloxane-3-l)propoxy)ethoxy)ethylacrylate (2-(2-(3-(1,1,1,3,5,5,5-heptamethyltrisiloxan-3-yl)propoxy)ethoxy)ethyl acrylate) or PEO-R-MA-40 (ω-methoxy poly(ethylene oxide) n undecyl-α-methacrylate) or PEO-R-MA-40 (ω-methoxy poly(ethylene oxide) n undecyl-α -methacrylate).

A film on which a drug for treating retinopathy is mounted; And a drug-releasing contact lens composed of a hydrogel contact lens substrate is stably positioned in the eye, and a drug-loaded film is positioned on one or more hydrogel contact lens substrates so that drug release from the drug-loaded film can proceed smoothly. I can. Preferably, a drug-mounted film may be positioned between the two hydrogel contact lens substrates. Such drug-releasing contact lenses may have a diameter of 13 to 15 mm to cover the pupil and cornea, and may have a center thickness of 0.2 to 0.3 mm depending on corrective vision or a mold used during manufacture.

These drug-releasing contact lenses can effectively deliver drugs to the retina only by wearing a contact lens, even if the drug is not injected directly into the vitreous cavity, and by controlling the biodegradation rate of the film, the drug is continuously released gradually to reduce the dosing frequency. Drug efficacy can be sustained.

<Method of manufacturing drug-releasing contact lenses>

According to another embodiment of the present invention, the present invention comprises the steps of: a) preparing a film containing a drug for treating retinopathy; b) preparing a hydrogel contact lens substrate; And c) it provides a method of manufacturing a drug-releasing contact lens for treatment of retinopathy comprising the step of laminating and disposing a film containing the drug and a hydrogel contact lens substrate.

Looking specifically at steps a) to c) of the manufacturing method are as follows.

Step a) is a process of manufacturing a film containing a drug for treating retinopathy.

Since the drug and film for the treatment of retinopathy are the same as described above, it will be omitted to avoid redundant description. A film containing such a drug may be prepared by mixing a drug and a polymer that is the main material of the film. For example, after mixing the biodegradable polymer solution, which is a film composition, and a hydrophilic solvent, a drug is further added and uniformly mixed, and a film can be prepared in the form of a contact lens using a mold. In this case, the film may have a shape positioned only on the cornea without covering the pupil to secure a field of view. When preparing the film, 0.01 to 10 parts by weight of a drug for treating retinopathy may be added to 100 parts by weight of the film composition. If the content of the drug is less than 0.01 parts by weight, the concentration of the drug is too low, and the delivery efficiency in the retina may decrease. If it exceeds 10 parts by weight, the initial release amount is large, while the bioavailability of the drug decreases, resulting in an uneconomic problem. Can occur.

Step b) is a process of manufacturing a hydrogel contact lens substrate for mounting a film containing a drug.

The hydrogel contact lens substrate may be polymerized through a double-continuous microemulsion (BME) system to form pores of a certain size. For example, a hydrogel contact lens substrate is prepared by polymerizing a hydrophilic monomer, a hydrophobic monomer, and water through a surfactant, and is separated into two phases of an oil phase and a water phase during the polymerization process. Since pores are formed between the pores, it is possible to form continuous pores. The pores formed in this way can be adjusted in size according to the ratio of monomer, water and surfactant, and the drug-releasing contact lens of the present invention having pores of 100 to 200 nm for mounting a film containing a drug The connectivity improves the delivery rate of the drug.

Here, the hydrophobic monomer may be 3-[tris(trimethylsiloxy)silyl]propyl methacrylate or glycidyl methacrylate, the hydrophilic monomer may be 2-hydroxyethyl methacrylate, and the surfactant is 2 -(2-(3-(1,1,1,3,5,5,5-heptamethyltrisiloxane-3-l)propoxy)ethoxy)ethylacrylate or PEO-R-MA-40(ω -Methoxy poly(ethylene oxide)n undecyl-α-methacrylate The composition of such a hydrogel contact lens base material is 3-[tris(trimethylsiloxy)silyl]propylmethacrylate, 2-hydroxy A combination of ethyl methacrylate and 2-(2-(3-(1,1,1,3,5,5,5-heptamethyltrisiloxane-3-l)propoxy)ethoxy)ethylacrylate, or Or it is preferably a combination of glycidyl methacrylate, 2-hydroxyethyl methacrylate and PEO-R-MA-40(ω-methoxy poly(ethylene oxide)n undecyl-α-methacrylate.

Step c) is a process of laminating and disposing a film containing a drug and a hydrogel contact lens substrate.

The film containing the drug may be laminated on the hydrogel contact lens substrate so that it can be stably positioned in the eye. For example, by laminating a film containing one drug and two hydrogel contact lens substrates (first and second hydrogel contact lens substrates), a film containing a drug on the first hydrogel contact lens substrate And placing the second hydrogel contact lens substrate on the film, the drug-releasing contact lens according to the present invention can be manufactured.

In the drug-releasing contact lens according to the present invention, since the drug is released as the film is decomposed by tears and enzymes secreted from the eye by mounting the drug on a biodegradable film, the effect of effective drug treatment and reduction of side effects due to intravitreal injection can be expected. .

1 is a film 10 mounted with a drug for treating retinopathy according to an embodiment of the present invention; And (a) a side view and (b) a plan view of a drug-releasing contact lens including the hydrogel contact lens substrate 20.
2 is a mounted film 10 on which a drug for treating retinopathy according to an embodiment of the present invention is mounted; And an exploded view of a drug-releasing contact lens including the hydrogel contact lens substrate 20.
3 is a result of confirming the drug-releasing effect of the drug-releasing contact lens according to an embodiment of the present invention. After 1 hour, fluorescence imaging was performed.
4 is a result of measuring the pore size of a drug-releasing contact lens according to an embodiment of the present invention using a field emission-scanning electron microscope (FE-SEM).

Hereinafter, the present invention will be described in more detail with reference to the accompanying drawings. However, these descriptions are provided by way of example only to aid understanding of the present invention, and the scope of the present invention is not limited by these exemplary descriptions.

Example 1. Preparation of drug-releasing contact lenses

1-1. Preparation of hydrogel contact lens substrate

In order to prepare a hydrogel contact lens substrate using the BME system, a hydrophilic monomer, a hydrophobic monomer, water, and a surfactant were mixed in the ratio according to Table 1, and then homogeneously stirred at room temperature for 1 minute. Then, the mixture was poured into a contact lens mold (diameter 14.2 mm, curvature 8.6 mm), and polymerized for 15 minutes at a wavelength of 365 nm using an ultraviolet polymerizer (DUVC 3624, SMT, Korea). Thickness 0.1 ~ 0.15 mm) was prepared.

ingredient Ratio (% by weight) 3-[Tris(trimethylsiloxy)silyl]propylmethacrylate (hydrophobic monomer) 16.94 water 16.94 2-hydroxyethyl methacrylate (hydrophilic monomer) 16.94 N,N-dimethylacrylamide 8.78 silmer ACR A008-UP (surfactant) 39.84 Ethylene glycol dimethacrylate (crosslinking agent) 0.28 2-hydroxy-2-methylpropiophenone (initiator) 0.28 Sum 100

1-2. Preparation of drugs for the treatment of retinopathy

As a drug for the treatment of retinopathy, a peptide-gold nanocomposite was prepared that inhibits angiogenesis by binding to VEGFR.

First, Flt1 peptide (3-mercaptopropionic acid-GGNQWFI-NH ₂ ) 3.5 mg was dissolved in 1 mL of DMSO (dimethyl sulfoxide) to prepare Flt1 peptide (50 uM), and polyethylene glycol (PEG) (MW = 5000) and Cyanin 5.5 was previously bound to prepare PEG-Cy5 (50 uM) at a concentration of 5 mg/mL.

Thirdly distilled water was added to a glass bottle, and the prepared Flt1 peptide (50 uM) and PEG-Cy5 (50 uM) were added in order at a molar ratio of 1:1 and shaken. Then, citrate-coated gold nanoparticles having a diameter of 15 to 20 nm were put in the glass bottle and adjusted to a concentration of 10 uM, and reacted at room temperature through a stirrer for 2 hours. Thereafter, the reaction product in the glass bottle was centrifuged at 17,000 rpm for 10 minutes, the supernatant was removed, and distilled water or PBS was added to prepare a gold nanofluorescent complex (anti-Flt1, Flt@AuNP-Cy5).

1-3. Preparation of drug-loaded film

A mixture of 180 mg of poly(D,L-lactide-co-glycolide) (lactide: glycolide = 65: 35) and 1,380 ug of ethylene acetate Next, 500 ul (100 uM) of the gold nanofluorescent composite (anti-Flt1) prepared in 1-2 was added and mixed until uniform, and the mixture was put into a contact lens hammold (diameter 14.2 mm, curvature 8.6 mm). A film (0.05 mm thick) is made in the form of a contact lens by rotational casting, and the residual solution is evaporated in a vacuum oven, and then the film is cut using a cork borer with a diameter of 9 mm and 5 mm, and a film with a width of 4 mm. I made it.

1-4. Preparation of drug-releasing contact lenses for treatment of retinopathy

Two contact lens substrates prepared in 1-1 and one drug-loaded film prepared in 1-3 were stacked to prepare a contact lens.

First, one contact lens substrate was placed on a mold, and then a drug-loaded film was placed, and another contact lens substrate was placed on the film. By injecting the solution mixed at the ratio according to Table 1 to the edge of the mold and performing photopolymerization in the same manner as in 1-1, finally, a drug-releasing contact lens (diameter 14.2 mm, curvature 8.6 mm, center thickness 0.2 ~ 0.3 mm) ) Was prepared.

Example 2. Confirmation of drug release effect using drug release contact lenses

In order to confirm the effectiveness of drug-releasing contact lenses actually delivered to the retina, animal experiments using rats were performed.

First, after wearing the drug-releasing contact lens prepared in Example 1 on the eye of a living rat, the eyeball was removed 1 hour later to confirm whether the drug reached the retina. As a control, 500 ul of the gold nanofluorescent complex (Flt@AuNP-Cy5) prepared in Example 1 was injected directly into the retina of the rat at the same concentration into the vitreous cavity.

Since cyanine 5.5 contained in the gold nanofluorescent complex exhibited fluorescence at 666 nm, imaging was performed using a Fluorescence-labeled Organism Bioimaging Instrument (FOBI, Neoscience Co, Korea).

As a result, as shown in FIG. 3, when the drug-releasing contact lens of Example 1 is worn, the drug is delivered into the macular area, whereas when the drug is directly injected into the retina, most of the drug is external to the retina. It was confirmed to exist in.

Through these results, it was found that the drug-releasing contact lens according to an embodiment of the present invention can be used as a medical tool that can safely and stably deliver drugs to the inside of the retina.

Example 3. Measurement of pore size of drug-releasing contact lenses

The drug-releasing contact lens prepared in Example 1 was freeze-dried at -60°C for 24 hours, and then gold coating was performed using an ion sputter coating machine (JEOL JFC-1100, Japan). Thereafter, the pore size of the gold-coated drug-releasing contact lens was measured using FE-SEM (JEOL JSM-6335F, Japan).

As a result, as shown in FIG. 4, it was confirmed that the drug-releasing contact lens of Example 1 had a pore size of about 100 to 140 nm.

So far, the present invention has been looked at around its preferred embodiments. Those of ordinary skill in the art to which the present invention pertains will be able to understand that the present invention may be implemented in a modified form without departing from the essential characteristics of the present invention. Therefore, the disclosed embodiments should be considered from an illustrative point of view rather than a limiting point of view. The scope of the present invention is shown in the claims rather than the above description, and all differences within the scope equivalent thereto should be construed as being included in the present invention.

Claims (9)

A film on which a drug for treatment of retinopathy is mounted; And
Hydrogel contact lens base
Drug-releasing contact lenses for treatment of retinopathy comprising a.
The method according to claim 1,
The drug for the treatment of retinopathy is an anti-vascular endothelial growth factor (anti-VEGF) that is a drug-releasing contact lens.
The method according to claim 1,
The film is polylactide, polyglycolide, polycaprolactone, polylactide-co-glycolide, polylactide-co-caprolactone, polyglycolide-co-caprolactone, polydioxanone, polytrimethylene carbonate , Polyglycolide-co-dioxanone, polyamide ester, polypeptide, polymaleic acid, polyanhydride, polysebazoanhydride, polyhydroxyalkanoate, polyhydroxybutyrate and polycyanoacrylate A drug-releasing contact lens that is one or more polymer films selected from.
The method according to claim 1,
The hydrogel contact lens substrate is a drug-releasing contact lens having a pore size of 100 to 200 nm.
The method according to claim 1,
The hydrogel contact lens substrate is 3-[tris(trimethylsiloxy)silyl]propyl methacrylate or glycidyl methacrylate as a hydrophobic monomer; 2-hydroxyethyl methacrylate as a hydrophilic monomer; And 2-(2-(3-(1,1,1,3,5,5,5-heptamethyltrisiloxane-3-l)propoxy)ethoxy)ethylacrylate or PEO-R- as a surfactant MA-40(ω-methoxy poly(ethylene oxide)n undecyl-α-methacrylate, a drug release contact lens comprising:
The method according to claim 1,
The drug-releasing contact lens is a drug-releasing contact lens in which a film on which one drug is mounted is positioned between two hydrogel contact lens substrates.
a) preparing a film containing a drug for treating retinopathy;
b) preparing a hydrogel contact lens substrate; And
c) laminating and disposing a film containing the drug and a hydrogel contact lens substrate
Method of producing a drug-releasing contact lens for treatment of retinopathy comprising a.
The method of claim 7,
The step a) is a method of mixing 100 parts by weight of the film composition and 0.01 to 10 parts by weight of a drug for treating retinopathy.
The method of claim 7,
The step c) is to laminate a film containing one drug and two hydrogel contact lens substrates,
A method comprising positioning a film comprising a drug on a first hydrogel contact lens substrate, and positioning a second hydrogel contact lens substrate on the film.

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