KR102009571B1 - Thermo-Responsive Hydrogel Contact Lens for Controlled Drug Delivery and Manufacturing Method Thereof - Google Patents

Abstract

The present invention relates to a temperature-sensitive drug delivery hydrogel contact lens and a method for manufacturing the same, in the case of the contact lens, it is possible to control the release rate and the release period of the mounted drug, effective drug treatment and reducing side effects In addition, even long-term storage can reduce the loss of drugs loaded on the contact lens.

Description

 Thermo-Responsive Hydrogel Contact Lens for Controlled Drug Delivery and Manufacturing Method Thereof}

The present invention relates to a hydrogel contact lens for temperature sensitive drug delivery and a method of manufacturing the same.

Currently, glaucoma-inducing factors such as diabetes mellitus, hypertrophy intake, and hypertension are increasing. As the incidence of various eye diseases increases due to the explosive increase in elderly population and worsening air pollution, the market for treatment and related research and development is growing. .

The use of eye drops for the treatment of bacterial conjunctivitis, cataracts and glaucoma is essential, but the use of eye drops for the treatment of eye diseases shows low corneal penetration rate of the drug, and drug retention time on the surface of the cornea is less than 10 minutes. In addition, a significant amount of the administered drug causes serious side effects such as vascular disease and heart disease through the blood vessels, and often stays above the toxic concentration on the cornea surface immediately after the administration of eye drops. That is, current eye drops treatment has problems such as high dosage frequency, residual waste and low corneal permeability.

On the other hand, in the case of a conventional contact lens that emits the drug, even when stored at room temperature, there is a problem that the long-term storage is difficult because the drug is released or lost. Therefore, there is a need for the development of a contact lens that can be continuously used to treat eye diseases.

The present inventors have completed the present invention by producing a novel drug delivery contact lens.

Republic of Korea Patent Registration No. 10-1652553

The problem to be solved by the present invention is to provide a hydrogel contact lens for drug delivery and a method of manufacturing the same that can be easily stored for a long period of time and continuously used in the treatment of eye diseases.

One aspect of the invention is a hydrogel contact lens substrate; And it provides a temperature-sensitive drug delivery hydrogel contact lens comprising a temperature-sensitive nanogel mounted drug for preventing or treating eye diseases.

Another aspect of the invention comprises the steps of preparing a temperature sensitive nanogel; Mounting a drug for preventing or treating eye diseases on the nanogels; And it provides a method for producing a temperature-sensitive drug delivery hydrogel contact lens comprising the step of mounting the drug-based nanogel on a hydrogel contact lens substrate.

As used herein, the term "nanogel" means a microvessel composed of organic materials having high stability and capable of transporting and releasing drugs. Nanogels can deliver drugs to specific target cells across biological barriers when loaded.

As used herein, the term "temperature sensitive nanogel" refers to a polymer capable of sol-to-gel phase transition, which is present in solution at room temperature and in viscous gel near body temperature. it means.

The nanogel of the present invention is preferably a biocompatible nanogel. When biocompatible nanogels are loaded with drugs for the prevention or treatment of eye diseases, they can effectively deliver drugs to cells while retaining them in the body for a long time. Prevention or treatment of eye diseases is possible. By "therapeutically effective amount" is meant the level or amount of the drug necessary to treat ocular disease or to reduce or prevent ocular injury or injury without causing serious negative or adverse effects on the eye or eye area.

As used herein, the term "eye disease" refers to a disease, disorder or condition involving or involving the eye area. Generally speaking, the ocular includes the eyeballs and the tissues and fluids that make up the eyeballs, the peripheral eye muscles, and the optic nerve sections within or adjacent to the eyeballs. "Ocular area" means all areas of the eyeball, including the anterior and posterior parts of the eye.

As used herein, the term "contact lens" means a structure that can be located on or in the eye of a wearer, and includes a contact lens that can correct, improve or change a user's field of view.

As used herein, the term "hydrogel" means a polymeric material capable of absorbing at least 10% by weight of water when fully hydrated.

As used herein, the term "hydrogel contact lens" means a contact lens including a hydrogel material, and preferably, may be a silicone hydrogel contact lens. "Silicone hydrogel contact lens" means a contact lens comprising a silicone hydrogel material, and "silicone hydrogel" means at least one silicone-containing monomer or at least one silicone-containing macromer or at least one By silicone-containing hydrogel obtained by copolymerization of a polymerizable composition comprising a crosslinkable silicone-containing prepolymer.

The contact lenses of the present invention were polymerized using a bicontinuous microemulsion (BME) system to form tops of thermosensitive nanogels and form pores of uniform size. Specifically, the contact lens is prepared by polymerizing a hydrophilic monomer, a hydrophobic monomer and water through a surfactant, and the pores are separated between the two phases, an oil phase and an water phase, during the polymerization process. Since it is formed, it is possible to form pores which are continuously connected. The pores thus made can be adjusted in size according to the ratio of monomer, water and surfactant, and the contact lens of the present invention having pores of 100 to 140 nm size for mounting the temperature sensitive gel has a drug delivery rate due to the pore connectivity. This is improved.

According to one embodiment of the invention, the temperature-sensitive nanogel on which the drug is mounted may be 70 to 130nm in diameter at room temperature, 20 to 40nm in diameter at 35 ℃ or more. Therefore, at room temperature, the hydrogel may be mounted on the pores of the contact lens substrate, and when the contact lens is worn, the nanogel decreases in diameter at the temperature of the cornea (body temperature, about 37 ° C.), and the drug is continuously maintained through the pores of the contact lens. Can be released.

As used herein, the term "room temperature" refers to a temperature in the range of 20 ± 5 ° C as a constant temperature in the normal atmosphere.

According to one embodiment of the invention, the temperature-sensitive nanogel on which the drug is mounted is poly (N-isopropylacrylamide), poly (vinylcaprolactame), One selected from the group consisting of poly [2- (dimethylamino) ethylmethacrylate], polyvinyl methyl ether and hydroxypropylcellulose The above temperature-sensitive polymer may be included, and may preferably include poly (N-isopropylacrylamide).

Nanogels based on poly (N-isopropylacrylamide) polymers have hydrophilic properties at room temperature (25 ° C), so they are hydrated and swell, resulting in diameters of 70-130 nm and can trap drugs. When the temperature rises above 35 ° C, the nanogel dehydrates and shrinks, and thus has a diameter of 20 to 40 nm, and may release the drug. Therefore, the drug is not released when stored at room temperature, and the drug is released by the temperature of the cornea only when worn, thereby reducing the loss of the drug mounted on the contact lens in a long-term storage and non-wear state.

According to one embodiment of the invention, the hydrogel contact lens substrate is a hydrophobic monomer 3- [tris (trimethylsiloxy) silyl] propyl methacrylate (3- [tris (trimethylsiloxy) sily] propylmethacrylate); And it may be prepared from a hydrophilic monomer 2-hydroxyethyl methacrylate (2-hydroxyethyl methacrylate; HEMA).

FIG. 1A shows the chemical formula of 3- [tris (trimethylsiloxy) silyl] propylmethacrylate and FIG. 1B shows 2-hydroxyethyl methacrylate.

According to one embodiment of the present invention, the drug for preventing or treating ocular disease is proliferative vitreoretinopathy, macular degeneration, retinitis pigmentosa, diabetic retinopathy, choroidal neovascularization, neovascular glaucoma, ischemic optic nerve disorder, prematurity retinopathy, premature infant Prevention of diseases selected from the group consisting of retinopathy, epidemic keratoconjunctivitis, neovascular iris disease, posterior capsular fibrosis, atopic keratitis, keratoconjunctivitis keratitis, psoriatic psoriatic keratitis, plicenomy keratoconjunctivitis, scleritis and diabetic macular edema Or for therapeutic use.

In the method of manufacturing a temperature sensitive drug delivery hydrogel contact lens of the present invention, a portion overlapping with the above description for the temperature sensitive drug delivery hydrogel contact lens may be used in the same sense as the above.

The temperature sensitive nanogel of the present invention may be prepared by polymerizing a monomer of a temperature sensitive polymer, for example, poly (N-isopropylacrylamide), in the presence of a cross-linker, an initiator and a surfactant. Temperature sensitive nanogels may be used in powder form through a drying process such as freeze drying. "Initiator" means a compound that initiates a polymerization reaction and may be a photoinitiator and a thermal initiator.

In the preparation of nanogels, for example, an N-isopropylacrylamide monomer, a surfactant, sodium dodecylsulfate (SDS), and a crosslinking agent, N, N'-methylenebisacrylamide (N, N'-methylenebisacrylamide; MBAm) can be used in an amount of 0.1 to 99.0: 1 to 100: 0.01 to 30 by weight.

Mounting the drug for preventing or treating eye diseases on the prepared temperature-sensitive nanogel can generally be used without limitation the method of mounting the drug on the nanogel. For example, the method may include lyophilizing the nanogel powder and the drug.

Mounting the temperature-sensitive nanogel on which the drug prepared in the step is mounted on the hydrogel contact lens substrate includes immersing the hydrogel contact lens substrate in a solution in which the drug-containing nanogel is dissolved in a hydrophilic solvent. can do. Additionally, by centrifuging the nanogel solution in which the hydrogel contact lens substrate is immersed, the nanogel may be primarily mounted in the pores of the contact lens substrate, and then immersed in the solution in which the nanogel in which the drug is loaded is dissolved. .

FIG. 2 is a flowchart illustrating a process of mounting a drug-sensitive temperature-sensitive nanogel on a hydrogel contact lens substrate and a drug release process according to an embodiment of the present invention.

Specifically, after immersing in a solution containing a nanogel loaded with a drug such as, for example, timolol maleate on a hydrogel contact lens substrate prepared by the BME system, it is mounted through a process comprising a centrifugation and an additional immersion step do. When the temperature is 35 ° C. or higher, the nanogel on which the drug on the hydrogel contact lens substrate is mounted is contracted by dehydration to release the drug.

The hydrogel contact lens substrate may be purchased and used as a product, or may be manufactured and used directly.

For example, the hydrogel contact lens substrate may be prepared by cross-polymerizing a material containing an oligosaccharide as an essential component together with an acrylic monomer.

According to one embodiment of the present invention, the drug-containing solution containing the nanogel may be dissolved in a ratio of 1: 1 to 3 of the drug-mounted nanogel relative to water or ethanol solvent on a volume basis. .

Since ethanol widens the matrix structure of the lens, nanogels can be embedded deep in the lens matrix, resulting in a longer drug release when ethanol is used compared to distilled water. Therefore, the release rate of the drug can be controlled according to the type of solvent used, and in order to release the drug slowly, it is preferable to dissolve the nanogel loaded with the drug in an ethanol solvent.

According to the temperature-sensitive drug delivery hydrogel contact lens of the present invention and a method for manufacturing the same, the release rate and duration of the drug mounted on the contact lens can be controlled, thereby effectively treating the drug and reducing side effects, and storing for a long time. Even if it is possible to reduce the loss of the drug on the contact lens.

FIG. 1A shows the chemical formula of 3- [tris (trimethylsiloxy) silyl] propylmethacrylate and FIG. 1B shows 2-hydroxyethyl methacrylate.
FIG. 2 shows a process and drug for mounting a temperature-sensitive nanogel loaded with a drug on a hydrogel contact lens substrate (BME CL) according to an embodiment of the present invention by centrifuging and soaking Flow chart showing the drug release process.
3 is a diagram showing the temperature sensitivity and size of the temperature sensitive p (NIPAM) -based nanogel prepared in Example <1-3>.
Figure 4 is a graph showing the drug release according to the temperature sensitivity of the hydrogel contact lens for temperature-sensitive drug delivery prepared in Example <1-4>.

The following examples illustrate one or more embodiments in more detail. However, these examples are provided to illustrate one or more embodiments illustratively and the scope of the present invention is not limited to these examples.

Example  One. Temperature sensitivity  Drug Loading Hydrogel  Preparation of Contact Lenses

<1-1> Hydrogel  Preparation of Contact Lens Substrate

To prepare a hydrogel contact lens substrate using a bicontinuous microemulsion (BME) system, hydrophilic monomers, hydrophobic monomers, water, and surfactants were mixed at a ratio according to Table 1 below, followed by 1 minute The mixture was stirred homogeneously at room temperature. The mixture was then injected into a contact lens quartz mold and polymerized for 15 minutes at a wavelength of 365 nm using an ultraviolet polymerizer to prepare a hydrogel contact lens substrate.

compound 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> Temperature sensitivity  p ( NIPAM )-base Nanogel  Produce

N-isopropylacrylamide (NIPAM) monomer (0,815g, 7.2mmol), surfactant sodium dodecylsulfate (SDS) (0.064g, 0.22mmol) and crosslinker N, N ' Methylene bisacrylamide (N, N'-Methylenebisacrylamide; MBAm) (0.023 g, 0.15 mmol) was dissolved in 100 ml of tertiary distilled water and placed in a 250 ml three-necked round bottom flask filled with argon gas and kept at 70 ° C. 1.0 ml of an aqueous solution of ammonium persulfate (APS) (54 mg, 0.20 mmol) was added. After polymerization at 70 ° C. for 7 hours, the reaction solution at room temperature was filtered, and then dialyzed in distilled water for 3 days, and then freeze-dried to poly (N-isopropylacrylamide) (p (NIPAM))-based nanogels. Powder was prepared.

<1-3> drug Mounted Temperature sensitivity Nanogel  Produce

18 mg of timolol maleate, a drug used to lower the intraocular pressure of the eye in 3 ml of phosphate buffered saline (PBS) and the temperature-sensitive nanogel prepared in <1-2>. The mg was mixed and stirred at room temperature for 3 hours. Then, after dialysis with distilled water for 3 hours, and lyophilized to prepare a temperature-sensitive nanogel loaded with the drug in powder form.

<1-4> drugs and Nano gel  Mounted Hydrogel  Preparation of Contact Lenses

In order to mount the temperature-sensitive nanogel containing the drug in the hydrogel contact lens, the temperature-sensitive nanogel containing the hydrogel contact lens substrate prepared in the above <1-1> and the drug prepared in the <1-3> Was dissolved in tertiary distilled water or ethanol in a volume ratio of 2: 1, respectively. Subsequently, the hydrogel contact lens substrate was immersed in 2 ml of the temperature-sensitive nanogel solution loaded with the drug, followed by centrifugation (lO ° C., 3500 rpm, 3 hours), followed by another 21 hours at the same temperature. A hydrogel contact lens equipped with mounted nanogels was prepared.

Experimental Example  One. Temperature sensitivity Nanogel  Identify the possibility of drug release with temperature

Timolol maleate used as a drug in a temperature-dependent drug in a temperature-sensitive nanogel loaded with the drug prepared in Example 1 using a transmission electron microscopy (TEM) and a dynamic light scattering analyzer (DLS) It was confirmed whether the can be released.

Figure 3 is a diagram showing the temperature sensitivity and size of the temperature sensitive p (NIPAM) -based nanogel prepared in Example 1.

Figure 3a shows a transmission electron micrograph, the reference is 200nm. b shows the graph which measured the spectral spectrum at 35 degreeC and 25 degreeC using the light scattering particle size analyzer.

As shown in FIG. 3, the temperature-sensitive nanogel of the present invention was measured at 70 to 130 nm at room temperature, which is a lower critical solution temperature (LCST), while at 20 to 40 nm at 35 ° C. or higher.

Therefore, it was confirmed that the nanogel of the present invention can release the drug in a temperature dependent manner.

Experimental Example  2. Temperature sensitivity Nano gel  Mounted Hydrogel  Determination of Drug Release According to Contact Lens Temperature

By measuring the concentration over time, it was confirmed that the thymolol maleate used as a drug is released in a temperature-dependent manner in the contact lens prepared in Example <1-4>.

Specifically, the contact lens was taken out in 1 ml of PBS, and then the absorbance of the PBS solution was measured with a UV spectrometer to calculate the concentration of timolol maleate having UV-absorbance at 295 nm.

Figure 4 is a graph showing the drug release according to the temperature sensitivity of the hydrogel contact lens prepared in Example 1.

Figure 4a shows the drug release concentration of the hydrogel contact lens prepared using distilled water when the nanogel is mounted on the hydrogel contact lens substrate, b is prepared using ethanol when the nanogel is mounted on the hydrogel contact lens substrate The drug release concentration of the hydrogel contact transients is shown.

As shown in Figure 4, the hydrogel contact lens of the present invention was confirmed that the release of the drug over time at 25 ℃ almost no change in the concentration of the released drug, even if time passes at 25 ℃.

In addition, it was confirmed that the duration of drug release is longer when ethanol is used compared to distilled water.

So far I looked at the center of the preferred embodiment for the present invention. Those skilled in the art will appreciate that the present invention can be implemented in a modified form without departing from the essential features of the present invention. Therefore, the disclosed embodiments should be considered in descriptive sense only and not for purposes of limitation. The scope of the present invention is shown not in the above description but in the claims, and all differences within the scope will be construed as being included in the present invention.

Claims (13)

Hydrogel contact lens substrates; And
In the thermosensitive drug delivery hydrogel contact lens comprising a temperature-sensitive nanogel containing the drug for preventing or treating eye diseases,
The hydrogel contact lens substrate is composed of hydrophobic monomer 3- [tris (trimethylsiloxy) silyl] propyl methacrylate (3- [tris (trimethylsiloxy) sily] propylmethacrylate) and hydrophilic monomer 2-hydroxyethyl methacrylate ( 2-hydroxyethyl methacrylate; HEMA)
The temperature sensitive nanogel is poly (N-isopropylacrylamide) (poly (N-isopropylacrylamide)),
The drug is timolol maleate,
The solvent used to mount the nanogel on the hydrogel contact lens substrate is ethanol
Hydrogel contact lenses for temperature sensitive drug delivery. According to claim 1, wherein the drug-sensitive temperature-sensitive nanogel has a diameter of 70 to 130nm at room temperature, the diameter of the hydrogel contact lens for drug delivery is 20 to 40nm above 35 ℃. delete delete The method of claim 1, wherein the drug for preventing or treating eye diseases includes primary open angle glaucoma, closed angle glaucoma, neovascular glaucoma, proliferative vitreoretinopathy, macular degeneration, pigmented retinopathy, diabetic retinopathy, choroidal neovascularization, and ischemic optic nerve. Group consisting of disorders, prematurity retinopathy, prematurity retinopathy, epidemic keratoconjunctivitis, neovascular iris disease, posterior capsular fibrosis, atopic keratitis, keratoconjunctivitis keratitis, psoriatic psoriatic keratitis, plicenary keratoconjunctivitis, scleritis and diabetic macular edema Hydrogel contact lens for temperature sensitive drug delivery that is for the prevention or treatment of a disease selected from. delete Synthesizing a temperature sensitive nanogel;
Mounting a drug for preventing or treating eye diseases on the nanogels; And
Mounting the drug-containing nanogel on a hydrogel contact lens substrate
In the method of manufacturing a temperature-sensitive drug delivery hydrogel contact lens comprising:
The hydrogel contact lens substrate is composed of hydrophobic monomer 3- [tris (trimethylsiloxy) silyl] propyl methacrylate (3- [tris (trimethylsiloxy) sily] propylmethacrylate) and hydrophilic monomer 2-hydroxyethyl methacrylate ( 2-hydroxyethyl methacrylate; HEMA)
The temperature sensitive nanogel is poly (N-isopropylacrylamide) (poly (N-isopropylacrylamide)),
The drug is timolol maleate,
Mounting the drug-containing nanogels on the hydrogel contact lens substrate is to immerse the hydrogel contact lens substrate in a solution in which the drug-containing nanogels are dissolved in an ethanol solvent.
Method for producing a hydrogel contact lens for temperature sensitive drug delivery. delete The method of claim 7, wherein the drug-containing solution containing the nanogel is a temperature-sensitive drug delivery hydro that is dissolved in a ratio of 1: 1 to 3 of the drug-installed nanogel relative to the ethanol solvent on a volume basis Method for producing gel contact lens. delete delete The method of claim 7, wherein the drug for preventing or treating eye diseases includes primary open angle glaucoma, closed angle glaucoma, neovascular glaucoma, proliferative vitreoretinopathy, macular degeneration, pigmented retinopathy, diabetic retinopathy, choroidal neovascularization, and ischemic optic nerve. Group consisting of disorders, prematurity retinopathy, prematurity retinopathy, epidemic keratoconjunctivitis, neovascular iris disease, posterior capsular fibrosis, atopic keratitis, keratoconjunctivitis keratitis, psoriatic psoriatic keratitis, plicenary keratoconjunctivitis, scleritis and diabetic macular edema Method for producing a temperature-sensitive drug delivery hydrogel contact lens that is a drug for the prevention or treatment of diseases selected from. delete

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