KR20190051318A - Thermo-Responsive Hydrogel Contact Lens for Controlled Drug Delivery and Manufacturing Method Thereof - Google Patents

Abstract

The present invention relates to a temperature sensitive hydrogel contact lens for medicine delivery and a method for manufacturing the same. In the case of the contact lens, since a release speed and a release period of loaded medicine can be controlled, it is possible to effectively treat medicine and have an effect of reducing side effects, and also, it is possible to reduce the loss of medicine loaded on the contact lens even when being stored for a long time.

Description

 Technical Field [0001] The present invention relates to a hydrogel contact lens for thermally responsive drug delivery, and a method of manufacturing the same. [0002] Thermo-Responsive Hydrogel Contact Lens for Controlled Drug Delivery and Manufacturing Method Thereof [

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

Currently, glaucoma induction factors such as diabetes, hypernutrition and hypertension are increasing, and the incidence of various ophthalmologic diseases is increasing due to the explosion of aging population and aggravated air pollution. .

Bacterial conjunctivitis, cataract and glaucoma treatment are essential to use eye drops. However, in the case of ophthalmic eye drops, the drug penetration rate is low and the drug remains on the surface of the cornea within 10 minutes. In addition, a considerable amount of the administered drug causes serious side effects such as vascular disease or heart disease through blood vessels, and often remains at the toxic concentration or higher on the surface of the cornea immediately after administration of eye drops. In other words, there is a problem such as high dosing frequency, residual waste, and low corneal permeability.

On the other hand, in the case of a conventional contact lens releasing drug, there is a problem that it is difficult to store the drug for a long period of time because the drug is released or lost even when stored at room temperature. Therefore, it is necessary to develop contact lenses that can be used continuously for the treatment of eye diseases.

Thus, the present inventors completed the present invention by manufacturing a contact lens for delivering a new drug.

Korean Patent Registration No. 10-1652553

The object of the present invention is to provide a hydrogel contact lens for drug delivery, which can be easily stored for a long period of time and can be continuously used for treating eye diseases, and a method for producing the same.

One aspect of the present invention relates to a hydrogel contact lens substrate; And a thermosensible nanogel on which a drug for preventing or treating eye diseases is mounted. The present invention also provides a thermosensitive drug delivery hydrogel contact lens.

Another aspect of the present invention is a method for preparing a thermosensitive nano-gel, comprising the steps of: preparing a thermosensitive nanogel; Mounting a drug for preventing or treating eye diseases on the nano gel; And mounting the drug loaded nanogel on the hydrogel contact lens substrate. The present invention also provides a method of manufacturing a hydrogel contact lens for thermally responsive drug delivery.

The term " nano gel " as used in the present invention means a microvessel composed of an organic material capable of transporting and releasing a drug with high stability. Nano-gels can transport drugs to specific target cells through biological barriers when the drug is loaded.

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

The nanogel of the present invention is preferably a biocompatible nanogel. The biocompatible nanogel enables the drug to be retained in the body for a long period of time while effectively delivering the drug to the cell when the drug for preventing or treating eye diseases is mounted. Therefore, a therapeutically effective amount lower than the amount of the eye disease drug using conventional eye drops Prevention or treatment of eye disease is possible. &Quot; Therapeutically effective amount " means the level or amount of drug required to treat or prevent or reduce eye injury or damage without causing serious adverse effects or side effects on the eye or eye area.

As used herein, the term " ocular disease " means a disease, disorder, or condition involving or involving an ocular region. Generally speaking, the ocular includes tissue and fluid that constitute eyeballs and eyeballs, muscles around the eyeballs, and intraocular or adjacent optic nerve sections. &Quot; Eye area " means all areas of the eye including the anterior and posterior parts of the eye.

As used herein, the term " contact lens " refers to a structure that can be placed on or in the eye of a wearer, and includes a contact lens that can correct, improve, or change the user's vision.

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 " refers to a contact lens comprising a hydrogel material, preferably a silicone hydrogel contact lens. &Quot; Silicone hydrogel contact lens " refers to a contact lens comprising a silicone hydrogel material, wherein the " silicone hydrogel " refers to at least one silicone-containing monomer or at least one silicone-containing macromer or at least one Means a 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 thermosensitive nanogel tops and uniform size pores. Specifically, the contact lens is prepared by polymerizing a hydrophilic monomer, a hydrophobic monomer, and water through a surfactant. In the polymerization process, the contact lens is separated into two phases, an oil phase and a water phase, So that continuous pores can be formed. The pores thus formed can be adjusted in size according to the ratio of the monomer, water and surfactant. 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 .

According to one embodiment of the present invention, the temperature-sensitive nanogel loaded with the drug may have a diameter of 70 to 130 nm at room temperature and a diameter of 20 to 40 nm at 35 ° C or higher. Therefore, when the contact lens is worn, the nanogel is reduced in diameter at the temperature of the cornea (body temperature, about 37 DEG C), and the drug is continuously supplied through the pores of the contact lens Lt; / RTI >

As used herein, the term " normal temperature " refers to a temperature within a range of 20 占 폚 to 5 占 폚 at a constant temperature in an ordinary atmosphere.

According to one embodiment of the present invention, the drug-loaded thermosensitive nanogel may be poly (N-isopropylacrylamide), poly (vinylcaprolactamate), poly One selected from the group consisting of poly [2- (dimethylamino) ethylmethacrylate], polyvinyl methyl ether, and hydroxypropylcellulose. Or more, and may preferably include poly (N-isopropylacrylamide).

The nanogels based on poly (N-isopropylacrylamide) polymers have hydrophilic properties at room temperature (25 ° C) and thus have a diameter of 70 to 130 nm because the nanogels are hydrated by hydration, When the temperature rises above 35 ° C, the nanogel is dehydrated and shrinks, so it has a diameter of 20 to 40 nm and can release the drug. Therefore, the drug is not released during storage at room temperature, and the drug is released by the temperature of the cornea only when worn, so that the loss of the drug loaded on the contact lens can be reduced in long-term storage and non-use.

According to one embodiment of the present invention, the hydrogel contact lens base material may be a hydrophobic monomer such as 3- [tris (trimethylsiloxy) silyl] propyl methacrylate (3- [Tris (trimethylsiloxy) sily] propylmethacrylate); And a hydrophilic monomer such as 2-hydroxyethyl methacrylate (HEMA).

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

According to one embodiment of the present invention, the medicament for preventing or treating ocular disease is selected from the group consisting of proliferative vitreoretinopathy, macular degeneration, pigmented retinopathy, diabetic retinopathy, choroidal neovascularization, neovascular glaucoma, ischemic optic nerve disorder, prematurity retinopathy, Prevention of diseases selected from the group consisting of retinopathy, epidemic conjunctivitis, neovascular iris disease, posterior capsular hyperplasia, atopic keratitis, corneal limbal keratitis, pharyngoscopic keratitis, flicentric keratoconjunctivitis, scleritis and diabetic macular edema Or for therapeutic purposes.

In the method of manufacturing a hydrogel contact lens for thermally responsive drug delivery according to the present invention, the portion of the hydrogel contact lens for thermally responsive drug delivery which is the same as the above-mentioned meaning may be used.

The temperature sensitive nanogel of the present invention can be prepared by polymerizing a monomer of a thermosensitive polymer such as poly (N-isopropylacrylamide) in the presence of a cross-linker, an initiator and a surfactant. The thermosensitive nanogel can be used in powder form through a drying process such as lyophilization. &Quot; Initiator " means a compound that initiates a polymerization reaction, and can be a photoinitiator and a initiator.

In the preparation of nanogels, for example, N-isopropyl acrylamide monomer, sodium dodecylsulfate (SDS) surfactant, and N, N'-methylenebisacrylamide (N, N'-methylenebisacrylamide) MBAm) in an amount of 0.1 to 99.0: 1 to 100: 0.01 to 30 by weight.

In the step of mounting a medicament for preventing or treating eye diseases in the thermosensitive nano gel, the method for mounting the drug on the nano gel can be used without limitation. For example, it may include a step of mixing the nanogel powder and the drug, followed by lyophilization.

The step of mounting the temperature-sensitive nanogel on which the drug prepared in the above step is mounted on the hydrogel contact lens substrate includes immersing the hydrogel contact lens substrate in a solution in which the drug-loaded nanogel is dissolved in a hydrophilic solvent can do. In addition, the nanogel solution immersed in the hydrogel contact lens substrate may be centrifuged to primarily mount the nanogel in the pores of the contact lens base, and then immersed in the solution in which the drug loaded nanogel is dissolved .

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

Specifically, immersion in a solution containing a nanogel on which a medicament such as thymolol maleate is immersed in a hydrogel contact lens base material prepared by a BME system, and then, the immersion is carried out through a process including centrifugation and a further immersion step do. When the temperature exceeds 35 ° C, the nanogel loaded with the drug on the hydrogel contact lens substrate shrinks due to dehydration and releases the drug.

The hydrogel contact lens base material can be purchased and used directly as a product, or can be directly manufactured and used.

For example, a hydrogel contact lens base material can be produced by cross-linking a material containing an oligosaccharide as an essential ingredient together with an acrylic monomer.

According to one embodiment of the present invention, the solution containing the drug loaded nanogel may be prepared by dissolving a drug-loaded nanogel in water or ethanol solvent at a ratio of 1: 1 to 3 .

Because ethanol expands the matrix structure of the lens, the nanogel can be mounted deep within the lens matrix, so that the duration of drug release when using ethanol versus distilled water is prolonged. Therefore, it is preferable to dissolve the drug-loaded nanogel in the ethanol solvent in order to gradually release the drug, depending on the type of the solvent to be used.

According to the hydrogel contact lens for transferring a thermosensitive drug according to the present invention and the method for manufacturing the same, it is possible to control the release rate and release period of the drug loaded on the contact lens, thereby effectively treating the drug and reducing side effects. The loss of the drug loaded on the contact lens can be reduced.

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

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

Example  One. Temperature Sensitivity  For drug loading Hydrogel  Manufacture of contact lenses

<1-1> Hydrogel  Manufacture of contact lens substrate

To prepare a hydrogel contact lens substrate using a bicontinuous microemulsion (BME) system, a hydrophilic monomer, a hydrophobic monomer, water and a surfactant were mixed in the ratios shown in Table 1, The mixture was homogeneously stirred at room temperature. The mixture was then injected into a contact lens quartz mold and polymerized for 15 minutes at 365 nm wavelength using an ultraviolet polymerization machine to produce a hydrogel contact lens substrate.

compound Ratio (% by weight) 3- [tris (trimethylsiloxy) silyl] propyl methacrylate (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 Nano-gel  Produce

N, N ', N'-diphenylmethane diisopropylamide (NIPAM) monomer (0.815 g, 7.2 mmol), a surfactant sodium dodecylsulfate (SDS) (0.064 g, 0.22 mmol) and a cross- (0.023 g, 0.15 mmol) was dissolved in 100 ml of distilled water and placed in a 250 ml three-neck round bottom flask. The flask was filled with argon gas, and the temperature was maintained at 70 占 폚 , 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, dialyzed against distilled water for 3 days, and lyophilized to obtain a poly (N-isopropylacrylamide) Powder.

&Lt; 1-3 > Mounted Temperature Sensitivity Nano-gel  Produce

18 mg of thymolol maleate, which is a drug used to lower the intraocular pressure of eyes, was added to 3 ml of phosphate buffered saline (PBS), and 30 mg of thermosensitive nano gel 60 Were mixed and stirred at room temperature for 3 hours. Thereafter, dialyzed with distilled water for 3 hours and then lyophilized to prepare a temperature-sensitive nanogel loaded with the drug in powder form.

&Lt; 1-4 > Nano Gel  Mounted Hydrogel  Manufacture of contact lenses

In order to mount the thermosensitive nano gel loaded with the drug in the hydrogel contact lens, the hydrogel contact lens substrate prepared in the above <1-1> and the thermosensitive nano gel mounted with the drug prepared in the above <1-3> Were respectively dissolved in tertiary distilled water or ethanol at a volume ratio of 2: 1. Thereafter, the substrate of the hydrogel contact lens was immersed in 2 ml of the thermosensitive nanogel solution loaded with the drug, followed by centrifugation (10 C, 3500 rpm, 3 hours) and then immersed again at the same temperature for 21 hours, A hydrogel contact lens equipped with a mounted nanogel was manufactured.

Experimental Example  One. Temperature Sensitivity Nano-gel  Identify drug release potential by temperature

The temperature-sensitive nanogels loaded with the drug prepared in Example 1 above using TEM (Transmission Electron Microscopy) and Dynamic Light Scattering (DLS) Was released.

FIG. 3 is a graph showing the temperature sensitivity and size of the thermosensitive p (NIPAM) -based nanogel prepared in Example 1. FIG.

3 (a) shows a transmission electron microscope photograph, and the reference is 200 nm. b is a graph showing the spectroscopic spectrum at 35 ° C and 25 ° C using a 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 a lower critical solution temperature (LCST), while it was measured 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  Confirm drug release according to contact lens temperature

The concentration according to time was measured, and it was confirmed whether or not thymolol maleate used as a drug was 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 the absorbance of the PBS solution was measured with a UV-spectroscope to calculate the concentration of thymolol maleate having UV-absorbance at 295 nm.

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

4 (a) shows the drug release concentration of the hydrogel contact lens prepared by using distilled water when the nano gel is mounted on the hydrogel contact lens substrate, and b shows the concentration of drug released when the nano gel is mounted on the base material of the hydrogel contact lens This shows the drug release concentration of the hydrogel contact lens.

As shown in FIG. 4, the hydrogel contact lens of the present invention showed substantially no change in the concentration of the released drug even though the passage of time elapses at 25 ° C, but it was confirmed that the drug released at 35 ° C over time.

In addition, it was confirmed that the duration of drug release was prolonged when ethanol was used as compared with distilled water.

The present invention has been described with reference to the preferred embodiments. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. Therefore, the disclosed embodiments should be considered in an illustrative rather than a restrictive sense. The scope of the present invention is indicated by the appended claims rather than by the foregoing description, and all differences within the scope of equivalents thereof should be construed as being included in the present invention.

Claims (13)

Hydrogel contact lens substrates; And
Temperature-sensitive nanogel with drug for preventing or treating eye diseases
Wherein the thermally responsive hydrogel contact lens is a thermally responsive drug. The thermally responsive hydrogel contact lens according to claim 1, wherein the temperature-sensitive nanogel loaded with the drug has a diameter of 70 to 130 nm at room temperature and a diameter of 20 to 40 nm at 35 ° C or more. The method of claim 1, wherein the drug-loaded thermosensitive nanogel is selected from the group consisting of poly (N-isopropylacrylamide), poly (vinylcaprolactam) At least one thermosensitive material selected from the group consisting of poly (methyl methacrylate) - (dimethylamino) ethyl methacrylate], polyvinyl methyl ether, and hydroxypropylcellulose. A hydrogel contact lens for drug delivery comprising a polymer. 2. The contact lens of claim 1, wherein the hydrogel contact lens substrate
(3- [Tris (trimethylsiloxy) silyl] propylmethacrylate, which is a hydrophobic monomer, and 2-hydroxyethyl methacrylate (HEMA), which is a hydrophilic monomer,
&Lt; / RTI &gt; The hydrogel contact lens for thermally responsive drug delivery according to claim 1, The method of claim 1, wherein the medicament for preventing or treating ocular disease is selected from the group consisting of primary open angle glaucoma, closed angle glaucoma, neovascular glaucoma, proliferative vitreoretinopathy, macular degeneration, pigmented retinopathy, diabetic retinopathy, choroidal neovascularization, Hypertrophic keratoconjunctivitis, retinitis pigmentosa, atopic keratitis, topical keratoconus keratitis, pharyngoscopic keratitis, flicentric keratoconjunctivitis, scleritis, and diabetic macular edema. Wherein the hydrogel contact lens is for preventing or treating a disease selected from the group consisting of: 2. The thermally responsive hydrogel contact lens of claim 1, wherein the drug is timolol maleate. Synthesizing a thermosensitive nanogel;
Mounting a drug for preventing or treating eye diseases on the nano gel; And
Mounting the drug-loaded nanogel on a hydrogel contact lens substrate
Wherein the hydrogel contact lens comprises a thermally conductive material. [8] The method of claim 7, wherein the step of mounting the drug-loaded nanogel on the hydrogel contact lens substrate comprises immersing the hydrogel contact lens base in a solution in which the drug-loaded nanogel is dissolved in a hydrophilic solvent Wherein the hydrogel contact lens is formed of a thermally responsive drug. [9] The method of claim 8, wherein the solution containing the nanogel on which the drug is loaded is prepared by dissolving the drug-loaded nanogel in water or ethanol solvent at a ratio of 1: 1 to 3, A method for manufacturing a hydrogel contact lens. The method of claim 7, wherein the temperature sensitive nanogel is selected from the group consisting of poly (N-isopropylacrylamide), poly (vinylcaprolactame), poly [2- (dimethylamino) ) Comprising at least one polymer selected from the group consisting of poly (methyl methacrylate), poly [2- (dimethylamino) ethyl methacrylate], polyvinyl methyl ether and hydroxypropylcellulose. (JP) METHOD FOR MANUFACTURING HYDROGEL CONTACT LENS FOR DRUG DELIVERY. 8. The composition of claim 7, wherein the hydrogel contact lens substrate
(3- [Tris (trimethylsiloxy) silyl] propylmethacrylate, which is a hydrophobic monomer, and 2-hydroxyethyl methacrylate (HEMA), which is a hydrophilic monomer,
&Lt; / RTI &gt; wherein the hydrogel contact lens is manufactured from a thermally responsive hydrogel contact lens. [Claim 7] The medicament for preventing or treating eye disease according to claim 7, wherein the medicament for preventing or treating ocular disease is selected from the group consisting of primary open angle glaucoma, closed angle glaucoma, neovascular glaucoma, proliferative vitreoretinopathy, macular degeneration, pigmented retinopathy, diabetic retinopathy, Hypertrophic keratoconjunctivitis, retinitis pigmentosa, atopic keratitis, topical keratoconus keratitis, pharyngoscopic keratitis, flicentric keratoconjunctivitis, scleritis, and diabetic macular edema. Wherein the drug is a drug for preventing or treating a disease selected from the group consisting of: 8. The method of claim 7, wherein the drug is a thymolol maleate.

Images