KR101860667B1 - Lysozyme-responsive hydrogel contact lens for controlled drug delivery and manufacture method thereof - Google Patents

Abstract

The present invention relates to a lysozyme-responsive hydrogel contact lens for drug delivery, and a manufacturing method thereof, wherein the lysozyme-responsive hydrogel contact emits drugs in response to lysozyme. More specifically, a chitosan-based polymer matrix decomposed by lysozyme is produced, and a drug is loaded on the polymer matrix. The resultant product is inserted into a hydrogel contact lens. Thus, the drug is not emitted when the lens is stored, and the drug is emitted as the chitosan-based matrix is hydrolyzed by lysozyme present in a lachrymal fluid when the lens is worn on an eye. In addition, the present invention can load a drug on a chitosan-based polymer matrix decomposed by lysozyme which is a lachrymal fluid enzyme, and can effectively fix the same to a lens without damaging the physical properties of a hydrogel contact lens. Moreover, according to the present invention, a drug is contained in a hydrogel contact lens. Thus, the drug is not emitted when the lens is stored without lysozyme, and the drug is emitted by lysozyme only when the lens is worn on an eye.

Description

TECHNICAL FIELD [0001] The present invention relates to a hydrogel contact lens for delivering a medicament, and a method for manufacturing the contact lens. BACKGROUND ART < RTI ID = 0.0 > [0002]

The present invention relates to a hydrogel contact lens for releasing a drug in response to losozymes. More particularly, the present invention relates to a hydrogel contact lens for producing a chitosan-based polymer matrix decomposed by losozymes, a drug loaded on the polymer matrix, By inserting it into the hydrogel contact lens, the drug is not released during storage of the lens, and the chitosan-based matrix is hydrolyzed by the losozyme present in the liquid when worn, and the drug is released. The present invention relates to a hydrogel contact lens and a manufacturing method thereof.

Currently, the market for eye disease treatment and research and development is expected to increase due to an increase in glaucoma induction factors such as diabetes, hypernutrition and hypertension, an explosion of aging population, and smartphone popularization.

In particular, unlike cataracts, which initially show decreased vision, glaucoma has an abnormal visual acuity at the initial stage, so the speakers feel abnormalities and often progress considerably at the time of admission.

In the case of drug administration using glaucoma and other ophthalmic treatment eyedrops, the drug only penetrates 1 to 5% of the cornea, and the residual time on the surface of the cornea is less than 10 minutes. The amount administered by about 80% causes serious side effects such as vascular disease or heart disease through blood vessels.

In other words, eye drops have many problems, such as high dosing frequency and equipment of residuals, incapability of preservation to aging, toxicity, low compliance and cure rate, so an improved treatment method showing new mechanism and delivery method must be developed Actually,

On the other hand, when a contact lens is used, the drug may be slowly released and sufficiently remain in the eye. That is, when the lens is worn, the drug spreads over the cornea and circulates through the lens matrix, staying in a thin film between the cornea and the lens, which may stay in the film for longer than it is delivered to the eye drops. Considering that drug delivery using contact lenses can be used for glaucoma, cataracts, conjunctivitis, etc., and the development of related new drugs is only possible in some global pharmaceutical companies, the use of smart contact lenses Development is important.

Korean Patent Registration No. 1371685 discloses a lens body which has a spherical surface to be worn on the eyeball and a lens body which is formed so as to be pulled outward on the inner surface of the lens body which contacts the eyeball, And a medicament portion accommodated in the accommodating portion and adapted to transmit a medicinal ingredient to the eyeball when the lens main body is worn. The accommodating portion may be formed in the shape of a circular entrance recess having a predetermined diameter at the center of the inner surface of the lens main body And a light transmitting portion is formed at the center of the lens body so that a wearer can see the front of the lens body. The receiving portion is formed in a ring shape along the edge of the light transmitting portion, so that the medicine can be received between the eyeball and the lens Thereby improving the therapeutic effect of the eyes and the treatment speed.

However, the above-mentioned patent No. 1371685 discloses that when a lens is stored in a storage liquid, a pharmacological ingredient can be released into a storage liquid, the drug release period and speed can not be controlled, and the pharmacy containing the pharmacological ingredient There is a problem.

In other words, in some cases, the contact lens is usually dipped in the drug container to absorb the drug, but in this case, the drug is released within a few hours, so that there is a great restriction on the drug release period, the speed and the expiration date. If a drug-releasing contact lens does not release the drug during storage, but the ability to control its release rate and duration is supplemented, contact lenses can play a significant role in eye care prescriptions. Therefore, it is very important to develop and commercialize a smart contact lens in which the stability to the eye is secured without impairing the optical properties that the contact lens should have, the release of the drug is not carried out during storage or storage, and the drug is released only when worn. to be.

Korean Patent No. 1371685

The present invention has been made in order to solve the problems of the prior art described above and to provide additional advantages, and in particular, when a decomposable substance decomposed into losozymes such as chitosan derivatives is inserted into the surface and inside of the hydrogel contact lens, A hydrogel contact lens for delivering a losozyme-responsive drug, wherein the drug is not released during storage without harming the physical properties of the gel contact lens, and releases the drug only by lysozyme of the liquid when worn, and a process for producing the same. .

In order to achieve the above object, the present invention provides a hydrogel contact lens comprising poly (hydroxyethylmethacrylate, pHEMA) or a silicone monomer as a main material and a drug, and the hydrogel contact lens And a susceptor which is fixed and hydrated in a receiving groove formed on an outer surface or an outer surface of the hydrogel contact lens.

In addition, the hydrogel contact lens of the present invention may further comprise at least one member selected from the group consisting of 2-hydroxymethacrylate (HEMA), N-vinylpyrrolidone, ethylene glycol dimethacrylate and azobisisobutyronitrile (AIBN) Wherein the chitosan derivative is selected from the group consisting of chitosan, carboxylated chitosan, acetylated chitosan, methacylated chitosan, and the like. methacrylated chitosan and acrylated chitosan. The sensing unit 20 includes an eye disease drug, aldehyde hyaluronic acid, and succinyl chitosan. .

In addition, the present invention relates to a process for synthesizing a biocompatible and loserolytic chitosan derivative, three-dimensional networking thereof, and a process for preparing a reaction part by loading a drug and a process for producing a hydrogel contact lens based on polyhydroxyethyl methacrylate (pHEMA) And forming a receiving groove on a surface or an outer surface of the manufactured hydrogel contact lens to fix and hydrate the sensitive part in the receiving groove. The hydrogel contact lens for Lassozyme- Are prepared.

In addition, the process for preparing the sensitive part of the present invention may be carried out by dissolving the ophthalmic drug in an aqueous solution of aldehyde hyaluronic acid (solid content 0.1 to 10.0% by weight) containing a large amount of aldehyde at room temperature, (0.1 to 10.0% by weight) of succinyl chitosan (molecular weight: 3,000-10,000,000) containing a carboxylic acid and an amine was added and stirred for 3 hours, Thereby obtaining a sensitive part which is a chitosan-based matrix powder containing a drug.

The process for producing the hydrogel contact lens of the present invention may further comprise a step of preparing a hydrogel contact lens comprising 60 to 95% by weight of 2-hydroxymethacrylate (HEMA), 0.1 to 40% by weight of N-vinylpyrrolidone for hydrophilicity, 0.1 to 2.0% by weight of acrylate and 0.01 to 0.50% by weight of azobisisobutyronitrile (AIBN) as an initiator, stirring the mixture at room temperature for 1 hour, stirring the resulting mixture into a contact lens mold, drying oven at 80 to 130 ° C for 1 to 6 hours to produce a hydrogel contact lens.

Further, in the step of forming a receiving groove on the surface or outer surface of the hydrogel contact lens and fixing and hydrating the sensitive part in the receiving groove, the sensitive part which is the chitosan-based matrix powder on which the drug is mounted is placed on the surface of the hydrogel lens, And then the edge of the sensitive part is again polymerized with a solution of HEMA and EDGMA containing an initiator to fix the sensitive part to the hydrogel lens.

The hydrogel contact lens for drug delivery according to the present invention and the method for manufacturing the same according to the present invention are characterized in that a drug is loaded on a chitosan-based matrix which is degraded by a leakage enzyme lasozyme and the properties of the hydrogel contact lens It is possible to obtain an effect that it can be fixed to the lens without hurting it.

The present invention also relates to a hydrogel-containing drug delivery hydrogel, which is contained in a hydrogel contact lens so that the drug is not released when the drug is stored in the absence of losozymes and the drug is released by loso- A gel contact lens and a method of manufacturing the same.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a flow chart illustrating the process for preparing a lysozyme degradable chitosan-based matrix and loading a dye according to the present invention.
FIG. 2 is a flow chart illustrating a process for loading a drug-containing lysozyme degradable chitosan-based matrix onto a hydrogel lens according to one embodiment of the present invention.
FIG. 3 is a photograph showing release of a dye according to lassozyme response of a drug-loaded hydrogel lens according to an embodiment of the present invention.

The present invention relates to a hydrogel contact lens for releasing a drug in response to losozyme. More particularly, the present invention relates to a hydrogel contact lens comprising a chitosan-based polymer matrix decomposed by a losozyme, The hydrogel contact lens is fixed and hydrated in the receiving groove 12 formed on the surface or the outer surface of the hydrogel contact lens using as the main material, so that the drug is not released during storage without damaging the physical properties of the hydrogel contact lens, The present invention relates to a hydrogel contact lens for delivering a drug to losojim-sensitive drug and a method for producing the contact lens.

In order to accomplish the present invention, a hydrogel contact lens (10) based on poly (hydroxyethylmethacrylate, pHEMA) or a silicone monomer and a drug are mounted, and the hydrogel contact lens (20) fixed and hydrated in the receiving groove (12) formed on the outer surface or the outer surface of the body (10). The hydrogel contact lens according to claim 1,

The hydrogel contact lens 10 is preferably made of poly (hydroxyethylmethacrylate, pHEMA) as a main material, but a silicone monomer may also be used. As the silicone monomer, methacryloxypropyl bis (trimethylsiloxane (3-methacryloxy-2-hydroxypropyloxy) propylbis (trimethylsiloxy) methylsilane is preferably used as the silane coupling agent.

In addition, the hydrogel contact lens 10 of the present invention may be prepared by mixing 2-hydroxymethacrylate (HEMA), N-vinylpyrrolidone, ethylene glycol dimethacrylate, and azobisisobutyronitrile (AIBN) The chitosan derivative may be chitosan, carboxylated chitosan, or acetylated chitosan. The chitosan derivative may be selected from the group consisting of chitosan, chitosan, ), Methacrylated chitosan, and acrylated chitosan. The sensing unit 20 is configured to include an eye disease drug, aldehyde hyaluronic acid, succinyl chitosan, and succinyl chitosan.

In addition, the present invention relates to a process for synthesizing a biocompatible and losozyme-degrading chitosan derivative, three-dimensionally networking the same, and preparing a sensitive part 20 by loading the drug, and a process for producing a chitosan derivative based on polyhydroxyethyl methacrylate (pHEMA) The process of manufacturing the hydrogel contact lens 10 and the receiving groove 12 are formed on the surface or the outer surface of the manufactured hydrogel contact lens 10 to fix and hydrate the sensitive portion 20 in the receiving groove 12 The present invention also provides a method for manufacturing a hydrogel contact lens for delivering a drug of the present invention.

In addition, the process of producing the sensing part 20 of the present invention may be performed by dissolving the ophthalmic drug in an aqueous solution of aldehyde hyaluronic acid (solid content 0.1 to 10.0% by weight) containing a large amount of aldehyde at room temperature An aqueous solution (solid content 0.1 to 10.0% by weight) of succinyl chitosan (weight average molecular weight 3,000-10,000,000) containing a carboxylic acid and an amine was added and stirred for 3 hours Thereby obtaining a chitosan-based matrix powder responsive part containing an eye disease drug through lyophilization.

In addition, the process for producing the hydrogel contact lens 10 of the present invention is characterized in that 60 to 95% by weight of 2-hydroxymethacrylate (HEMA), 0.1 to 40% by weight of N-vinylpyrrolidone for hydrophilic property, 0.1 to 2.0% by weight of glycol dimethacrylate and 0.01 to 0.50% by weight of azobisisobutyronitrile (AIBN) as an initiator, stirring the mixture at room temperature for 1 hour, stirring the resulting mixture into a contact lens mold, The hydrogel contact lens 10 is produced by polymerization in a drying oven at 80 to 130 ° C for 1 to 6 hours.

The step of forming the receiving groove 12 on the surface or outer surface of the manufactured hydrogel contact lens 10 and fixing and hydrating the sensitive part 20 in the receiving groove 12 may be performed by using a chitosan- The sensitive part 20 which is a matrix powder is physically attached to the surface of the hydrogel lens 10 or the receiving groove 12 and then the edge of the sensitive part 20 is again polymerized with a solution of HEMA and EDGMA containing an initiator And the sensitive portion 20 is fixed to the hydrogel lens 10.

That is, the hydrogel contact lens 10 for delivering Lassozyme-mediated drug provided according to one aspect of the present invention may be made of polyhydroxyethylmethacrylate (pHEMA) or a hydrogel contact lens 10 Based chitosan-based matrix on which the drug is loaded, and then hydrolyzing the chitosan-based matrix of losozymes and releasing the drug loaded on the chitosan-based matrix .

As described above, the hydrogel contact lens 10, which is a main component of the present invention, is made of polyhydroxyethylmethacrylate (pHEMA) or a silicone monomer as a main component, and includes polyhydroxyethylmethacrylate polyhydroxyethylmethacrylate, pHEMA) as a main component, 2-hydroxymethacrylate (HEMA), N-vinylpyrrolidone, ethylene glycol dimethacrylate and azobisisobutyronitrile (AIBN) .

When a silicone monomer is used as a main material, it may be constituted by polymerizing the silicone monomer with a monomer containing an acrylic group or a vinyl group. Examples of the acrylic group-containing monomer include N, N-dimethylacrylamide (DMA), 2-hydroxyethylmethacrylate (HEMA), glycerol methacrylate, 2-hydroxyethylmethacrylamide, polyethylene glycol monomethacrylate (Meth) acrylate, methacrylic acid, and acrylic acid. Examples of the vinyl group-containing monomer include N-vinyl lactam (e.g., N-vinyl pyrrolidone (NVP) -Methylacetamide, N-vinyl-N-ethylacetamide, N-vinyl-N-ethylformamide and N-vinylformamide can be used.

Further, it is preferable to add a polymerization catalyst in the polymerization reaction. The polymerization catalyst may be a compound such as lauroyl peroxide, benzoyl peroxide, isopropyl percarbonate, or azobisisobutyronitrile, which generates free radicals by reaction, or a compound such as aromatic? -Hydroxy ketone or tertiary amine and diketone Lt; / RTI > system. Examples of photoinitiator systems include 2-hydroxy-2-methyl-1-phenyl-propan-1-one, and combinations of camphorquinone and ethyl 4- (N, N-dimethylamino) benzoate. The catalyst may be used in an amount of about 0.1 to about 2 parts by weight per 100 parts by weight of the reactive monomer, and the polymerization reaction may be initiated by appropriately selecting and using heat, visible light, ultraviolet light or other means depending on the kind of polymerization initiator. Examples of such a polymerization initiator include 2-hydroxy-2-methyl-1-phenyl-propan-1-one which causes a polymerization reaction by ultraviolet rays.

In one embodiment, the hydrogel contact lens of the present invention comprises 60 to 95% by weight of 2-hydroxy methacrylate (HEMA), 0.1 to 40% by weight of N-vinylpyrrolidone for hydrophilicity, ethylene glycol di 0.1 to 2.0% by weight of methacrylate, 0.01 to 0.50% by weight of azobisisobutyronitrile (AIBN) as an initiator, and the mixture is stirred at room temperature for 1 hour. The stirred mixture is injected into a contact lens mold, (drying oven) at 80 to 130 ° C for 2 to 6 hours.

In addition, the hydrogel contact lens 10 of the present invention can be formed on the outer surface, that is, the surface not in contact with the eye, in which the receiving groove 12, in which the sensitive portion 20 can be fixed and hydrated, have.

The sensitive part 20, which is a main component of the present invention, is fixed and hydrated in the receiving groove 12 formed on the outer surface or outer surface of the hydrogel contact lens 10 on which the drug is mounted, Wherein the chitosan derivative is decomposed into chitosan derivatives.

At this time, the chitosan derivatives include any one of chitosan, carboxylated chitosan, acetylated chitosan, methacrylated chitosan, and acrylated chitosan. . These chitosan derivatives have already been well known for its structure and function, and are characterized by being degraded by losozymes in the aqueous phase.

In addition, the sensing unit 20 of the present invention is characterized in that it comprises an eye disease drug, aldehyde hyaluronic acid, and succinyl chitosan.

Referring to FIG. 1, a process for producing the sensing part 20 is described. First, a ring-opening amide coupling reaction between chitosan (weight average molecular weight 3,000-10,000,000) and succinyl anhydride (succinyl anhydride) Succinyl chitosan was prepared by linking a large amount of the succinyl-functional chitosan through an amide bond to an amine functional group.

Next, in the case of hyaluronic acid (aldehyde hyaluronic acid: molecular weight 10 kDa-100MDa), aldehyde hyaluronic acid having a large amount of aldehyde functional groups was produced through a reduction reaction.

Then, an aqueous solution of aldehyde hyaluronic acid (solid content 0.1 to 10.0 wt%) was prepared at room temperature, and Rhodamine B, a red dye, was added to the solution instead of the drug. An aqueous solution of succinyl chitosan (solid content 0.1 to 10.0 wt.%) Was added to the solution and stirred for 3 hours to obtain cross-linked chitosan-based hydrated gels through a number of imine bonds. The sensitizing portion 20, which is a chitosan-based network powder containing Rhodamine 6G, was obtained by freeze-drying. (Succinic Chitosan: Aldehyde Hyaluronic Acid: Dye = 0.1-99, 1-99.0, 0.1 -50). Rhodamine B was used instead of glaucoma or cataract drugs such as Timolol maleate.

2, a receiving groove 12 is formed on a surface or an outer surface of the manufactured hydrogel contact lens 10 so that the receiving portion 12 is fixed and hydrated in the receiving groove 12, The sensitizing unit 20, which is the chitosan-based matrix powder on which the drug is loaded, is physically attached to the surface of the hydrogel lens or the receiving groove 12, and further polymerization or reaction between the powder and the lens surface is performed. Thereby fixing the sensitive portion 20 to the hydrogel contact lens 10. [

3, a hydrogel contact lens for transferring Lassozyme-medicated drug loaded with a dye (contact lens using polyhydroxyethyl methacrylate as a main material) manufactured according to one embodiment described above is described with reference to FIG. 3, 3 (a) is a photograph in which two lassozyme-sensitive hydrogel contact lenses 10 are contained in artificial tears, and FIG. 3 (b) is a photograph showing the release of drugs or dyes depending on the presence or absence of lassozyme addition. ), In addition to the artificial tears lacking lassozyme on their side, the lassozyme-sensitive hydrogel contact lens 10 was placed for 12 hours at 37 ° C. On the right side, , The dissolution of the matrix based on lassozyme-sensitized chitosan is released and the dye is released.

The composition of artificial tears used in this study was as follows: losozyme (1.2 mg / mL, chichen egg white, ≥90%, Aldrich), albumin (3.88 mg / mL, bovine serum, Aldrich), sodium chloride (7 mg / mL), potassium chloride (1.7 mg / mL) and calcium chloride (3.88 mg / mL).

That is, as can be seen from FIG. 3, it can be confirmed that the dye is not released in artificial tears lacking losozyme, so that the dye is not released during storage, and the dye is released in artificial tears containing losozyme .

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the invention is not limited to the disclosed exemplary embodiments, but, on the contrary, It is possible to carry out various changes in the present invention.

10: Hydrogel contact lenses
12: receptacle groove
20:

Claims (7)

A hydrogel contact lens 10 based on polyhydroxyethylmethacrylate (PHEMA) or a silicone monomer as a main component;
And a sensitive part 20 on which the drug is mounted and immobilized and hydrated in the receiving groove 12 formed on the outer surface of the hydrogel contact lens 10 through the mold of the contact lens,
The sensing unit 20 is physically attached to the receiving groove 12 and is then fixed to the receiving groove 12 by polymerizing the edge of the sensing unit 20 with a HEMA and EDGMA solution containing an initiator. Wherein the contact lens is made of a metal.
The method according to claim 1,
The hydrogel contact lens (10)
2-hydroxy methacrylate (HEMA); and
N-vinylpyrrolidone; and
Ethylene glycol dimethacrylate; And
(AIBN, Azobisisobutyronitrile). ≪ / RTI >< RTI ID = 0.0 > 21. < / RTI >
The method according to claim 1,
The sensing unit 20 includes:
And a chitosan derivative which is decomposed into losozymes. ≪ RTI ID = 0.0 > 11. < / RTI >
The method of claim 3,
The chitosan derivative
The composition according to any one of claims 1 to 3, characterized in that it comprises any one of chitosan, carboxylated chitosan, acetylated chitosan, methacrylated chitosan and acrylated chitosan. Hydrogel contact lenses for drug delivery.
The method according to claim 1,
The sensing unit 20 includes:
Claims [1] A hydrogel contact lens for delivering Lassozyme-mediated drug, comprising an eye disease drug, aldehyde hyaluronic acid, and succinyl chitosan.
Synthesizing chitosan derivatives of biocompatibility and losozyme degradability, and three-dimensionally networking the chitosan derivatives, and mounting the drug to manufacture the sensitive portion 20;
Preparing a hydrogel contact lens 10 using polyhydroxyethyl methacrylate (pHEMA) or a silicone monomer as a main material; And
Forming a receiving groove (12) on the outer surface of the manufactured hydrogel contact lens (10) to fix and hydrate the sensitive portion (20) in the receiving groove (12);
And,
The receiving groove 12 is made through a mold of a contact lens,
The sensing unit 20 is physically attached to the receiving groove 12 and is then fixed to the receiving groove 12 by polymerizing the edge of the sensing unit 20 with a HEMA and EDGMA solution containing an initiator. Wherein the hydrogel contact lens has a thickness of 10 mm or less.
The method according to claim 6,
The step of manufacturing the sensing portion 20 includes:
After dissolving the ophthalmic drug in an aqueous solution of aldehyde hyaluronic acid containing a large amount of aldehyde at room temperature, succinyl chitosan containing a carboxylic acid and an amine group, Wherein the sensitizing part (20) is a chitosan-based matrix powder containing an eye disease drug by adding an aqueous solution, stirring the mixture, and lyophilizing the mixture to obtain a sensitized part (20).

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