JP2018140037A - Annular device for prevention or treatment of corneal epithelium disease - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an annular device for forming a stable a tear film on a cornea surface as a prevention or treatment method for a corneal epithelium disease.SOLUTION: An annular device for preventing or treating a corneal epithelium disease worn on a sclera surface includes an annular part having an inner diameter that allows the entire cornea to be exposed, and an opening defined by the inner diameter. A tear film is formed on a cornea surface by an inner edge, which is the entity of the periphery of the inner diameter of the annular part, holding tears.SELECTED DRAWING: Figure 1

Description

The present invention relates to an annular device for wearing on the sclera surface for the purpose of preventing or treating corneal epithelial disease.

The cornea is a transparent film located on the outermost surface of the eyeball, has a function as an optical lens, and constitutes the outer wall of the eyeball together with the sclera. The structure of the cornea is divided into the epithelium, parenchyma, and endothelium from the body surface side, and since the epithelium is the outermost layer, damage (damage) is likely to occur due to various factors.

The corneal epithelium is usually covered with tears and is protected from external stimuli (eg, ultraviolet light, allergens and various physical stimuli). However, there is a decrease in tear volume and changes in tear components due to various factors such as drying of the outside air by air conditioning, reduction of blinking by staring on the personal computer screen, wearing of contact lenses, or aging, and the stability of the tear film. Sex is reduced. As a result, it is thought that it becomes easy to receive the damage by an external stimulus, and the disorder resulting from this is easy to generate | occur | produce.

As a method for treating a corneal disorder, depending on the severity of a symptom, an instillation of a drug, application of an ointment, corneal transplantation, and the like can be given. Regardless of the degree, in any case, the patient's economic and mental burden is great, and the development of a simple treatment method is desired to eliminate this.

One method of treating a corneal epithelial disorder is to wear a contact lens on the cornea to prevent the corneal epithelium from falling off. By using a contact lens as a covering material, it is possible to prevent exposure of the damaged site to external stimuli, so that recovery is accelerated. However, in this method, it is common to use eye drops together, but there is a problem that the medicinal effect cannot be obtained because the eye drops are taken into the contact lens. Further, depending on the oxygen permeability of the contact lens, there is a problem that the amount of oxygen supplied to the corneal epithelium is insufficient. Furthermore, since a serious injury caused by contact of the contact lens with the corneal epithelium (including enlargement of the damaged site and damage to the healthy site) is considered, a new treatment method is required.

International Publication No. 2010/092735 International Publication No. 2014/192853

The inventors of the present invention have focused on tears while advancing research on a new method for treating corneal epithelial disease. Strictly speaking, when the contact lens is worn, tear fluid exists between the contact lens and the corneal epithelium, and the corneal epithelium is protected from the outside air by both the contact lens and the tear fluid. Here, the present inventors can prevent contact between the corneal epithelium and the outside air even when the contact lens is not worn by forming a stable tear film on the corneal surface. I thought. And as a result of earnest examination about the formation method of a tear film, it came to pay attention to the cyclic | annular device which has an opening part in the center. In Patent Document 1 and Patent Document 2, an annular device having an opening in the center is disclosed. However, the formation of a tear film when the annular device is worn is suggested unless there is any description. It has not been done.

Accordingly, an object of the present invention is to provide an annular device for forming a stable tear film on the corneal surface as a method for preventing or treating corneal epithelial disease.

When the annular device as described in Patent Documents 1 and 2 is worn, the cornea is exposed. However, at this time, if the inner edge of the annular device has a certain thickness or more, the peripheral edge of the opening functions as a bank, and a tear film is formed on the cornea surface. It was issued. Thus, since the tear fluid stays longer, contact with the outside air of the corneal epithelium is suppressed, so that the risk of corneal damage is reduced and healing of the corneal epithelial disorder is effectively promoted. Furthermore, the therapeutic agent can be effectively delivered to the damaged site by instilling the therapeutic agent into the formed tear film.

That is, one aspect of the present invention is as follows.
(1) An annular device for preventing or treating corneal epithelial disease worn on the surface of the sclera, comprising an annular portion having an inner diameter that allows the entire cornea to be exposed, and an opening defined by the inner diameter, The annular device is characterized in that a tear film is formed on the corneal surface by an inner edge part, which is an entity around the inner diameter, of the annular part holding a tear.
(2) The said annular device characterized by the thickness of the said inner edge part being 0.03-0.17 mm.
(3) The said annular device characterized by the diameter of the said opening part being 10 mm-15 mm.
(4) When the annular device is worn on the sclera, the annular device has a plurality of concentric grooves on the surface of the annular portion located on the sclera side.
(5) The annular device, wherein the corneal epithelial disease to be treated is any one of punctate surface keratitis, corneal epithelial defect, corneal epithelial erosion, and corneal ulcer.

According to the present invention, an annular device for forming a stable tear film on the corneal surface can be provided. Since the tear film reduces direct contact between the cornea and the outside air, it not only suppresses the occurrence of corneal epithelial damage, but also suppresses the spread of damage already received and is effective for healing. Act on.

1A and 1B are a cross-sectional view and a top view illustrating an annular device according to one embodiment of the present invention. FIG. 2 is a cross-sectional view and a top view showing an annular device according to another aspect of the present invention. FIG. 3 is a cross-sectional view and a top view showing an annular device according to another aspect of the present invention.

Hereinafter, the details of the annular device of the present invention will be described, but the technical scope of the present invention is not limited only to the matters of this item, and the present invention can take various modes as long as the object is achieved. obtain.

An annular device according to one embodiment of the present invention is a device for wearing on the surface of the sclera, and has an opening that is a through-hole exposing the cornea, and the annular portion (curved thin film piece) has a constant thickness. It is characterized by having. Further, as another aspect, it is further characterized in that a plurality of, for example, two substantially circular grooves are provided on the sclera side surface of the annular portion.

The planar shape of the annular device of the present invention is not particularly limited, but is preferably circular as shown in the figure so that the sclera surface is covered when the device is mounted. However, the shape may be oval or oval as long as the ease of wearing the ring device and the feeling of wearing are not significantly impaired.

Hereinafter, an annular device of one embodiment of the present invention will be described with reference to FIG. The basic configuration of the annular device is not particularly limited as long as there is no problem in wearing and the annular device can cover the sclera surface. The outer diameter A is about 16 to 20 mm, preferably 18 to 20 mm in consideration of the upper limit of the burst width from the viewpoint of ease of mounting on the eyeball, wearing feeling, and scleral surface coverage. On the other hand, the inner diameter B (opening diameter) is preferably about 10 to 15 mm in order to prevent the inner edge portion a of the annular device from contacting the cornea.

a is an annular region having a width of 0.3 to 0.5 mm that extends from an arbitrary point on the inner peripheral edge 1A of the annular device toward a nearest point on the outer peripheral edge 1B described later. The outer edge b is an annular region having a width of 0.3 to 0.5 mm extending from an arbitrary point on the outer peripheral edge 1B of the annular device toward the nearest point on the inner edge a. The central part c is the remaining part excluding the inner edge part a and the outer edge part b in the annular device. The width F of the annular device is the width of the entire annular part including the inner edge part a and the outer edge part b.

The annular device has an opening 2 that exposes the cornea, and when worn on the surface of the sclera, the peripheral edge (inner edge a) of the opening 2 functions as a bank and forms a tear film on the cornea surface. It can be used for the prevention or treatment of corneal epithelial disease.

It should be noted that the range and contribution of the inner edge a functioning as a bank are variable depending on the posture of the wearer and the like. Specifically, for example, when the wearer stands upright and faces the horizontal direction, the semicircular circumference mainly vertically below the inner edge portion a functions as a bank, and if the wearer is in the supine position, The entire periphery will function as a bank. Further, in addition to these conditions, a certain amount of tears is retained by the surface tension acting at the peripheral part, so that the entire peripheral part of the opening 2 can contribute to the stability of the tear film.

Examples of the corneal epithelial disease include, but are not limited to, punctate superficial keratitis, corneal epithelial defect, corneal epithelial erosion, corneal ulcer and the like.

In the annular device, the thickness of the annular portion 1 affects the tear film formation. When the annular device is worn, since the peripheral edge of the opening 2 functions as a bank and forms a tear film, the thickness of the inner edge portion a is particularly important in the annular portion 1. The thickness C of the inner edge is preferably 0.03 to 0.17 mm. When the thickness is less than 0.03 mm, the function as a bank is deteriorated, so that the thickness of the tear film is not sufficiently ensured. In addition, when it exceeds 0.17 mm, the thickness D of the intermediate portion designed on the basis of this value is increased, so that the feeling of wearing is lowered. More preferably, it is 0.05-0.15 mm.

In addition, the thickness C of the inner edge is defined as the thickness at the outer end of the inner edge a, that is, the inner peripheral edge 1A. Similarly, the thickness E of the outer edge portion described later is the thickness at the outer peripheral edge 1B.

The thickness of the annular portion 1 other than the inner edge portion a is not particularly limited, but the thickness on the sclera during wearing is improved by making the thickness D of the intermediate portion larger than the thickness C of the inner edge portion. Specifically, the thickness D of the intermediate portion is preferably 110 to 300%, more preferably 120 to 280%, and still more preferably 150 to 250% with respect to the thickness C of the inner edge portion. By adopting a configuration in which the intermediate portion c has the maximum thickness, it is possible to remarkably reduce the influence of eyelid pressure due to blinking, and it is possible to effectively prevent the positional deviation and dropout of the annular device. The thickness E of the outer edge may be the same as the thickness C of the inner edge, but is not limited thereto.

In addition, from the viewpoint of wearing feeling of the annular device and the above-described position shift / drop-off prevention, as shown in FIG. 1, the outer edge b is continuous from the outer peripheral edge 1B of the curved thin film piece 1 toward the intermediate part c. It is desirable that the thickness be increased. Similarly, it is desirable that the inner edge portion a is formed so that the thickness continuously increases from the inner peripheral edge 1A of the curved thin film piece 1 to the intermediate portion c side.

Since the opening 2 in the annular device of the present invention is a part exposing the cornea, the curved thin film piece 1 which is the substance of the annular device is a through-hole that does not touch the cornea when the annular device is worn on the eye. It is preferable. As for the position of the opening 2, as shown in FIG. 1, the inner peripheral edge 1 </ b> A is preferably concentric with the outer peripheral edge 1 </ b> B, but is not limited thereto. Specifically, the shape of the entire annular device only needs to be adjusted so that the cornea is exposed with the opening 2 when the annular device is worn on the sclera. Although the shape of the opening part 2 is not specifically limited, Like the outer peripheral part, it should just be substantially circular, and it is preferable that it is substantially circular.

The base curve (BC) of the annular device is appropriately selected from the curvature of the sclera, but is usually 8.8 to 13 mm, preferably 10 to 12 mm. From the viewpoint of improving the ease of mounting on the eye, the handling of the device, and the like, the annular device may be provided with a cut or notch that divides the annular curved thin film piece 1.

As shown in FIGS. 2 and 3, the annular device may have a structure in which at least one substantially circular groove is provided on the rear surface of the central portion c (the surface that becomes the sclera side when worn). By arranging the substantially circular groove on the rear surface side of the central portion c, the stability on the sclera when the annular device is attached is improved. The position of the groove is not particularly limited, and the groove may be arranged closer to the inner edge side or the outer edge side, or may be arranged near the center. When there are two or more substantially circular grooves, the distance between the grooves is not particularly limited. For example, it may be 0.5 times or more the width of the smallest substantially circular groove. As the number of substantially circular grooves increases, the negative pressure generated by blinking when the annular device is worn increases, so that the annular device is easily held at a desired position, and the stability on the eyeball is improved.

Although the depth of the substantially circular groove is not particularly limited, for example, it can be set within a range of 1 to 90%, preferably 5 to 50% with respect to the thickness D of the intermediate portion. When the depth of the substantially circular groove is less than 1% with respect to the thickness D of the intermediate portion, the negative pressure is not sufficiently generated, so that the annular device is not stably held on the eyeball. Moreover, when the depth of the substantially circular groove is larger than 90% with respect to the thickness D of the intermediate portion, it is not preferable because the shape retaining property of the annular device is lowered.

[Material of annular device]
The annular device is preferably made of a hydrogel. Examples of the hydrogel include a hydrogel produced using a hydrophilic monomer, and a hydrogel produced by adding a hydrophobic monomer or a crosslinkable monomer or both to a hydrophilic monomer.

The hydrophilic monomer contributes to the improvement of the water content of the hydrogel. Hydrophobic monomers can affect the sustained release performance of the contained drug amount when the device contains a drug, in addition to the action of adjusting the water content and swelling rate of the hydrogel. The content of the crosslinkable monomer makes it possible to control the density of the polymer chains of the hydrogel, and by controlling the crosslink density, the diffusion of the drug is inhibited, the release of the contained drug is delayed, and the release rate of the drug is reduced. It becomes possible to control. The crosslinkable monomer can not only control the drug release rate, but also can impart mechanical strength, shape stability, and solvent resistance to the hydrogel.

The water content of hydrogel (water content (% by weight) = [(WD) / W] × 100 (W: water content, D: dry weight)) is the water content of hydrogel contact lenses that have been put to practical use. Although it will not specifically limit if it is comparable as a rate, For example, it can be set as 30 to 70 weight%. When the annular device contains a drug, the water content can be appropriately selected according to the target drug from the viewpoint of the uptake amount and release behavior of the target drug.

As the hydrophilic monomer, those having one or more hydrophilic groups in the molecule are preferable. For example, 2-hydroxyethyl (meth) acrylate, 2-hydroxymethyl (meth) acrylate, hydroxypropyl (meth) acrylate, glycerol (meta ) Acrylate, acrylamide, N, N-dimethyl (meth) acrylamide, N, N-diethyl (meth) acrylamide, N-vinylpyrrolidone, diacetone acrylamide, N-vinylacetamide, (meth) acrylic acid, (meth) acryloxy Examples thereof include ethyl succinic acid, itaconic acid, methacrylamidopropyltriammonium chloride, and 2,3-dihydroxypropyl (meth) acrylate. Among these, two or more hydrophilic monomers may be used in combination. Among the hydrophilic monomers, 2-hydroxyethyl (meth) acrylate is preferable.

The blending ratio of the hydrophilic monomer is not particularly limited, but it is preferably 50% by weight or more based on the total polymerization components because it affects the water content of the obtained cyclic device. When the blending ratio of the hydrophilic monomer is less than 50% by weight, it is not preferable because sufficient water content cannot be imparted and the flexibility of the annular device is lowered.

Examples of the hydrophobic monomer include siloxanyl (meth) acrylate, trifluoroethyl (meth) acrylate, methacrylamide, cyclohexyl (meth) acrylate, normal butyl (meth) acrylate, and the like. Two or more kinds may be used in combination.

The hydrophobic monomer can change the water content of the obtained cyclic device according to the blending amount. However, when the blending ratio of the hydrophobic monomer is high, the water content is extremely lowered, and the flexibility of the obtained cyclic device is lowered. For example, it is preferably less than 30% by weight based on the total amount of monomers.

Examples of the crosslinkable monomer include ethylene glycol di (meth) acrylate, methylenebisacrylamide, 2-hydroxy-1,3-dimethacryloxypropane, trimethylolpropane triacrylate, and the like. You may use it in combination.

The blending amount of the crosslinkable monomer is preferably 0.1 to 10% by weight with respect to the total amount of monomers from the viewpoint of the effect of controlling the shape of the obtained cyclic device. When the amount is less than 0.1% by weight, the network structure of the annular device is insufficient. On the other hand, when the amount exceeds 10% by weight, the network structure becomes excessive, the annular device becomes brittle, and flexibility decreases.

Polymerization initiators used for polymerizing the above monomer mixture include peroxides such as lauroyl peroxide, cumene hydroperoxide, and benzoyl peroxide, which are general radical polymerization initiators, azobisvaleronitrile, azo Examples thereof include bisisobutyronitrile. The addition amount of the polymerization initiator is preferably about 10 to 3500 ppm with respect to the total amount of monomers.

The annular device may be blended with an ultraviolet absorber. Specifically, 2-hydroxy-4- (meth) acryloyloxybenzophenone, 2-hydroxy-4- (meth) acryloyloxy-5-t-butylbenzophenone, 2- (2′-hydroxy-5 ′-(meta) ) Acryloyloxyethylphenyl) -2H-benzotriazole, 2- (2′-hydroxy-5 ′-(meth) acryloyloxyethylphenyl) -5-chloro-2H-benzotriazole, 2-hydroxy-4-methacryloyloxymethyl Phenyl benzoate etc. are mentioned, What is necessary is just to mix | blend arbitrary quantity according to desired ultraviolet-ray absorption ability.

[Method of manufacturing annular device]
The present annular device can be manufactured by a conventionally known method, for example, a cast mold manufacturing method or a lace cut manufacturing method, but the method for manufacturing the annular device of the present invention is not limited thereto. The cast mold manufacturing method is a manufacturing method for obtaining a circular device by performing a polymerization reaction in a molding die using a molding die designed in advance so as to have a desired shape (annular) after polymerization. The lace cut manufacturing method is a manufacturing method in which a block-like polymer is first obtained, and then, the block body is cut into a shape of an annular device, polished, or the like.

Cast mold manufacturing method First, a polymerization initiator is added to a hydrophilic monomer, or a mixture of monomers obtained by adding a hydrophobic monomer and / or a crosslinkable monomer to a hydrophilic monomer, and the mixture is stirred and dissolved to mix the monomers. Obtain a liquid.

The obtained monomer mixture is placed in a mold made of metal, glass, plastic, etc., sealed, heated stepwise or continuously in a constant temperature bath or the like in a range of 25 ° C. to 130 ° C., and in 5 to 120 hours. Complete the polymerization. In the polymerization, ultraviolet rays, electron beams, gamma rays, or the like can be used. In addition, solution polymerization can be applied by adding water or an organic solvent to the monomer mixture.

After completion of the polymerization, the mixture is cooled to room temperature, and the resulting polymer is taken out of the mold and cut and polished as necessary. The obtained device (annular device) is hydrated and swollen to obtain a hydrogel. Examples of the liquid (swelling liquid) used for hydration swelling include water, physiological saline, isotonic buffer, and the like, but a mixed liquid with a water-soluble organic solvent can also be used. The swelling liquid is heated to 40 to 100 ° C. and immersed for a certain period of time so as to be quickly hydrated and swollen. Moreover, it becomes possible to remove the unreacted monomer contained in the polymer by the swelling treatment.

Race cut manufacturing method First, a block-shaped polymer is obtained by a method similar to the cast mold manufacturing method using a mold having a block shape after polymerization, and then cut from the obtained block body. A cornea lens is prepared at An opening of a desired size is opened in the obtained cornea lens, and the peripheral portion is polished to obtain an annular device. At this time, it is also possible to cut into a lens-shaped device after first opening the opening.

Hereinafter, the present invention will be described in more detail with reference to examples. However, the present invention is not limited to these examples, and the present invention can take various modes as long as the problems of the present invention can be solved. .

[Production method of annular device]
After mixing, 99 g of 2-hydroxyethyl methacrylate as a hydrophilic monomer, 1 g of ethylene glycol dimethacrylate as a crosslinkable monomer, and 0.15 g of 2,2′-azobisisobutyronitrile as a polymerization initiator are shown in Table 1 after polymerization. Heat polymerization was carried out in a mold designed in advance so as to have the structures of Examples 1 to 6, Comparative Examples 1 and 2 and Reference Example 1 having outer diameter, inner diameter, thickness and / or groove (nitrogen atmosphere). Under room temperature to 100 ° C., 40 hours). The obtained device before swelling was swollen by heating in physiological saline at 60 ° C. for 30 minutes, and subjected to high-pressure steam sterilization to obtain a ring device.

The thickness of the annular device was measured using DIAL THICKNESS GAUGE (G-1A, manufactured by Ozaki Seisakusho). The thickness of the inner edge was measured at a position 0.3 mm away from the end on the device opening side, and the thickness of the middle was measured near the center between the end of the device opening and the end of the device outer edge. .

[Evaluation of tear film thickness]
After wearing the annular devices (or contact lenses) of Examples 1 to 4, Comparative Examples 1 to 2 and Reference Examples 1 to 4 to the subject, the thickness of the tear film formed by observation with a slit lamp microscope Table 1 shows the results of the evaluation. Reference Example 1 is an example showing that no damage is caused by wearing the annular device in a healthy eyeball having no pathological findings before wearing the annular device of the present invention. The meanings of the symbols in the table are as follows.
A: Remarkably thick tear film is formed compared to normal B: A thick tear film is formed compared to normal X: No change from normal

[Evaluation of wearing feeling and curability of eye diseases]
After wearing the annular devices (or contact lenses) of Examples 1 to 4, Comparative Examples 1 to 2 and Reference Examples 1 to 4 to the subject, the curability of the eye disease was as follows by observation with a slit lamp microscope: Evaluation was performed according to the conditions shown. In addition, Reference Example 1 is an example showing that no damage is caused by mounting the annular device when there is no finding before mounting the annular device of the present invention. The meanings of the symbols in the table are as follows.
○: Completely cured ×: Unhealed

From the results shown in Table 1, in the annular devices of Examples 1 to 4, it was confirmed that a significantly thick tear film was formed as compared with normal cases, and that this caused eye diseases to be cured with a short period of wearing. .

On the other hand, it was confirmed that the annular device of Comparative Example 1 did not function as a bank of tears because the thickness of the inner edge was too small, and did not contribute to the healing of eye diseases. Although the annular device of Comparative Example 2 had good tear film formation and healing properties, it was reported that the inner edge (and outer edge) had a large thickness, and a foreign body feeling that could not be worn was reported. It is thought that it is not suitable for.

The annular device of Reference Example 1 was the same as that of Example 2. However, no corneal damage was confirmed, and the results showed that the annular device of the present invention can be used safely. Reference Example 2 shows that normal contact lenses do not contribute to the healing of eye diseases. Reference examples 3 and 4 are annular devices included in the present invention, and the thickness of the inner edge is slightly small, which indicates that the period required for healing of the eye disease is increased.

1: annular portion 2: opening 1A: inner peripheral edge 1B: outer peripheral edge A: outer diameter B: inner diameter C: inner edge thickness D: middle edge thickness E: outer edge thickness F: annular device width a: inner edge Part b: outer edge part c: central part

Claims (5)

An annular device for preventing or treating corneal epithelial disease worn on the surface of the sclera,
An annulus having an inner diameter that allows the entire cornea to be exposed;
An opening defined by the inner diameter;
With
The annular device is characterized in that a tear film is formed on the corneal surface by an inner edge part, which is an entity around the inner diameter, of the annular part holding a tear. The annular device according to claim 1, wherein the inner edge has a thickness of 0.03 to 0.17 mm. The diameter of the said opening part is 10 mm-15 mm, The annular device of Claim 1 or 2 characterized by the above-mentioned. When the annular device is worn on the sclera, the annular part has a plurality of concentric grooves on the surface located on the sclera side. Annular device according to. The annular according to any one of claims 1 to 4, wherein the corneal epithelial disease to be treated is any one of punctate superficial keratitis, corneal epithelial defect, corneal epithelial erosion, or corneal ulcer. device.