JP5549045B2 - Aqueous eye drops for prevention or improvement of hyperevaporation type dry eye - Google Patents

Description

  The present invention relates to an aqueous eye drop, and more particularly to an aqueous eye drop effective for preventing or improving dry eye associated with increased evaporation of tears.

  In the modern society in which personal computers and the like have become widespread, there are many scenes of overuse of the eyes, and the number of people suffering from dry eyes (dry eyes) is rapidly increasing.

  In general, dry eye is a condition in which the cornea or conjunctiva on the surface of the eyeball is damaged due to a decrease in the amount of lacrimal secretion or a qualitative change in tears. , Blurred eyes, itchy eyes, dry eyes, conjunctival hyperemia, and discomfort when wearing contact lenses.

  On the normal eye surface, tears form a thin film upon blinking, protecting the eye from dryness, dust and bacteria. However, when it becomes dry eye, tears cannot sufficiently protect the surface of the eye, and the cornea and conjunctiva are damaged. Since dry eye not only dries the eyes but also damages the surface of the eye, it can shift to various eye diseases, and therefore its prevention and early treatment are important. In particular, contact lens wearers often have keratoconjunctival disorders, and the treatment is urgent. It is also said that 60% of patients with eye strain are accompanied by dry eye, and dry eye is considered to be one of the main causes of eye strain. Therefore, it is considered that prevention or improvement of dry eye is also effective for prevention or improvement of eye strain (see Non-Patent Document 1).

  The surface of the eye is protected from the outside by being covered with tears. Tear fluid is composed of three layers, an oil layer, an aqueous layer, and a mucin layer. When the three-layer structure of tear fluid breaks down, dry eye is induced.

  Dry eyes can be broadly classified into two types: dry eye with reduced tear (secretion) and dry eye with increased evaporation. In recent years, with the rapid spread of computers and the increase in the number of contact lens wearers, the rate of hyperevaporation type dry eye caused by the tear oil layer failure has increased rapidly. Conventional eye drops for dry eye are mainly composed of sodium ions and potassium ions, mainly for the purpose of replenishing water, or artificial eye drop type eye drops or chondroitin sulfate sodium hyaluronate, etc. Ophthalmic solution containing mucopolysaccharides, mainly for retention of water, was effective in treating tear-reducing dry eye caused by a decrease in water, but caused by an oil layer disorder It cannot be said that it is effective enough for the treatment of hyperevaporation type dry eye.

  Oil-based eye drops and eye ointments may be used for the evaporation-type dry eye for the purpose of replenishing the oil. However, when the oil is administered directly to the eye, its irritation or viscosity causes pain and It is difficult to use continuously because it causes cloudiness of the field of view, stickiness, and the like.

  Therefore, it has been desired to develop an aqueous eye drop for the purpose of preventing and improving dry evaporation eyes with little irritation and good usability.

  As an evaporative dry eye treatment, an eye drop for treating dry eye in which 1 to 10% by volume of oil is added to an eye drop made of artificial tears is known (see Patent Document 1). The effect of the polysaccharide on the tear oil layer is not known, and there is no known aqueous eye drop that contains oil and mucopolysaccharide and is effective for hyperevaporation type dry eye.

JP-A-10-218760 “Dry Eye Medical PPP” edited by Dry Eye Study Group, Medical View, 230-231, 2002

  An object of the present invention is to provide an aqueous eye drop that is effective for enhanced evaporation type dry eye with low irritation and good usability.

  As a result of intensive studies to solve the above problems, the present inventors have found that an aqueous eye drop containing an oil and a mucopolysaccharide promotes the formation of a tear oil layer and prevents or improves hyperevaporative dry eye. It has been found effective, and the present invention has been completed.

  That is, the present invention is an aqueous eye drop characterized by containing an oil and a mucopolysaccharide.

  Another aspect of the present invention is an aqueous eye drop for preventing or ameliorating enhanced evaporation type dry eye characterized by containing an oil and a mucopolysaccharide.

  According to the present invention, it is possible to provide a water-based ophthalmic solution that promotes the formation of a tear oil layer, is effective in preventing or improving dry eye associated with increased evaporation of tears, has little irritation, and is easy to use. .

  The `` oil '' in the present invention is not particularly limited as long as it is an oil that promotes the formation of a tear fluid layer.For example, castor oil, soybean oil, olive oil, wheat germ oil, peppermint oil, sunflower oil, sesame oil, cottonseed oil, Corn oil, coconut oil, peanut oil, peanut oil, almond oil, safflower oil, jojoba oil, camellia oil, rapeseed oil, etc., vegetable oils such as squalane, and minerals such as liquid paraffin and light liquid paraffin An oil component having polarity, such as castor oil, which is excellent in ability to form a tear oil layer, is preferable.

  The content (formulation) of the oil is 0.001 to 10% by mass in the aqueous eye drop, preferably 0.01 to 1% by mass, and more preferably 0.1 to 0.5% by mass. If it is less than 0.001% by mass, the tear oil layer is not sufficiently formed, and the effect of suppressing water evaporation cannot be obtained sufficiently, which is not preferable. On the other hand, if it exceeds 10% by mass, stickiness, blurred vision, irritation and the like may be caused.

  Examples of the “mucopolysaccharide” in the present invention include hyaluronic acid and chondroitin, heparin, chondroitin sulfate, heparan sulfate, keratan sulfate, dermatan sulfate and the like or salts thereof. Examples of the salt include sodium salt and potassium salt. Among these, sodium hyaluronate or sodium chondroitin sulfate is preferable.

  The content (formulation) of mucopolysaccharide is 0.001 to 10% by mass in the aqueous eye drop, preferably 0.01 to 1% by mass, and more preferably 0.01 to 0.1% by mass. If it is less than 0.001% by mass, a sufficient tear fluid layer formation promoting effect cannot be exhibited, which is not preferable. On the other hand, if it exceeds 10% by mass, stickiness, blurred vision, irritation and the like may be caused, which is not preferable.

  The aqueous eye drop of the present invention may be in any form as long as it is a method capable of stably retaining the oil in the eye drop, but is preferably an emulsion, particularly an O / W type emulsion. Examples include a method of emulsifying with lecithin or a nonionic surfactant and dispersing the fine oil droplets in an aqueous ophthalmic solution.

  As lecithin used for emulsification, diacyl ester type glycerophospholipid such as phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidic acid, natural product-derived lecithin obtained from animals and plants such as soybeans and egg yolk, etc., or hydrogenation thereof Among them, hydrogenated lecithin is preferable and hydrogenated soybean lecithin is more preferable in terms of excellent oxidation stability.

  The content (formulation) of lecithin is 0.001 to 10 parts by mass, preferably 0.01 to 1 part by mass with respect to 1 part by mass of oil.

  Nonionic surfactants used for emulsification include polyoxyethylene hydrogenated castor oil, polyethylene glycol fatty acid esters, glycerin fatty acid esters, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters and polyoxyethylene Polyoxypropylene block copolymers and the like can be mentioned, but polyoxyethylene hydrogenated castor oil and polyoxyethylene sorbitan fatty acid esters having an HLB value of 10 or more are preferable, and polyoxyethylene hydrogenated castor oil is more preferable.

  The content (formulation) of the nonionic surfactant is 0.01 to 1 part by mass and preferably 0.1 to 0.8 part by mass with respect to 1 part by mass of the oil. If the amount is less than 0.01 parts by weight, it is difficult to uniformly disperse the oil in the preparation over a long period of time. It is because it falls.

  Moreover, you may use a lecithin and a nonionic surfactant in combination of several types.

  When the eye drop of the present invention is an O / W emulsion, the average particle diameter of the emulsion is preferably 200 nm or less, and preferably 50 nm to 150 nm in order to ensure the transparency and stability of the eye drop. More preferred. This is because if it is less than 50 nm, the formation efficiency of the tear oil layer is lowered after instillation, which is not preferable. This particle size can be measured using a laser diffraction / scattering particle size distribution measuring apparatus or the like.

  The aqueous eye drop of the present invention is preferably isotonic in order to relieve irritation at the time of eye drop, and may contain an osmotic pressure adjusting agent. Examples of the osmotic pressure adjusting agent include polyhydric alcohols or sugars. Furthermore, examples of the polyhydric alcohol include glycerin, sorbitol, mannitol, trehalose, xylitol, propylene glycol, and polyethylene glycol. Examples of the sugar include glucose. These polyhydric alcohols and sugars may be used alone or in combination of two or more.

  The content (formulation) of the polyhydric alcohol or sugar is 0.01 to 4% by mass in the eye drop, and is formulated so that the osmotic pressure of the eye drop is 228 to 458 mOsm in consideration of irritation to the eye. It is preferable to use glycerin.

  In the aqueous eye drop of the present invention, active ingredients such as amino acids, thickeners, inorganic salts, stabilizers, antioxidants, chelating agents, preservatives, buffering agents, as long as the effects of the present invention are not impaired. Various additives such as a cooling agent, a pH adjuster, and a thickener can be blended as necessary.

  Hereinafter, the present invention will be described in more detail with reference to Comparative Examples, Production Examples, Examples and Test Examples.

Comparative Example 1
In purified water, sodium chloride, potassium chloride and sodium hyaluronate are dissolved to 0.05% by weight, 0.1% by weight and 0.05% by weight, respectively, using boric acid, borax and glycerin, An eye drop of 100 mL having a pH of 7.4 and an osmotic pressure of 286 mOsm was prepared.

Comparative Example 2
10. After adding 67.5 g of purified water to 10.0 g of glycerin (Japanese Pharmacopoeia compatible product) and homogenizing it, the mixture is heated to 70 ° C. and stirred with polysorbate 80 (Nikkor TO-10M, manufactured by Nikko Chemicals). 0 g was added and dispersed. While heating at 70 ° C., 12.5 g of castor oil (Japanese Pharmacopoeia compatible product) was added and stirred with a homogenizer (Hiscotron (trade name), manufactured by Hitachi, Ltd.) to obtain a preliminary emulsion. A fine emulsion was obtained from this emulsion using a high-pressure homogenizer (PANDA 2K type, Niro Soavi SpA). In the process of diluting the obtained emulsion 10 times with purified water, mannitol was added to adjust the osmotic pressure to prepare 100 mL of an eye drop having an osmotic pressure of 286 mOsm.

Production Example 1
After adding 43.2 g of purified water to 29.8 g of glycerin (Japanese Pharmacopoeia compatible product) and homogenizing it, the mixture is heated to 70 ° C. and stirred with polyoxyethylene hydrogenated castor oil 60 (Nikkor HCO-60, Nikko Chemicals) 7.0 g) was added. While heating at 70 ° C., 20 g of castor oil (Japanese Pharmacopoeia compatible product) was added and stirred with a homogenizer (Hiscotron (trade name), manufactured by Hitachi, Ltd.) to obtain a preliminary emulsion. A fine emulsion was obtained from this emulsion using a high-pressure homogenizer (PANDA 2K type, Niro Soavi SpA).

Production Example 2
19.6 g of purified water is added to 58.2 g of glycerin (Japanese Pharmacopoeia), homogenized, heated to 70 ° C., and stirred with hydrogenated soybean lecithin (Resinol S-10M (trade name), Nikko Chemicals) 2.2 g) was added and dispersed. While heating at 70 ° C., 20 g of castor oil (Japanese Pharmacopoeia compatible product) was added and stirred with a homogenizer (Hiscotron (trade name), manufactured by Hitachi, Ltd.) to obtain a preliminary emulsion. This emulsion was emulsified using a high-pressure homogenizer (Minilab 830H (trade name), manufactured by Runny Co., Ltd.) to obtain a fine emulsion.

Comparative Example 3 and Examples 1-5
In the process of diluting the emulsion obtained in Production Examples 1 and 2 with purified water, each component shown in Table 1 is dissolved, glycerin is added to adjust the osmotic pressure, and 100 mL each of the eye drops shown in Table 1 is prepared. did.

Examples 6 and 9
In the process of changing the castor oil to soybean oil and liquid paraffin and preparing a fine emulsion in the same manner as in Production Example 2 and diluting with purified water, each component shown in Table 2 is dissolved and osmotic pressure is increased. Glycerin was added for adjustment, and 100 mL each of the eye drops listed in Table 2 was prepared.

Example 7
Castor oil is changed to olive oil, polysorbate 80 is further added, a fine emulsion is prepared in the same manner as in Production Example 2, and each component shown in Table 2 is dissolved in the process of diluting with purified water, Glycerin was added for adjustment, and 100 mL of eye drops described in Table 2 was prepared.

Example 8
In the process of changing the castor oil to squalane and preparing a fine emulsion in the same manner as in Production Example 1 and diluting with purified water, each component shown in Table 2 is dissolved, and glycerin is added to adjust the osmotic pressure. 100 mL of eye drops described in Table 2 were prepared.

Test Example 1 Moisture Evaporation Measurement Test The amount of water transpiration from the eye surface was measured using TEWAMETER TM300 (COURAGE + KHAZAKA GmbH). A male white rabbit (Kitayama Labes) weighing approximately 2.5 kg was fixed with an Oshida-type fixator, then 50 μL of Benoceal 0.4 mass% ophthalmic solution (trade name, Santen Pharmaceutical) was instilled, and ocular surface anesthesia was performed. . After 5 minutes, the lacrimal fluid in the conjunctival sac was wiped off, 50 μL of the test eye drop sample was applied, and the amount of water transpiration from the eye surface after 10 minutes, 20 minutes, and 30 minutes was measured. The amount of moisture transpiration was calculated as the rate of change according to the following formula, with the value immediately before instillation being 100%. The number of examples in each group was 5.
The results are shown in Table 2.

Calculation formula:% X = (x / y) × 100
% X: rate of change in moisture transpiration, x: moisture transpiration at each measurement time, y: transpiration immediately before instillation

  From Table 3, it was revealed that the amount of water transpiration was significantly suppressed in the case of the eye drops prepared in Example 1 according to the present invention as compared with the eye drops prepared in Comparative Examples 1 to 3.

Test Example 2 Tear Oil Layer Observation Test Dry eye observation device DR-1 (manufactured by Kowa Co., Ltd.) was used for observation of the tear oil layer. DR-1 is a device that irradiates the cornea with white light and measures the reflected light with a video camera. The tear film has a three-layer structure of a mucus layer, an aqueous layer and an oil layer from the corneal surface. This apparatus measures the interference image of light reflected on the oil layer surface and the oil layer back surface (boundary surface with the water layer). That is, the interference image obtained by this apparatus shows the state of the tear fluid layer. In general, the interference image obtained with this device is a uniform gray or white color for normal eyes, and an oil layer is non-uniform for dry-evaporation dry eyes, so an image with a mixture of red and blue colors is observed. Is done. In more severe dry eyes, since the oil layer is not present, the interference image disappears and the cornea is exposed (“New Ophthalmology” 14 (11), 1605-1612, 1997,
Am. J. et al. Ophthalmol. 122, 818-824, 1996).

After fixing a male Japanese white rabbit having a body weight of about 2.5 kg with an Oshida type fixator, 50 μL of Benoxeal 0.4 mass% ophthalmic solution was instilled, and ocular surface anesthesia was performed. After 5 minutes, the tear fluid in the conjunctival sac was wiped off, 50 μL of the test eye drop sample was instilled, and after 15 minutes, the state of the tear oil layer was observed.
The results are shown in FIGS.

  From FIGS. 1 and 2, when the eye drops prepared in Comparative Examples 1 and 2 were instilled, the tear oil layer was hardly recovered, many dry spots were seen, and the cornea was in an exposed state. When the eye drop of Comparative Example 3 was instilled, the dry spots decreased and partial recovery of the tear fluid layer was observed, but the cornea was partially exposed. On the other hand, from FIG. 4 to FIG. 8, when the eye drops prepared in Example 1 and Examples 6 to 9 containing oil and mucopolysaccharide were instilled, there was almost no dry spot, and a substantially uniform tear oil layer Recovery was observed.

A: A uniform oil layer is formed and is almost normal. ○: An oil layer is formed. Δ: A portion of the cornea is exposed. ×: A cornea is exposed.

  From Table 4, it became clear that the eye drop according to the present invention has an action of promoting the formation of a tear oil layer.

  According to the present invention, it is expected to develop an O / W emulsion aqueous eye drop effective for prevention and improvement of dry eye and various symptoms associated with increased tear evaporation.

It is a photograph which shows the state of the tear oil layer when the eye drop prepared in Comparative Example 1 is instilled. It is a photograph which shows the state of the tear oil layer when the eye drop prepared in Comparative Example 2 is instilled. It is a photograph which shows the state of the tear oil layer when the eye drop prepared in Comparative Example 3 is instilled. It is a photograph which shows the state of the tear oil layer when the eyedrops prepared in Example 1 are instilled. It is a photograph which shows the state of the tear oil layer when the eye drop prepared in Example 6 is instilled. It is a photograph which shows the state of the tear oil layer when the eye drop prepared in Example 7 is instilled. It is a photograph which shows the state of the tear oil layer when the eye drop prepared in Example 8 is instilled. It is a photograph which shows the state of the tear oil layer when the eye drop prepared in Example 9 is instilled.

Claims (1)

0.01-0 . Aqueous eye drops for preventing or ameliorating enhanced evaporation type dry eye characterized by containing 1% by mass of oil and mucopolysaccharide (aqueous eye drops containing a cooling agent, chlorobutanol, or a cellulose-based thickener) except for).

Images