WO2014163142A1

WO2014163142A1 - Ophthalmic composition

Info

Publication number: WO2014163142A1
Application number: PCT/JP2014/059838
Authority: WO
Inventors: 裕一大橋; 白石　敦; 小林　剛
Original assignee: 国立大学法人愛媛大学
Priority date: 2013-04-03
Filing date: 2014-04-03
Publication date: 2014-10-09
Also published as: JPWO2014163142A1

Abstract

The present invention addresses the problem of providing an ophthalmic composition that holds promise for having a long-lasting effect and therapeutic effect on serious cases and is efficacious in treating dry eye. The ophthalmic composition comprises as an active ingredient a compound having a moisture adjusting effect in a digestive tract. A preferable example of the compound having a moisture adjusting effect in a digestive tract is a member selected from among bisacodyl, picosulfate and pharmaceutically acceptable salts thereof. The active ingredient of the ophthalmic composition according to the present invention can increase tear volume in an eye to be treated. When bisacodyl or picosulfate is used as the active ingredient of the ophthalmic composition according to the present invention, an increase in tear volume can be observed several minutes to several hours, for example 3 hours, after instillation.

Description

Ophthalmic composition

The present invention relates to an ophthalmic composition comprising as an active ingredient a compound having a water regulating action in the digestive tract. More particularly, it relates to a pharmaceutical composition effective for the treatment of dry eye.

The state where the health of the surface of the eye, cornea, or conjunctiva is impaired due to the decrease or change in tears is called dry eye. The lack of tears due to decreased secretion of tears, dryness of the eyes due to excessive evaporation of tears, and poor tear stability cause rough surfaces of the cornea and conjunctiva, resulting in symptoms such as eye discomfort and fatigue.

It is said that the cause is complex. There have been reports of cases of dry eye due to aging and after eye surgery such as long-term or long-term use of contact lenses and LASIK. There are also severe dry eyes with few tears due to autoimmune diseases such as Sjogren's syndrome and illnesses such as Stevens Johnson syndrome. In addition, life that keeps watching the screens of computers, televisions, mobile phones, and tablet terminals reduces blinking and makes it easier for tears to evaporate. Also, air-conditioned rooms tend to be generally dry. Furthermore, since the secretion of tears is governed by the parasympathetic nerve, it is considered that the secretion decreases in a stressful state with sympathetic nerve predominance. There are reports that eye symptoms caused by hay fever are related to dry eye.

Currently, dry eye is treated with artificial tears of equal osmotic pressure (active ingredients: sodium chloride, potassium chloride, sodium carbonate, sodium hydrogen phosphate hydrate, boric acid) and hyaluronic acid. In addition, eye drops containing rebamipide having mucin production promoting action as an active ingredient and eye drops containing diquafosol sodium as an active ingredient are used. Diquafosol sodium acts on the P2Y2 receptor on the conjunctival epithelium and the conjunctival goblet cell membrane to increase the intracellular calcium ion concentration, thereby promoting water and mucin secretion and making the ocular surface environment more normal. It is thought to be close to the condition and to improve dry eye symptoms and keratoconjunctival epithelial disorder.

On the other hand, bisacodyl is included in constipation drugs for over-the-counter medicines to improve unpleasant symptoms such as constipation and associated head weight, abdominal fullness, loss of appetite (decreased appetite), and abnormal intestinal fermentation. . In addition to acting on the parasympathetic nerve endings of the large intestine to increase peristalsis, bisacodyl acts directly on the intestinal mucosa to stimulate the defecation reflex and promote defecation. As with bisacodyl, picosulfate sodium is known as a component that is combined with a constipation drug to have a laxative action by enhancing the peristaltic movement of the large intestine and suppressing water absorption. Various dosage forms containing these as active ingredients have been developed for the purpose of acting on the digestive tract (for example, Patent Documents 1 and 2).

As the action of bisacodyl, by reducing the expression level of AQP3 in the colonic mucosal epithelial cells, it is suggested that water movement from the intestinal tract side to the vascular side may be suppressed, and that it may show a swallowing action, as this mechanism, bisacodyl is first increased secretion of COX2 and PGE ₂ from the large intestine of macrophages, then it has been reported that PGE ₂ has reduced the expression of AQP3 colon mucosal epithelial cells (non-Patent Document 1 ).

JP2012-224619 JP2002-003377

None of the medicines currently used for the treatment of dry eye are considered to be sufficient for sustained effects or severe cases. Needless to say, it would be desirable to have a means that can more effectively treat dry eye.

The present inventors have intensively studied methods for treating dry eye for many years. Since the conjunctiva of the eye secretes and absorbs water in the same way as the digestive tract, we examined the administration of a drug that has the effect of suppressing water absorption in the digestive tract as an instillation. As a result, when a dry eye model mouse was instilled with an aqueous solution of bisacodyl or picosulfate sodium, which is a component of constipation drugs that are generally marketed, it has the effect of significantly increasing tear volume 3 hours after the end of the period. The present invention has been completed.

The present invention provides the following.
[1] An ophthalmic composition comprising, as an active ingredient, a compound having a moisture regulating action in the gastrointestinal tract.
[2] The ophthalmic composition according to [1] for treating a disease or condition associated with tear volume.
[3] The ophthalmic composition according to [2], wherein the disease or condition related to tear volume is dry eye.
[4] The ophthalmic composition according to any one of [1] to [3], which is an eye drop.
[5] The compound according to any one of [1] to [4], wherein the compound having a water regulating action in the gastrointestinal tract is any one selected from bisacodyl, picosulfate and a pharmaceutically acceptable salt thereof. Ophthalmic composition.
[6] The ophthalmic composition according to any one of [1] to [5], containing 0.05 to 3% of an active ingredient.

0.2% bisacodyl eye drop test for normal mice. Normal mice showed a tendency to increase tear volume 3 hours after instillation of 0.2% bisacodyl. 0.2% bisacodyl instillation experiment for dry eye model mouse. In dry eye model mice, a significant increase in tear volume was observed 3 hours after instillation of 0.2% bisacodyl. *: P <0.05 (Wilcoxon rank sum test), n = 10 Change in tears 3 hours after instillation (normal mice). In normal mice, bisacodyl concentration-dependent increase in tear volume was observed. Normal mice were not significantly different from the placebo group. *: P <0.05 (Wilcoxon rank sum test), n = 10 Change in tears 3 hours after instillation (dry eye model mouse). In dry eye model mice, Bisacodyl concentration-dependent increase in tear volume was observed. *: P <0.05, **: p <0.01 (Wilcoxon signed rank test), n = 10 Relative expression level (vs. placebo-treated control). Bisacodyl instillation increased IL-1β and IL-6 expression but not AQP3. *: P <0.05 (Mann-Whitney U test) n = 10 0.75% laxoberon eye drop test for normal mice. In normal mice, an increase in tear volume was observed 2 to 3 hours after laxoberon instillation. *: P <0.05 (Wilcoxon signed rank test), n = 22 Quantification of prostaglandin E ₂ (PGE ₂ ) in the conjunctiva after Bisacodyl instillation. Bisacodyl instillation increased PGE ₂ in the conjunctiva in both normal and dry eye model mice. *: p <0.05, * *: p <0.01 (Wilcoxon U test), n = 12 (normal mouse), n = 6 (dry eye model mouse) Expression of PGE ₂ synthase gene in the conjunctiva after Bisacodyl instillation. After normal mice were instilled with 1% bisacodyl (containing 10% DMSO) or placebo (10% DMSO), conjunctiva was collected 1 hour, 2 hours, and 3 hours after the instillation. Increased expression of Ptgs2 mRNA was observed by bisacodyl instillation. *: p <0.05, * *: p <0.01 (Wilcoxon U test), n = 8 Effect of bisacodyl instillation on dry eye model eyes. Dry eye model mice were instilled with bisacodyl or placebo 3 times a day for 1 week. There was no difference in BUT between 1 week before the start of instillation and just before the start of instillation. However, as a result of instillation for 1 week, prolonged BUT was observed and the stability of the tear film was improved. BUT prolongation was also observed at 1 week after the end of instillation. *: P <0.05, * *: p <0.01 (Wilcoxon U test), n = 8 An example of corneal fluorescein staining of a dry eye model eye. One week before the start of instillation and immediately before the start of instillation, a stained site showing corneal epithelial disorder was found in a wide range of the cornea. On the other hand, as a result of instillation 3 times a day for 1 week, it was found that the staining range was reduced and corneal epithelial disorder was reduced.

In the present invention, when a numerical range is expressed using “n to m”, the range includes the values n and m at both ends unless otherwise specified.

In the present invention, the term “ophthalmic composition” means a pharmaceutical composition in a form suitable for application to the eye, unless otherwise specified. The ophthalmic composition is adjusted in pH and / or osmotic pressure as appropriate for application to the eye as needed, may be adjusted in viscosity, and may be sterile. Ophthalmic compositions include eye drops, eye perfusates, eye ointments, eye viscosities, contact lens mounting fluids and contact lens care agents.

The present invention provides an ophthalmic composition comprising, as an active ingredient, a compound having a water regulating action in the digestive tract. Particularly preferred examples of the active ingredient of the ophthalmic composition of the present invention are bisacodyl, picosulfate and pharmaceutically acceptable salts thereof. According to the study by the present inventors, an increase in PGE ₂ in the conjunctiva was observed in both normal mice and dry eye model mice by bisacodyl instillation (see the Examples section of the present specification). This is similar to the effect of bisacodyl reported on the colonic mucosa.

Bisacodyl (chemical name: 4,4 '-(Pyridin-2-ylmethylene) bis (phenylacetate) has the following structure.

Picosulfate (chemical name 4,4 '-(pyridin-2-ylmethylene) bis (phenylsulfate)) is a commercially available drug and is contained as sodium picosulfate of the following formula.

The picosulfate salt used in the ophthalmic composition of the present invention is not particularly limited as long as it is pharmaceutically acceptable. Examples thereof include alkali metal salts (for example, sodium salts and potassium salts), alkaline earth metal salts. (Eg magnesium salt, calcium salt), ammonium salt, mono-, di- or tri-lower (alkyl or hydroxyalkyl) ammonium salt (eg ethanolammonium salt, diethanolammonium salt, triethanolammonium salt, tromethamine salt), hydrochloride , Hydrobromide, hydroiodide, nitrate, phosphate, sulfate, formate, acetate, citrate, oxalate, fumarate, maleate, succinate, malic acid Salt, tartrate, aspartate, trichloroacetate, trifluoroacetate, methanesulfonate Benzenesulfonate, p- toluenesulfonate, may be mentioned mesitylene sulfonate and naphthalene sulfonate. Further, when referring to the compound of the present invention or a salt thereof, it may be an anhydride or a solvate, and the solvate includes a hydrate, a methanol solvate, an ethanol solvate, a propanol solvate, and 2-propanol. Japanese products are included.

In the ophthalmic composition of the present invention, the active ingredient may be one or a plurality of combinations. The content of the active ingredient (as a total amount when a plurality of active ingredients are used) is 0.0001 to 5%, preferably 0.001 to 3%, more preferably 0.05 to 3%, and particularly preferably about 0.1 to 1%.

The dose of the ophthalmic composition of the present invention can be appropriately designed by those skilled in the art. For example, in the case of eye drops, it can be applied every several hours or once to several times a day.

The administration period of the ophthalmic composition of the present invention can be appropriately designed by those skilled in the art. For example, in the case of eye drops, administration 1 to several times a day, several days to several weeks, for example 3 Can be used continuously for 7 days or 14 days.

The ophthalmic composition of the present invention can be used to treat diseases or conditions related to tear volume. In the present invention, the term “treatment” includes prevention and treatment unless otherwise specified. Prevention includes reducing the risk of onset. The ophthalmic composition of the present invention is particularly suitable for use for the treatment of dry eye. Dry eye is generally a chronic disease of tears and keratoconjunctival epithelium due to various factors, and is accompanied by eye discomfort and abnormal visual function, and is also used in this sense in the present invention.

Although there are various causes and conditions of dry eye, the ophthalmic composition of the present invention can be suitably used for any of them. For example, the ophthalmic composition of the present invention can be used in severe dry eyes such as Sjogren's syndrome even with dry eyes with reduced tear secretion (normally irritating secretion is normal). Yes, even if the lacrimal stimulatory secretion is also reduced. Also, transpiration-type dry eyes (because of staring at a PC monitor, etc., blinking is reduced, oil is not properly supplied due to aging, etc., and moisture cannot be kept on the eye surface. Reduced dry eye even if allergic or contact lenses are worn for a long time, or the surface of the keratoconjunctiva is damaged or the surface of the eye is rough Even so, it can also be applied to wet-type dry eyes (mainly because the tear discharge function does not work correctly and the surface of the eye is susceptible to irritation).

The ophthalmic composition of the present invention is also useful for corneal epithelial disorders related to dry eye.

The active ingredient of the ophthalmic composition of the present invention can increase the amount of tears in the target eye. When bisacodyl or picosulfate is used as the active ingredient of the ophthalmic composition of the present invention, an increase in tear volume can be observed after instillation, minutes to hours, for example, 3 hours. Prior art eye drops for the treatment of dry eye were not sufficient for long-lasting and severe cases, but the ophthalmic composition of the present invention provided long-lasting and / or severe cases. I can expect. Regarding persistence, according to the study of the present invention, when dry eye model mice were instilled 3 times a day with an ophthalmic composition formulated according to the present invention for 1 week, BUT (tear layer destruction) (Time) was prolonged, the stability of the tear film was improved, and BUT was also observed at the time when 1 week had elapsed after the completion of instillation (see the Examples section of the present specification).

Whether or not it is dry eye and whether or not the amount of tears is increased by applying the ophthalmic composition of the present invention can be confirmed by a known inspection method. Examples of known inspection methods include screening with a slit lamp, staining inspection, Schirmer test (using filter paper or phenol red thread), BUT measurement (measurement of tear film breakage time), clearance test, and the like.

In the ophthalmic composition of the present invention, various pharmaceutically acceptable additives can be blended as long as the effects of the present invention are not impaired.

An isotonic agent can be blended in the ophthalmic composition of the present invention. Examples of isotonic agents that can be used in the present invention include inorganic salts such as sodium chloride and potassium chloride. Inorganic salts are used depending on what is used, but are usually used in an amount of about 0.001 to 5%, preferably about 0.001 to 1%, more preferably about 0.005 to 0.5%.

The ophthalmic composition of the present invention is used by adjusting to an osmotic pressure within a range acceptable for a living body, if necessary. The osmotic pressure is about 100 to 1200 mOsm, preferably about 100 to 600 mOsm, particularly preferably about 150 to 400 mOsm, and the osmotic pressure ratio with respect to physiological saline is usually 0.4 to 4.1, preferably 0.3 to 2.1, particularly preferably 0.5 to 1.4. Degree.

In the ophthalmic composition of the present invention, an additive (buffer) for pH adjustment can be blended. Examples of the buffer that can be used in the present invention include borate buffer, phosphate buffer, carbonate buffer, citrate buffer, acetate buffer, HEPES buffer, and MOPS buffer. More specific examples include: boric acid, sodium borate, potassium tetraborate, potassium metaborate, etc., phosphoric acid, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, carbonic acid, sodium hydrogen carbonate, carbonic acid Examples thereof include compounds such as sodium, citric acid, sodium citrate, potassium citrate, acetic acid, sodium acetate, HEPES, and MOPS, and combinations of two or more compounds selected from these groups.

The ophthalmic composition of the present invention is used after adjusting to a pH within a range applicable to a living body, if necessary. The pH is, for example, pH 4.0 to 9.0, preferably 5.0 to 8.5, more preferably 5.5 to 8.5.

The ophthalmic composition of the present invention can be set to an appropriate viscosity to obtain a desired effect. The viscosity of the ophthalmic composition affects the comfort (use feeling) and drug retention capacity when applied to the ocular mucosa, so an appropriate viscosity is designed and the designed viscosity is maintained stably over the long term. It is good to be done. The appropriate viscosity is, for example, a viscosity at 20 ° C. of 1.5 mPa · s or more, typically 1.5 to 300 mPa · s, preferably 2 to 200 mPa · s, particularly preferably 5 to 100 mPa · s, more preferably Can be designed to about 10 to 80 mPa · s. The viscosity can be adjusted using the buffer, the pH adjuster, the thickener (for example, methylcellulose, hydroxypropylmethylcellulose) and the like.

Other examples of additives that can be used in the ophthalmic composition of the present invention include solubilizers (for example, triethanolamine, diethanolamine), stabilizers (for example, anhydrous sodium sulfite), suspending agents and emulsifiers. (For example, sodium carboxymethylcellulose, polysorbate 80) Surfactants, preservatives (for example, parabens), bactericides or antibacterial agents, fragrances or refreshing agents, and various additives such as sugars can be mentioned.

The ophthalmic composition of the present invention can be formulated by combining other active ingredients. Examples of other active ingredients that can be used in the present invention include a decongestant component, an eye muscle modulator component, an anti-inflammatory component or an astringent component, an antihistamine component or an antiallergy that are commonly used in ophthalmic compositions. Medicinal components, vitamins, amino acids, local anesthetic components, steroid components and the like can be mentioned.

The ophthalmic composition of the present invention can be produced by a known method. A filtration sterilization process, an aseptic filling process into a container, and the like can be added.

When the ophthalmic composition of the present invention is used as an ophthalmic solution, if appropriate, components other than the active ingredient can have a configuration similar to that of an existing ophthalmic solution. Some examples are given below.

Example 1 (pH 5.0)
Boric acid 20.0
Methyl paraoxybenzoate 0.26
Propyl paraoxybenzoate 0.14
Sterile purified water ad 1000.0

Example 2 (pH 6.5)
Methyl paraoxybenzoate 0.26
Propyl paraoxybenzoate 0.14
Sterile purified water ad 1000.0

Example 4 (Viscous eye drops)
Methylcellulose (4000CPS) 0.3
Sodium chloride 0.9
Benzethonium chloride 0.02
Sterile purified water ad 100.0

Example 5 (In the case of eye drop oil. The active ingredient can be dissolved or suspended in the oil.)
Aluminum monostearate 2g
Refined vegetable oil ad 100g

In addition, when the ophthalmic composition of the present invention is used as an ophthalmic solution, if appropriate, a dosage form in use (for example, a solution and a set of an active ingredient stored in a container separate from the solution) ).

Hereinafter, the present invention will be described using examples.

[Experiment 1: Bisacodyl eye drop experiment]
Bisacodyl ophthalmic experiments were conducted using normal mice or dry eye model mice (resection of lacrimal glands). C57BL / 6 12-week-old mice were tested in 5 mice (10 eyes) each. The dry eye model mice were anesthetized by intraperitoneal injection of 0.2% 4% trichloroacetaldehyde female C57BL / 6 mice at 8 weeks of age. It was created by excising the lacrimal gland from the lacrimal gland opening in the vicinity of the opening. In this experiment, subjects 4 weeks after the lacrimal gland resection were used.

Bisacodyl (Sigma-Aldrich Co. LLC) was dissolved in dimethyl sulfoxide (DMSO) to prepare a 10% (w / v) solution. 20% of Bisacodyl DMSO solution (10%) was added to 980 μl of physiological saline to prepare 0.2% bisacodyl ophthalmic solution (containing 2% DMSO). A solution obtained by adding 20 μl of DMSO to 980 μl of physiological saline was used as a placebo ophthalmic solution (2% DMSO).

A 0.2% bisacodyl solution (containing 2% DMSO) or a placebo (2% DMSO) was prepared, and each eye drop was instilled 3 times at 25 μL, 5 minute intervals. On the first day, a placebo was applied, and on the second day, 0.2% bisacodyl ophthalmic solution was administered. Prior to instillation, 1 hour after instillation, 2 hours, 3 hours and 6 hours later, the amount of tears was measured with a phenol red thread (Zonequick (registered trademark) Showa Yakuhin Kako Co., Ltd., measurement time 30 seconds).

The results are shown in FIGS. In dry eye mice, a significant increase in tear volume was observed 3 hours after instillation of 0.2% bisacodyl.

[Experiment 2: Examination of Bisacodyl concentration]
The concentration of bisacodyl was examined using normal mice or dry eye model mice.
As in Experiment 1, prepare a DMSO solution of bisacodyl (10%), add 20 μl, 50 μl, or 100 μl to 980 μl, 950 μl, and 900 μl of physiological saline, respectively, and add bisacodyl ophthalmic solution (0.2%, 0.5%). %, 1%). 0.2% bisacodyl (2% DMSO), 0.5% bisacodyl (5% DMSO), 1% bisacodyl (10% DMSO), or placepo (DMSO) was instilled. The amount of tear fluid before and after instillation was measured with a phenol red thread (Zonequick (registered trademark) Showa Yakuhin Kako Co., Ltd., measurement time 30 seconds).

In normal mice, bisacodyl concentration-dependent increase in tear volume was observed, and no significant difference from the placebo group was observed (FIG. 3). In dry eye model mice, a significant increase in tear volume dependent on the bisacodyl concentration was observed (Fig. 4).

[Experiment 3: Examination of gene expression level]
C57BL / 6 12-week-old normal mice were injected with 0.2% bisacodyl (containing 2% DMSO) or placebo (2% DMSO) at a dose of 25 μL per eye, 3 times at 5 minute intervals, then 1 hour after instillation, 2 The conjunctiva was collected after 3 hours. Total RNA was extracted from the conjunctiva using RNeasy Fibrous Tissue Mini Kit (Qiagen) and reverse transcription was performed using SuperScript (registered trademark) VILO ^™ cDNA Synthesis Kit (Life Technologies Corporation) to synthesize cDNA. Real-time PCR was performed using cDNA as a template, and AQP1, AQP3, IL-1β, IL-6, and TNFα mRNA were quantified. For mRNA quantification by Real-time PCR, StepOnePlus ^™ Real-Time PCR System (Life Technologies Corporation) and TaqMan (registered trademark) gene expression assay (Life Technologies Corporation) were used. The IDs of TaqMan® gene expression assays used for the analysis are Mm00431834 # m1 (Aqp1), Mm01208559 # m1 (AQP3), Mm00434228 # m1 (IL-1β), Mm00446190 # m1 (IL-6), Mm00443260 # g1 (TNFα).

The results are shown in FIG. Increased expression of IL-1β and IL-6 was observed by bisacodyl instillation. On the other hand, no decrease in AQP3 was observed in this experiment.

[Experiment 4: Picosulfate instillation experiment]
Picosulfate instillation experiment was conducted using normal mice. C57BL / 6 12-week-old mice, 11 (22 eyes) were used as subjects.

0.75% picosulfate sodium (Laxoberon) was prepared, and 25 μL per eye was instilled 3 times at 5-minute intervals. Prior to instillation, 1 hour after instillation, 2 hours, 3 hours, and 4 hours later, the amount of tears was measured with a phenol red thread (Zonequick (registered trademark) Showa Yakuhin Kako Co., Ltd., measurement time 30 seconds).

The results are shown in FIG. A significant increase in tear volume was observed 2 to 3 hours after instillation.

[Experiment 5: Determination of prostaglandin E ₂ (PGE ₂ ) in the conjunctiva after Bisacodyl instillation]
C57BL / 6 12-week-old normal mouse or dry eye model mouse (4 weeks after pairectomy), 1% bisacodyl (including 10% DMSO) or placebo (10% DMSO) at a dose of 25 μL per eye, every 5 minutes After 3 drops, the conjunctiva was collected 3 hours later. The quantification of PGE ₂ using Prostaglandin E2 Parameter Assay Kit (R & D).

The results are shown in FIG. Bisacodyl instillation increased PGE ₂ in the conjunctiva in both normal and dry eye model mice. This is similar to the action of the bisacodyl reported in colonic mucosa, possibly an absorption inhibition or secretagogue moisture by modulation of ion pump or ion channel via PGE ₂ can be expected.

[Experiment 6: Expression of PGE ₂ synthase (Cyclooxygenase) gene in the conjunctiva after Bisacodyl eye drop]
C57BL / 6 12-week-old normal mice were treated with 1% bisacodyl (containing 10% DMSO) or placebo (10% DMSO) at a dose of 25 μL, 3 times at 5 min intervals, then 1 hour after instillation, 2 The conjunctiva was collected after 3 hours. Total RNA was extracted from the conjunctiva using RNeasy Fibrous Tissue Mini Kit (Qiagen) and reverse transcription was performed using SuperScript (registered trademark) VILO ^™ cDNA Synthesis Kit (Life Technologies Corporation) to synthesize cDNA. Real-time PCR was performed using cDNA as a template, and Ptgs1 (Cyclooxygenase-1, COX-1) and Ptgs2 (Cyclooxygenase-2, COX-2) mRNAs were quantified. For mRNA quantification by Real-time PCR, StepOnePlus ^™ Real-Time PCR System (Life Technologies Corporation) and TaqMan (registered trademark) gene expression assay (Life Technologies Corporation) were used. The IDs of the TaqMan® gene expression assay used for the analysis are Mm00477214 # m1 (Ptgs1) and Mm00478374 # m1 (Ptgs2).

The results are shown in FIG. Increased expression of Ptgs2 mRNA was observed by bisacodyl instillation.

[Experiment 7: Effect of bisacodyl instillation on dry eye model eyes]
C57BL / 6 6-month-old dry eye model mice (4 months after lacrimal gland excision) with 1% bisacodyl (containing 10% DMSO) or placebo (10% DMSO) at a dose of 25 μL per eye, 3 times daily I went there for a week. In order to evaluate the stability of the tear film and the degree of corneal epithelial damage, we measured the tear film break time (BUT) and stained the cornea with fluorescein. BUT measurement and corneal fluorescein staining were performed for 1 week before the start of instillation, immediately before the start of instillation, at the end of instillation, and 1 week after the end of instillation.

The result of BUT measurement is shown in FIG. There was no difference in BUT between one week before instillation and just before instillation. On the other hand, as a result of instillation 3 times a day for 1 week, it was found that BUT was prolonged and the stability of the tear film was improved. It was found that BUT prolongation was also observed at 1 week after the end of instillation.

An example of corneal fluorescein staining of a dry eye model eye is shown in FIG. One week before the start of instillation and immediately before the start of instillation, a stained site showing corneal epithelial disorder was found in a wide range of the cornea. On the other hand, as a result of instillation 3 times a day for 1 week, it was found that the staining range was reduced and corneal epithelial disorder was reduced.

Claims

An ophthalmic composition comprising as an active ingredient a compound having a water regulating action in the digestive tract.
The ophthalmic composition according to claim 1, for treating a disease or condition associated with tear volume.
3. The ophthalmic composition according to claim 2, wherein the disease or condition related to tear volume is dry eye.
The ophthalmic composition according to any one of claims 1 to 3, which is an ophthalmic solution.
The ophthalmic composition according to any one of claims 1 to 4, wherein the compound having a water regulating action in the gastrointestinal tract is any one selected from bisacodyl, picosulfate and a pharmaceutically acceptable salt thereof. .
The ophthalmic composition according to any one of claims 1 to 5, comprising 0.05 to 3% of an active ingredient.