TW202404617A - Ophthalmic composition - Google Patents

Abstract

The present invention provides a novel ophthalmic composition. The ophthalmic composition comprises polysulfated chondroitin sulfate as an active ingredient thereof. This composition is effective for preventing and/or treating keratoconjunctive disorder, and/or for increasing the amount of tear liquid, and/or for preventing or treating dry eye.

Description

Ophthalmic compositions

The present invention relates to an ophthalmic composition that can be used to treat and/or prevent dry eye syndrome and the like.

In recent years, due to prolonged use of smartphones or personal computers, dry air due to air conditioning, use of contact lenses, etc., an increase in the number of people are troubled by the symptoms of dry eye syndrome (also called keratoconjunctivitis sicca). Dry eye syndrome is a condition caused by reduced tear production, an imbalance in the tear layer, and/or excessive loss of water from the surface of the eye (e.g., due to meibomian gland insufficiency, Sjogren's Syndrome, eyelid closure Incomplete, caused by incomplete blinking caused by the operation of visual display terminals (Visual Display Terminals), etc.), and the cornea is not adequately protected by tears, resulting in corneal disorders. Therefore, one or more symptoms such as dry eyes, foreign body sensation, pain, fatigue, blurred vision, and congestion will generally occur.

As a treatment for dry eye syndrome, artificial tears containing sodium chloride, potassium chloride, etc., and composed close to tears, or eye drops containing active ingredients (for example, containing rebamipide, sodium hyaluronate, diquafosol) are generally used. One or more of sodium (diquafosol sodium), chondroitin sulfate sodium (also known as chondroitin sulfate sodium), hypromellose (also known as hydroxypropyl methylcellulose), etc., as active ingredients eye drops).

In addition, other active ingredients have also been proposed. For example, Patent Document 1 discloses that "in order to produce a pharmaceutical composition for treating dry eye disease, etc., at least one pharmacologically compatible viscosity regulating factor and at least one A mucopolysaccharide with heparin activity, and pharmaceutical auxiliaries used as needed." [Prior technical literature] [Patent Document]

[Patent Document 1] Japanese Patent Publication No. 2005-513106

[Problem to be solved by the invention]

As mentioned above, as ophthalmic compositions for treating dry eye syndrome, a plurality of products are already on the market. However, effective agents for treating dry eye syndrome are still being searched for. The example of the above-mentioned Patent Document 1 describes "a composition containing sodium hyaluronate, sodium heparin, etc. with a heparin activity of 2,000 I.U." However, in order to treat dry eye syndrome, it is considered that at least one of the healing effect of corneal and conjunctival disorders and the effect of increasing tear volume is required. However, there is no description of pharmacological experiments in Patent Document 1. Therefore, to what extent does it have effect on dry eye syndrome? The effect is unclear.

Therefore, an object of the present invention is to provide a novel ophthalmic composition which has a healing effect on corneal and conjunctival disorders and/or an increasing effect on tear volume, and which can effectively treat dry eye syndrome. [Technical means to solve the problem]

The present inventors conducted repeated studies in order to solve the above-mentioned problems, and found that an ophthalmic composition containing polysulfated chondroitin sulfate can solve the above-mentioned problems.

The present invention relates to an ophthalmic composition having the following composition. [1] An ophthalmic composition containing polysulfated chondroitin sulfate as an active ingredient and used for preventing and/or treating corneal and conjunctival disorders and/or for increasing tear volume. [2] An ophthalmic composition containing polysulfated chondroitin sulfate as an active ingredient and used for preventing and/or treating dry eye syndrome. [Effects of the invention]

Since the composition of the present invention has a healing effect on corneal and conjunctival disorders and/or an increasing effect on tear volume, it is also effective in preventing and/or treating dry eye syndrome.

The composition of the present invention contains polysulfated chondroitin sulfate and/or its salts. Polysulfated chondroitin sulfate is a polymer in which a disaccharide composed of N-acetyl-D-galactamine sugar and D-glucuronic acid is used as a repeating unit, and each unit (disaccharide) contains A polymer having about 2 to 4, preferably about 2 to 3, sulfate ester residues.

Polysulfated chondroitin sulfate can be produced by "condensing chondroitin components such as chondroitin and chondroitin sulfate (A, C, D, E) with sulfating agents such as chlorosulfuric acid, concentrated sulfuric acid, and sulfur trioxide-pyridine complex. "Reaction" can be easily produced by a known method. Furthermore, chondroitin sulfate A has a sulfate residue at position 4 of acetylgalactosamine, chondroitin sulfate C has a sulfate residue at position 6 of acetylgalactosamine, and chondroitin sulfate D has Chondroitin sulfate E has sulfate residues at the 4- and 6-positions of acetylgalactosamine. Basic ones.

Preferable examples of polysulfated chondroitin sulfate include heparin analogues listed in the Japanese Pharmacopoeia's Specifications for External Pharmaceutical Ingredients. Specifically, polysulfated chondroitin sulfate exhibits the following values as physicochemical properties. a) Sulfate group content: 25.8~37.3% by weight b) Ultimate viscosity: 0.09～0.18

Polysulfated chondroitin sulfate can also be used in the form of a free acid derived from a sulfate residue, but an alkali salt is usually used.

Examples of the alkali salt include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium, and magnesium salts.

The weight average molecular weight of the polysulfated chondroitin sulfate or its salt used in the present invention is not particularly limited, but is usually about 8,000 to 10,000,000, preferably about 8,000 to 1,000,000, more preferably about 10,000 to 100,000, especially 10,000. ~50,000 or so.

The content rate of polysulfated chondroitin sulfate and/or its salt as the active ingredient is preferably 0.001 to 10 w/v%, more preferably 0.5 to 5 w/v%, and particularly preferably 1.0 to 3.0 w/v%. .

In this specification, w/v% or content rate is a value obtained by expressing the weight (g) of each component contained in the ophthalmic composition as a percentage relative to the total volume (mL) of the ophthalmic composition. In other words, w/v% is equivalent to the weight (g) of each component in 100 mL of the ophthalmic composition.

The above composition can be used to prevent and/or treat corneal and/or conjunctival disorders (including corneal disorders and conjunctival disorders. Especially corneal disorders), and/or to increase tear volume, and/or to prevent and/or treat dry eye syndrome. Corneal disorders include corneal damage (such as damage to the corneal epithelium or corneal parenchyma), including corneal ulcers, superficial punctate keratopathy, and corneal epithelial defects. Conjunctival disorders include conjunctival damage (such as damage to the conjunctival epithelium, etc.), including, for example, conjunctival epithelial defects.

The dosage form of the above composition is not particularly limited as long as it can be used for the above purpose. Preferred examples include eye drops, eye washes, eye ointments, and the like. Particularly preferred are eye drops (also known as eye drops or eye drops). The above composition is preferably a sterile composition.

The dosage and frequency of administration of the above-mentioned composition are not particularly limited as long as they are within the range permitted by ophthalmology, and can be adjusted appropriately according to the degree of symptoms, age, weight, etc. of the patient. For example, when it is used in the form of eye drops, it is preferably generally 1 to 2 drops each time and administered 1 to 10 times, 2 to 8 times, or 3 to 6 times a day.

In addition to polysulfated chondroitin sulfate, the above composition may also include other active ingredients (for example, selected from the group consisting of rebamipide, sodium hyaluronate, diquafosol sodium, chondroitin sulfate sodium, hypromellose, etc. More than one ingredient), or may not contain other active ingredients. As one embodiment of the above composition, a composition containing only polysulfated chondroitin sulfate as an active ingredient can be exemplified.

If necessary, the above composition may also contain additives commonly used in ophthalmic compositions. For example, one or a plurality of additives such as buffers, isotonic agents, stabilizers, thickeners, pH adjusters, preservatives, and surfactants may be included.

Examples of the buffer include: boric acid, borax, citric acid, sodium citrate, phosphoric acid, sodium hydrogen phosphate, sodium dihydrogen phosphate, tartaric acid, gluconic acid, acetic acid, sodium acetate, carbonic acid, sodium bicarbonate, ε- Aminocaproic acid, etc. These may be used individually, or 2 or more types may be used together. The total buffer content in the composition is preferably 0.001 to 5 w/v%, more preferably 0.01 to 3 w/v%, and even more preferably 0.02 to 1 w/v%.

Examples of isotonic agents include calcium chloride, sodium chloride, potassium chloride, magnesium chloride, magnesium sulfate, concentrated glycerin, propylene glycol, and the like. These may be used individually, or 2 or more types may be used together. The total content rate of the isotonic agent in the composition is preferably 0.001 to 5 w/v%, more preferably 0.01 to 3 w/v%, even more preferably 0.05 to 2 w/v%.

Examples of stabilizers include: ethylenediaminetetraacetic acid, sodium ethylenediaminetetraacetate, cyclodextrin, sulfite, citric acid, citrate, butylhydroxymethoxybenzene, and dibutylhydroxytoluene. wait. These may be used individually, or 2 or more types may be used together. The total content of the stabilizer in the composition is preferably 0.001 to 5 w/v%, more preferably 0.01 to 3 w/v%, even more preferably 0.05 to 2 w/v%.

Examples of thickeners include polyvinylpyrrolidone, carboxymethylcellulose, hydroxyethylcellulose, methylcellulose, polyvinyl alcohol, polyacrylic acid, carboxyvinyl polymer, and sanxianjiao wait. These may be used individually, or 2 or more types may be used together. The total content of the thickener in the composition is preferably 0.001 to 5 w/v%, more preferably 0.01 to 3 w/v%, and even more preferably 0.05 to 2 w/v%.

Examples of the pH adjuster include potassium hydroxide, sodium hydroxide, calcium hydroxide, magnesium hydroxide, sodium carbonate, sodium bicarbonate, hydrochloric acid, citric acid, boric acid, phosphoric acid, acetic acid, propionic acid, oxalic acid, Tartaric acid, succinic acid and their salts, etc. These may be used individually, or 2 or more types may be used together. The pH adjuster is used to set the pH of the composition to 4.0 to 9.0, preferably 4.5 to 8.5, and particularly preferably 5.0 to 8.0. The total content of the pH adjuster in the composition is usually 0.001 to 1 w/v%.

Examples of the preservative include: sodium benzoate, benzalkonium chloride, phenysonine chloride, ethanol, lohexidine gluconate, sodium ethylenediaminetetraacetate, sorbic acid, potassium sorbate, p-hydroxy Paraoxybenzoic acid ester (methylparaben, ethylparaben, propylparaben, butylparaben, etc.), phenylethanol, chlorobutanol, etc. These may be used individually, or 2 or more types may be used together. The total content rate of preservatives in the composition is preferably 0.001 to 3 w/v%, more preferably 0.01 to 2.5 w/v%, even more preferably 0.05 to 2 w/v%.

Examples of surfactants include nonionic surfactants, amphoteric surfactants, anionic surfactants, cationic surfactants, and the like. These may be used individually or in combination of 2 or more types. Examples of the nonionic surfactant include polyoxyethylene castor oil, polyoxyethylene hardened castor oil, polyoxyethylene sorbitol fatty acid ester, polyoxyethylene-polyoxypropylene block copolymer, polyethylene Diol monostearate, etc. Examples of amphoteric surfactants include N-[2-[[2-(alkylamino)ethyl]amino]ethyl]glycine and salts thereof. Examples of the anionic surfactant include alkyl benzene sulfonate, alkyl sulfate, polyoxyethylene alkyl sulfate, and the like. Examples of the cationic surfactant include benzalkonium chloride, benzonine chloride, and the like. The total content rate of surfactants in the composition is preferably 0.001 to 3 w/v%, more preferably 0.01 to 2 w/v%, and even more preferably 0.05 to 1 w/v%.

The above composition preferably uses water (such as distilled water, purified water, sterilized purified water) as a solvent or base agent, more preferably aqueous eye drops, and particularly preferably sterile aqueous eye drops. The water content in the composition is preferably 80 w/v% or more, more preferably 85 w/v% or more, even more preferably 90 w/v% or more.

When the above composition is eye drops, the viscosity is preferably in the range of 1 to 100000 mPa･s, particularly preferably in the range of 1 to 10000 mPa･s. The above-mentioned viscosity can be measured, for example, according to the rotational viscometer method of Method 2 of "2.53 Viscometry Method" of the 18th revised edition of the Japanese Pharmacopoeia.

When the above composition is an eye drop, the osmotic pressure ratio (osmotic molar concentration of the ophthalmic composition/osmotic molar concentration of physiological saline [286 mOsm]) is preferably 0.4 to 3.0, more preferably Preferably, it is 0.6~2.0, and particularly preferably, it is 0.7~1.3. The osmotic pressure ratio can be determined according to "2.47 Osmotic pressure measurement method (Osmolarity determination method)" in the 18th revised edition of the Japanese Pharmacopoeia.

In the previous paragraphs, the preferred compound names of the essential components and optional components used in the composition of the present invention are described, but the composition of the present invention also includes compositions obtained by combining any of these and the combination of each component. A composition obtained by any combination of contents. In addition, the numerical ranges of viscosity, pH, content rate, osmotic pressure ratio, etc. may be combined arbitrarily. When a plurality of numerical ranges are described, the upper limit or lower limit of each numerical range may be arbitrarily combined.

Hereinafter, the present invention will be described in more detail using examples, but the present invention is not limited by the examples. [Example]

In the following examples, as polysulfated chondroitin sulfate or its salt, heparin analogues (abbreviated as MPS) included in the Japanese Pharmacopoeia Overseas Drug Ingredient Specifications were used. The organic sulfate group was 25.8 to 37.3% w/w, and glucuronide was used. Acid content 19.0~24.0%w/w, Maruho Co., Ltd.). Sodium hyaluronate (abbreviated as HA, Sigma-Aldrich) and chondroitin sulfate sodium (abbreviated as ChS, organic sulfate group: 15 to 17% w/w, Maruho Co., Ltd.) were used as comparative substances. As the administration medium, physiological saline solution (Otsuka Pharmaceutical Factory Co., Ltd.) was used.

[Example 1] Healing effect of MPS on corneal damage Using 8-week-old male SD rats, the outer orbit of the eye socket was made in the following manner according to the method of Murakami et al. (New Ophthalmology 21 (1): 87-90 (2004)) Lacrimal gland removal model (dry eye syndrome model). After the model was made, the corneal damage score after eyedrop administration was evaluated. Based on the body weight of the rats, the rats were divided into a normal group and a treatment group in a manner that would not cause deviation between groups. In the administration group, rats were given general anesthesia by inhalation of isoflurane (Mylan Pharmaceutical Co., Ltd.), and then the analgesic Lepetan injection (Otsuka Pharmaceutical Co., Ltd.) was intramuscularly administered, followed by incision and sterilization. Below the ears, and remove the tear glands outside the eye sockets. At the 6th week after removal of the lacrimal glands, the rats in the administration group were further divided into 5 groups (8 rats in each group) based on the amount of tear secretion in a manner that did not cause deviation between groups. When measuring the amount of tear secretion, Schirmer test paper (AYUMI Pharmaceutical Co., Ltd.) was inserted between the lower eyelid and the eyeball of the rat, and an electronic vernier caliper was used to measure the length moistened by tear fluid. The normal group was given eye drops of physiological saline solution, and the five treatment groups were given eye drops of physiological saline solution (control group), 0.3% HA, 1% ChS, 0.3% MPS, and 3% MPS respectively; 6 times a day (each time 5 μL), repeated eye drops for 14 days (8 animals per group: only one eye was used). The % of each ingredient is w/v%. On the day after the final eye drops, mydriatic agent (Mydrin ^{(registered trademark)} P eye drops, Santen Pharmaceutical Co., Ltd.) was dropped into the eyes of the rats, and then fluorescent test paper (Fluores ^{(registered trademark))} for eye examination was applied. Paper 0.7 mg, AYUMI Pharmaceutical Co., Ltd.) was dropped with 0.1 mL of physiological saline solution (Otsuka Pharmaceutical Co., Ltd.), and the fluorescent test paper was stained by contacting the limbus of the rat's cornea near the sclera. For the upper, middle and lower corneas, the degree of staining is judged based on the following criteria, and the total score of the three parts is evaluated so that the full score is 9 points.

(Judgment criteria) 0: Not dyed 1: The staining is sparse and the stained parts of each spot are separated. 2: The staining is moderate, and some of the dot-like stained parts are adjacent to each other. 3: Dense dyeing, the dyed parts of each spot are adjacent to each other

The results are shown in Table 1 and Figure 1. Each data in Table 1 represents the measured mean ± standard error of the scores of 8 animals. The lower the corneal damage score, the less damage to the cornea. ^{The **} mark in Table 1 and Figure 1 indicates that the p value calculated by the Student t-test (Student t-test) and using the normal group as the benchmark does not reach 0.01, and the ^†† mark indicates that the p value calculated by Dunnett's multiple The p value calculated by Dunnett's multiple comparison test and using the control group as the benchmark did not reach 0.01.

[Table 1] Group name Corneal damage treatment corneal damage score Normal group (physiological saline solution) without 0.9±0.4 Control group (physiological saline solution) have 7.0±0.8 ^** 0.3% HA group 8.1±0.5 1% ChS group 6.3±0.6 0.3% MPS group 5.9±0.6 3% MPS group 1.8±0.6 ^

As shown in Table 1, in the 0.3% HA group, no reduction in corneal damage score was observed, but in the 1% ChS group and 0.3% MPS group, a tendency to reduce the corneal damage score was observed. In particular, the MPS group showed lower scores than the 1% ChS group at a concentration of 0.3%. Furthermore, compared with the control group, the corneal damage score of the group in which the concentration of MPS was increased to 3% was significantly lower, and corneal damage was significantly improved.

[Example 2] Increased effect of MPS on tear secretion. A model of removal of lacrimal glands outside the orbit (dry eye model) was prepared using the same method as Example 1, and physiological saline solution was dropped into the eyes of each of the three groups ( Control group), 3% ChS, 3% MPS, 6 times a day (5 μL each time), repeated eye drops for 14 days (8 animals per group: only one eye is used). On the day after repeated eye drops for 14 days, each group was given eye drops once, and the amount of tear secretion was measured 40 minutes later. The amount of tear secretion was determined as follows: Schirmer test paper (AYUMI Pharmaceutical Co., Ltd.) was inserted between the lower eyelid and the eyeball of the rat, and an electronic vernier caliper was used to measure the length moistened by tear fluid. The results are shown in Table 2. Each data represents the mean ± standard error of the tear secretion measurements of 8 animals. In Table 2, ^{the ‡‡} mark indicates that the p value calculated by the Student t-test (Student t-test) and using the control group as the benchmark does not reach 0.01, and the ^‡ mark indicates that the p value does not reach 0.05.

[Table 2] Group name Corneal damage treatment Tear secretion volume (mm) Control group (physiological saline solution) have 3.80±0.26 3% ChS group 4.62±0.21 ^‡ 3% MPS group 4.97±0.11 ^‡‡

As shown in Table 2, the 3% ChS group and the 3% MPS group showed a significant increase in tear secretion compared to the control group. The 3% MPS group increased the tear secretion compared to the 3% ChS group.

As shown in Examples 1 and 2, MPS significantly improved the corneal damage caused by removal of the lacrimal gland outside the orbit, and significantly increased the reduced tear secretion. Therefore, it was confirmed that the ophthalmic composition of the present invention has an excellent healing effect of corneal and conjunctival disorders and an excellent effect of increasing tear secretion, that is, it has an effect of improving dry eye syndrome.

without

[Fig. 1] is a graph showing the corneal damage score obtained in Example 1 (corneal damage healing experiment).

Claims (2)

An ophthalmic composition containing polysulfated chondroitin sulfate as an active ingredient and used for preventing and/or treating corneal and conjunctival disorders and/or for increasing tear volume. An ophthalmic composition contains polysulfated chondroitin sulfate as an active ingredient and is used for preventing and/or treating dry eye syndrome.