JP6589725B2 - Liquid ophthalmic composition, ophthalmic product, and method for suppressing cloudiness - Google Patents

Description

  The present invention relates to a liquid ophthalmic composition containing liquid paraffin, an ophthalmic product, and a method for suppressing white turbidity.

  The tear oil layer is composed of lipids secreted from the meibomian glands. It is known that the oil layer decreases with aging and hormonal changes. It is further known to be facilitated by contact lens wear. Decreasing the oil layer destabilizes the tear oil layer, causes dry eye, and causes eye strain. So far, eye drops and eye ointments containing oily components (vegetable oil, liquid paraffin, white petrolatum, etc.) for the treatment of dry eye are known.

JP 2008-94839 A

  However, the above-mentioned eye drops and eye ointments have not been sufficient in stabilizing the tear oil layer. In addition, white petrolatum or the like commonly used for eye ointments is surprisingly clear that the tear film stability effect is not sufficient, and it is also clear that the tear film stability effect is not obtained simply by using an oil component. Became. The present inventors paid attention to the tear oil layer change due to aging etc. as a cause of eye strain, and as a result of developing the technology for stabilizing the oil layer, oily components (castor oil, sesame oil, liquid paraffin, white petrolatum, etc.) Among them, liquid paraffin was found to have the highest tear oil layer stabilization effect. However, the liquid ophthalmic composition having an increased liquid paraffin content has revealed a problem in formulation stability that precipitates are generated at a high temperature in the composition. The present invention has been made in view of the above problems, and an object of the present invention is to provide an ophthalmic composition, an ophthalmic product, and a white turbidity suppression method that have a high tear oil layer stabilizing effect and are stabilized at a high temperature. .

  The present inventors have found that a liquid ophthalmic composition containing liquid paraffin has a high oil layer stabilizing effect, and has found that the liquid ophthalmic composition has “poor high-temperature formulation stability”. The inventors have found that the problem of “high-temperature formulation stability is poor” can be solved by the addition of vitamin A, and have made the present invention.

Accordingly, the present invention provides the following liquid ophthalmic composition, ophthalmic product, and a method for suppressing white turbidity.
[1]. A liquid ophthalmic composition containing (A) liquid paraffin 99 W / V% or more and less than 100 W / V% and (B) vitamin A 10,000 to 200,000 units / 100 mL.
[2]. (A) The liquid ophthalmic composition according to [1], wherein vitamin A is one or more selected from retinol palmitate and retinol acetate.
[3]. The liquid ophthalmic composition according to [1] or [2], further comprising (C) vitamin E.
[4]. (C) Liquid ophthalmic composition as described in [3] whose compounding quantity of component is 0.01-0.4 W / V%.
[5]. (C) The liquid ophthalmic composition according to [3] or [4], wherein vitamin E is vitamin E acetate.
[6]. The liquid ophthalmic composition according to any one of [1] to [5], which is a tear oil layer stabilizer.
[7]. An ophthalmic product comprising the liquid ophthalmic composition according to any one of [1] to [6], a plastic container filled with the liquid ophthalmic composition, and an enclosure in which the plastic container is sealed. .
[8]. The ophthalmic product according to [7], wherein an inert gas concentration in a space volume formed between the enclosure and the plastic container is 50% by volume or more.
[9]. The ophthalmic product according to [7] or [8], wherein an oxygen scavenger is enclosed in a space formed between the enclosure and the plastic container.
[10]. The ophthalmic product according to any one of [7] to [9], wherein the enclosure is an enclosure having a deoxygenating function.
[11]. (A) The cloudiness suppression method of the said ophthalmic composition which mix | blends the vitamin A 10,000 to 200,000 units / 100mL with the ophthalmic composition containing 99 W / V% or more of liquid paraffin and less than 100 W / V%.

  According to the present invention, it is possible to provide a liquid ophthalmic composition, an ophthalmic product, and a white turbidity suppressing method that have a high tear oil layer stabilizing effect and excellent high-temperature formulation stability.

[Liquid ophthalmic composition]
Hereinafter, the present invention will be described in detail. The liquid ophthalmic composition of the present invention contains liquid paraffin 99 W / V% or more and less than 100 W / V% and vitamin A 10,000 to 200,000 units / 100 mL.

(A) Liquid paraffin Liquid paraffin is also called mineral oil and mineral oil, and includes liquid paraffin and light liquid paraffin. Among these, liquid paraffin is preferable. The compounding amount in the liquid ophthalmic composition is 99 W / V% (mass / volume, g / 100 mL or less) and less than 100 W / V%, preferably 99 to 99.995 W / V%, preferably 99.5 99.995 W / V% is more preferable. Below the lower limit, there is a problem that when the component (B) is blended, the formulation permeability becomes low, making the foreign matter test process difficult, and the production cannot be performed efficiently. At 100% by mass, vitamin A sufficient to sufficiently improve high-temperature formulation stability cannot be blended.

(B) Vitamin A
By using vitamin A, it is possible to achieve both the tear oil layer stability and the problem of “poor high-temperature formulation stability” possessed by a liquid ophthalmic composition containing liquid paraffin. This cannot be achieved simply by the oily component. Examples of vitamin A include, in addition to vitamin A itself, vitamin A-containing mixtures such as vitamin A oil, vitamin A derivatives such as vitamin A fatty acid esters, etc., alone or in combination of two or more Can be used. Specific examples include retinol palmitate, retinol acetate, retinol, retinoic acid, and retinoid. Of these, retinol palmitate is preferred. The compounding amount in the liquid ophthalmic composition is 1 to 200,000 units, preferably 2.5 to 100,000 units, more preferably 3 to 50,000 units. Below the lower limit and above the upper limit, the formulation stability is poor. For example, in the case of 1.74 million international units / g, the blending amount in the liquid ophthalmic composition is 0.006 to 0.11 W / V%, preferably 0.015 to 0.055 W / V%, more preferably 0.0175 to 0.028 W / V%.

(C) Vitamin E
The ophthalmic composition of the present invention may be formulated with (C) vitamin E from the viewpoint of enhancing the effect of improving the problem of “poor stability of high-temperature preparation” possessed by a liquid ophthalmic composition containing liquid paraffin. preferable. As vitamin E, for example, tocopherol, tocotrienol, their salts, and derivatives (esters) are used as a generic term. Specifically, for example, there are d-α-tocopherol, dl-α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol and the like, and examples of these derivatives include vitamin E acetate (tocopherol acetate). , Vitamin E nicotinic acid ester, vitamin E succinic acid ester, vitamin E linolenic acid ester and the like can be mentioned, and these can be used singly or in appropriate combination of two or more. Of these, tocopherol acetate (such as d-α-tocopherol acetate and dl-α-tocopherol acetate) is preferable. The blending amount in the liquid ophthalmic composition is preferably 0.01 to 0.4 W / V%, more preferably 0.01 to 0.2 W / V%, from the viewpoint of improving high-temperature formulation stability. 1 to 0.15 W / V% is more preferable.

  The ophthalmic composition of the present invention can be blended with other components in appropriate amounts within a range not impairing the effects of the present invention. Examples of other components include surfactants, polyhydric alcohols, thickeners, cooling agents, antioxidants, drugs, and the like.

  Examples of the surfactant include polyoxyethylene polyoxypropylene glycol, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, glycine-type amphoteric surfactants such as alkyldiaminoethylglycine, alkyl quaternary ammonium salts (specific examples) In particular, cationic surfactants such as benzalkonium chloride, benzethonium chloride, and the like can be used, and one kind can be used alone, or two or more kinds can be used in appropriate combination. The compounding amount of the surfactant can be appropriately selected from the range of 0.0001 to 9.9 W / V in the ophthalmic composition. In addition, since the ophthalmic composition of the present invention can achieve formulation stability even without a surfactant, the amount of the surfactant is less than 0.1 W / V% in the composition, or no formulation It can be.

  Examples of the polyhydric alcohol include glycerin, propylene glycol, butylene glycol, polyethylene glycol, and the like. These can be used alone or in combination of two or more. The blending amount of the polyhydric alcohol is preferably 0.001 to 5 W / V% in the ophthalmic composition.

  Examples of the thickener include polyvinyl pyrrolidone, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, polyvinyl alcohol, sodium hyaluronate, sodium chondroitin sulfate, polyacrylic acid, carboxyvinyl polymer, and the like. The above can be used in appropriate combination. The blending amount of the thickening agent is preferably 0.003 to 3 W / V% in the ophthalmic composition.

  Examples of the refreshing agent include menthol, camphor, borneol, geraniol, cineol, linalool, and the like. These can be used alone or in combination of two or more. Examples of the antioxidant include dibutylhydroxytoluene. The amount of each of the refreshing agent and the antioxidant is preferably 0.0001 to 0.2 w / v% in the ophthalmic composition.

Examples of drugs (pharmaceutical active ingredients) include decongestants (for example, naphazoline hydrochloride, tetrahydrozoline hydrochloride, phenylephrine hydrochloride, epinephrine, ephedrine hydrochloride, dl-methylephedrine hydrochloride, tetrahydrozoline nitrate, naphazoline nitrate, etc.) Anti-inflammatory and astringents (eg neostigmine methyl sulfate, ε-aminocaproic acid, allantoin, berberine chloride hydrate, zinc sulfate, zinc lactate, lysozyme hydrochloride, dipotassium glycyrrhizinate, ammonium glycyrrhizinate, glycyrrhetinic acid, methyl salicylate , Tranexamic acid, sodium azulene sulfonate, etc.), antihistamines (eg, iproheptin hydrochloride, diphenhydramine hydrochloride, diphenhydramine, isothipentyl hydrochloride, chlorpheniramine male) Salt, etc.), antiallergic agents (e.g., sodium cromoglycate, etc.), water-soluble vitamins (activated vitamin B _2, vitamin B _6, vitamin B12, etc.), fat-soluble vitamins, amino acids (e.g., potassium L- aspartic acid, Magnesium L-aspartate, aminoethylsulfonic acid, sodium chondroitin sulfate, glutathione, etc.), sulfa drugs, fungicides (eg, sulfur, isopropylmethylphenol, hinokitiol, etc.), local anesthetics (eg, lidocaine, lidocaine hydrochloride, procaine hydrochloride) , Dibucaine hydrochloride and the like) and mydriatics (eg tropicamide and the like). The effective content of each drug can be selected as the content of the drug, but 0.001 to 5 W / V% in the composition is preferable from the viewpoint of irritation to the eye, stability of the composition, and the like. . The said other component can be mix | blended individually by 1 type or in combination of 2 or more types as appropriate.

  The ophthalmic composition of the present invention is preferably substantially free of water, and the amount of water is preferably 0.1 W / V% or less in the liquid ophthalmic composition.

  Vaseline can be used in combination with the ophthalmic composition of the present invention. However, from the viewpoint of stabilizing the tear oil layer and stabilizing the high-temperature preparation, the blending amount in the liquid ophthalmic composition is 1 W / V% or less. Preferably, 0.5 W / V% or less is more preferable, and 0 W / V% is more preferable.

  The ophthalmic composition of the present invention is a liquid oily ophthalmic composition, which is different from an ointment or the like. In the present invention, the “liquid” has fluidity and has a viscosity of 300 mPa · s or less (25 ° C., rotation speed 2 rpm, Brookfield viscometer corn plate type, manufactured by Eiko Seiki Co., Ltd.).

  Although the manufacturing method of the ophthalmic composition of the present invention is not particularly limited, for example, each component is mixed at 50 to 90 ° C. with a pulsator, propeller blade, paddle blade, turbine blade, etc. Make final volume such as 100 mL.

  The ophthalmic composition of the present invention can be suitably used as an eye drop, an eye drop for contact lenses, an eye wash, and the like, but can be particularly preferably used as an eye drop. When used as eye drops or eye drops for contact lenses, the effect of the present invention can be further exhibited by instilling 30 to 60 μL per time and 3 to 6 times per day. When using as an eye wash, the effect of this invention can be exhibited more by washing eyes 3-6mL per time and 3-6 times per day. In particular, in order to stabilize the tear oil layer, it is preferable to instill the ophthalmic composition of the present invention.

Since the ophthalmic composition of the present invention has a tear fluid layer stabilizing action, it can be used as a tear fluid layer stabilizer. Further, the present invention provides the above ophthalmic composition, wherein (B) vitamin A 10,000 to 200,000 units / 100 mL is blended with (A) an ophthalmic composition containing 99 W / V% or more and less than 100 W / V% of liquid paraffin. Provided is a method for suppressing cloudiness of an object. Suitable components, amounts and the like of these inventions are the same as described above.

[Ophthalmic products]
The liquid ophthalmic composition of the present invention can be an ophthalmic product having a plastic container filled with the liquid ophthalmic composition and an enclosure in which the plastic container is sealed.

  The plastic container is not particularly limited, and materials such as polyethylene, polyethylene terephthalate, polypropylene, polybutylene, polycarbonate, polyarylate, vinyl chloride, or a composite of these materials can be used. Polyethylene terephthalate is particularly preferable.

  A plastic container filled with the ophthalmic composition is sealed with an enclosure. As the envelope, for example, polyethylene, polyethylene terephthalate, polypropylene, polybutylene, polycarbonate, polyester, nylon, cellophane, polyvinyl chloride film, aluminum foil, polyvinyl alcohol / polyamide film deposited with aluminum, and polyvinylidene chloride were coated. A composite or multilayer film of these, such as a film or a laminate film, may be mentioned.

Oxygen permeability ^{coefficient, 10cc / (m 2 · 24hr} · atm) or less ^{(i.e., 0~10cc / (m 2 · 24hr} · atm)) of oxygen-impermeable enclosure is preferred.

From the viewpoint of enhancing the effect of improving the problem of “poor stability of high-temperature preparation” possessed by the liquid ophthalmic composition containing liquid paraffin, the following methods are preferable for the enclosure and the plastic container.
(1) The inert gas concentration in the volume formed between the enclosure and the plastic container is set to 50% by volume or more.
(2) An oxygen scavenger is enclosed in a space formed between the enclosure and the plastic container.
(3) Enclosure having an oxygen scavenging function

(1) Examples of the inert gas include nitrogen, helium, neon, and argon. Of these, nitrogen gas is preferred. The concentration of the inert gas is preferably 50% by volume or more, more preferably 80% by volume or more, and still more preferably 90% by volume or more in the space volume formed between the enclosure and the plastic container. An upper limit is not specifically limited, It is 100 volume% or less. In order to achieve such a concentration, the space formed between the enclosure and the plastic container may be replaced with an inert gas.

(2) Deoxygenating agent As the deoxidizing agent, specifically, AGELESS (FX, SA, Z-PT, GL, G) manufactured by Mitsubishi Gas Chemical Co., Ltd., Vitalon manufactured by Tokiwa Sangyo Co., Ltd., or the like is used. be able to.

(3) Enclosure having a deoxygenating function The envelope having a deoxygenating function includes Oxycatch (registered trademark) ICA manufactured by Kyodo Printing Co., Ltd., Cryovac (registered trademark) OS film manufactured by Shield Air, and Star Histar O2 manufactured by Plastic Industry Co., Ltd., Ageless Omak manufactured by Mitsubishi Gas Chemical Co., Ltd., Oxydec manufactured by Toyo Seikan Co., Ltd., and the like can be used.

[White turbidity suppression method]
The present invention provides (A) an ophthalmic composition containing 99 W / V% or more and less than 100 W / V% of liquid paraffin, wherein (B) vitamin A 10,000 to 200,000 units / 100 mL is blended. A method for suppressing cloudiness is provided. Preferred components, blending amounts, etc. are the same as above.

  EXAMPLES Hereinafter, although an Example and a comparative example are shown and this invention is demonstrated concretely, this invention is not restrict | limited to the following Example.

[Examples 1 to 24, Comparative Examples 1 to 7]
Each component of the composition described in the following table was mixed, stirred at 60 ° C. with a propeller blade, and after confirmation of dissolution, an oily eye drop was prepared with liquid paraffin to a final volume of 100 mL or the like. The following evaluation was performed about the obtained oil-based eye drop. The results are also shown in the table.

[Tear oil layer stability test]
The tear fluid layer stability was evaluated by measuring BUT (break up time) using a dry eye observation device DR-1 (manufactured by Kowa Co., Ltd.). DR-1 is an apparatus capable of measuring an interference image of light reflected at the boundary surface between the tear fluid layer surface and the tear fluid layer. In healthy eyes, a uniform gray or white interference image is observed, and the interference image disappears when the tear oil layer collapses. Each subject was instilled with each oily eye drop and 10 minutes later, blinked several times, and the time (BUT) from the blink until the tear oil layer collapsed was measured. The test subjects selected three people with a BUT of 10 seconds or less. A result is shown on the following evaluation criteria from the average value of three persons.
[Evaluation of tear fluid stability]
◎: Oil layer BUT is 60 seconds or more ○: Oil layer BUT is 30 seconds or more and less than 60 seconds Δ: Oil layer BUT is 10 seconds or more and less than 30 seconds ×: Oil layer BUT is less than 10 seconds

[Formulation stability test]
15 mL of each oily eye drop was filled in a polyethylene terephthalate container (15 mL: oxygen permeability coefficient of 10 cc / ( m ² · 24 hr · atm ) or less). This was put in a PET (polyethylene terephthalate / polyethylene) film envelope deposited with aluminum and sealed.

  In addition, the example with the inert gas in the table replaces the space with the described gas, and the one with the oxygen scavenger encloses the oxygen scavenger (ageless Z-PT) in the space. An envelope having a deoxygenating function (Ageless Omak manufactured by Mitsubishi Gas Chemical Co., Ltd.) was used for those described as film.

These were stored at 50 ° C. and 75% RH for 1 month, and the appearance after returning to room temperature was visually evaluated based on the following evaluation criteria.
[Formulation stability evaluation]
◎: Colorless and transparent ○: Slightly cloudy, but clear and colorless when shaken △: Slightly cloudy, but no problem in foreign matter test ×: Overall cloudy, unacceptable for foreign matter test Appropriate There is a big difference between being totally cloudy and slightly cloudy. In the present invention, Δ or more was regarded as acceptable formulation stability.

The raw materials used in preparing the examples and comparative examples are shown below. Unless otherwise specified, the amount of each component in the table is a pure conversion amount.
Liquid paraffin (manufactured by Kaneda Co., Ltd., High Call M352)
Retinol palmitate (manufactured by DSM Nutrition Japan K.K., retinol palmitate, 1.74 million international units / g)
Tocopherol acetate (Riken Vitamin Co., Ltd., Riken E Acetate α)
Dibutylhydroxytoluene (Wako Pure Chemical Industries, Ltd.)
Castor oil (manufactured by Kaneda Corporation)
Sesame oil (manufactured by Kaneda Corporation)
Vaseline (Maruishi Pharmaceutical Co., Ltd.)
Menthol: l-menthol (manufactured by Takasago International Corporation)
Borneol: d-borneol (Ogi Pharmaceutical Co., Ltd.)
Chlorobutanol (Merck)
Dibutylhydroxytoluene (Wako Pure Chemical Industries, Ltd.)
Retinol acetate: Retinol acetate (manufactured by Wako Pure Chemical Industries, Ltd.)

Claims (11)

A liquid ophthalmic composition containing (A) liquid paraffin 99 W / V% or more and less than 100 W / V% and (B) vitamin A 10,000 to 200,000 units / 100 mL.   (A) The liquid ophthalmic composition according to claim 1, wherein the vitamin A is at least one selected from retinol palmitate and retinol acetate.   The liquid ophthalmic composition according to claim 1 or 2, further comprising (C) vitamin E.   The liquid ophthalmic composition according to claim 3, wherein the amount of component (C) is 0.01 to 0.4 W / V%.   (C) Vitamin E is vitamin E acetate, The liquid ophthalmic composition of Claim 3 or 4.   The liquid ophthalmic composition according to any one of claims 1 to 5, which is a tear oil layer stabilizer.   An ophthalmic product comprising the liquid ophthalmic composition according to claim 1, a plastic container filled with the liquid ophthalmic composition, and an enclosure in which the plastic container is sealed.   The ophthalmic product according to claim 7, wherein an inert gas concentration in a space volume formed between the enclosure and the plastic container is 50% by volume or more.   The ophthalmic product according to claim 7 or 8, wherein an oxygen scavenger is enclosed in a space formed between the enclosure and the plastic container.   The ophthalmic product according to any one of claims 7 to 9, wherein the enclosure is an enclosure having a deoxygenating function. (A) The cloudiness suppression method of the said ophthalmic composition which mix | blends the vitamin A 10,000 to 200,000 units / 100mL with the ophthalmic composition containing 99 W / V% or more of liquid paraffin and less than 100 W / V%.