JP7117017B2 - Ophthalmic product and masking method - Google Patents

Description

TECHNICAL FIELD The present invention relates to ophthalmic products and masking methods in which the odor of oxygen absorbers is suppressed.

Use of an oxygen absorber is known as a method of stabilizing easily oxidizable components. Also in the field of eye drops, it is known that by enclosing the eye drops and the oxygen absorber in a container, the oxygen in the container can be absorbed and the readily oxidizable substances in the eye drops can be stabilized. (JP-A-6-40907). On the other hand, active ingredients such as fat-soluble vitamin A are attracting attention as effective ingredients for treating cornea/conjunctiva, nasal mucosa and pharynx. Smell amplifies.

JP-A-6-40907

However, if an oxygen absorber containing iron as a main component (hereinafter also referred to as an iron-based oxygen absorber) is placed in the enclosure and stored for a long period of time, a peculiar offensive odor, such as that of burning, occurs due to the deoxidizing action. It has been found that the problem that the foreign matter smells when the package is opened is caused by the adhesion to the envelope or the filling of the envelope. On the other hand, fat-soluble active ingredients such as vitamin A are attracting attention as effective ingredients for treating cornea/conjunctiva, nasal mucosa and pharynx. However, these active ingredients have a peculiar odor, and the odor increases over time. The use of oxygen absorbers in ophthalmic products containing vitamin A has been unsatisfactory in improving odor upon opening. In view of the above, an ophthalmic product in which an ophthalmic composition containing an easily oxidizable compound such as vitamin A is housed in a container and further enclosed and sealed with an enclosure together with an iron-based oxygen absorber. In the above, a masking method for suppressing the peculiar offensive odor caused by the deoxidizing action when the envelope is opened has been desired.

As a result of intensive studies to achieve the above object, the present inventors have found that an ophthalmic composition containing easily oxidizable vitamin A or the like is housed in a container having a main body and a cap, and further comprises iron as a main component. In an ophthalmic product enclosed and sealed with an enclosure together with an oxygen absorber, the capacity of the main body, the oxygen permeability of the main body, and the volume of the space formed between the enclosure and the container are set within a specific range. By doing so, the cooling agent volatilizes from the container, volatilizes and stays from the ophthalmic composition into the container, and further from the container into the enclosure, causing a strange odor (derived from oxygen absorbers and easily oxidized ) can be easily masked at low cost.

Accordingly, the present invention provides the following ophthalmic products and masking methods.
[1]. (A) easily oxidizable,
(B) a cooling agent;
(C) a nonionic surfactant, and (D) one or more components selected from dibutylhydroxytoluene, dibutylhydroxyanisole, propyl parahydroxybenzoate, butyl parahydroxybenzoate and chlorobutanol, wherein an ophthalmic composition comprising An ophthalmic product housed in a container comprising a main body containing an ophthalmic composition and a cap, the container being surrounded and sealed with an enclosure together with an iron-based oxygen absorber,
The capacity of the main body is 1 to 25 mL,
The oxygen permeability of the main body is 10 cc/(m ² · 24 hr · atm) or more,
An ophthalmic product, wherein the volume of the space formed between the enclosure and the container is 200 V/V % or less of the volume of the container.
[2]. (A) The ophthalmic product according to [1], wherein the component is vitamin A.
[3]. The ophthalmic product according to [1] or [2], wherein component (B) is one or more selected from l-menthol, dl-camphor, d-camphor, d-borneol, geraniol and eucalyptus oil.
[4]. The ophthalmic product according to any one of [1] to [3], wherein the amount of component (B) in the ophthalmic composition is 0.0001 w/v% or more.
[5]. (C) component is one or more selected from polyoxyethylene hydrogenated castor oil 60, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene (20) sorbitan oleate and polyoxyethylene polyoxypropylene glycol [1 ] to [4].
[6]. (A) easily oxidizable,
(B) a cooling agent;
(C) a nonionic surfactant, and (D) one or more components selected from dibutylhydroxytoluene, dibutylhydroxyanisole, propyl parahydroxybenzoate, butyl parahydroxybenzoate and chlorobutanol, wherein an ophthalmic composition comprising An ophthalmic product housed in a container comprising a main body containing an ophthalmic composition and a cap, wherein the container and an iron-based oxygen absorber are enclosed and sealed with an enclosure,
The capacity of the main body is 1 to 25 mL,
The oxygen permeability of the main body is 10 cc/(m ² · 24 hr · atm) or more,
A method of masking an odor when the envelope is opened, wherein the volume of the space formed between the envelope and the container is 200 V/V% or less of the volume of the container.

According to the present invention, an ophthalmic product containing an easily oxidizable ophthalmic composition together with an iron-based oxygen absorber packaged in an enclosure suppresses a specific offensive odor when the enclosure is opened. A manufactured ophthalmic product and masking method can be provided.

The present invention will be described in detail below.
[Ophthalmic composition]
The ophthalmic composition of the present invention comprises (A) an easily oxidizable agent, (B) a cooling agent, (C) a nonionic surfactant, and (D) dibutylhydroxytoluene, dibutylhydroxyanisole, propyl parahydroxybenzoate, It contains one or more components selected from butyl paraoxybenzoate and chlorobutanol.

[(A) component]
As the (A) easily oxidized, either a water-soluble easily oxidized or a hydrophobic easily oxidized can be used, and one kind can be used alone or two or more kinds can be used in combination as appropriate. Examples of water-soluble readily oxidizing agents include sodium azulene sulfonate, vitamin B ₂ (flavin adenine dinucleotide, etc.), vitamin B ₆ (pyridoxine hydrochloride, etc.), vitamin B ₁₂ (cyanocobalamin, etc.), vitamin C (ascorbic acid, etc.). etc.

As hydrophobic easily oxidized substances, among the components listed in the Japanese Pharmacopoeia, Japanese Non-Pharmacopoeia Pharmaceuticals Standards, Pharmaceutical Additives Database, Pharmaceutical Additives Standards, Cosmetic Ingredients Standards, Cosmetic Ingredients Standards, and Food Additives Standards, Substances with "slightly soluble" to "sparsely soluble" in water can be used, and include all substances that undergo oxidative degradation. Specific oxidizable substances include, but are limited to, vitamin A, vitamin D, vitamin E, vitamin K, diphenhydramine, indomethacin, tacrolimus (FK506), macrolite antibiotics such as rifampicin, and forskolin. not to be

Among them, vitamin A promotes corneal and conjunctival repair, promotes mucin production, improves dry eye, and improves tired eyes and blurred vision. In addition, vitamin A is easily decomposed and emits a unique odor, so that the effects of the present invention can be exhibited more effectively. . Examples of the above-mentioned vitamin A include vitamin A itself, vitamin A-containing mixtures such as vitamin A oil, and vitamin A derivatives such as vitamin A fatty acid esters. Specific examples include retinol palmitate, retinol acetate, retinol, retinoic acid, retinoid, β-carotene and the like. Among them, retinol palmitate and retinol acetate are preferred, and retinol palmitate is more preferred.

Retinol palmitate is usually commercially available at 1,000,000 to 1,800,000 international units/g (hereinafter sometimes abbreviated as IU/g). Retinol palmitate (1,740,000 I.U.), retinol palmitate manufactured by Sigma-Aldrich, and the like.

Examples of vitamin D include cholecalciferol, 1α,25-dihydroxycholecalciferol and derivatives thereof. Examples of vitamin E include α-tocopherol, d-α-tocopherol acetate and derivatives thereof, and examples of vitamin K include phytylmenadione and derivatives thereof. Among them, from the viewpoint of being useful as an ophthalmic substance, the component (A) includes fat-soluble vitamins such as retinol palmitate and d-α-tocopherol acetate, macrolide antibiotics such as tacrolimus (FK506) and rifampicin, and fors. Choline and the like are preferred.

The amount of component (A) in the ophthalmic composition is preferably 0.005 to 2 w/v% (mass/volume %, g/100 mL, the same shall apply hereinafter), more preferably 0.01 to 1 w/v%. . When vitamin A is added, it is preferably 5,000 to 300,000 IU/100 mL, more preferably 5,000 to 100,000 IU/100 mL, and even more preferably 5,000 to 50,000 IU/100 mL. A high concentration of vitamin A enhances the effects on the eyes (promoting corneal and conjunctival repair, promoting mucin production, improving dry eye, and improving tired and blurred vision).

[(B) Component]
Cooling agents include l-menthol, dl-camphor, d-camphor, d-borneol, eucalyptus oil, bergamot oil, geraniol, linalool, cineol, fennel oil, spearmint oil, peppermint oil, rose oil, cool mint oil and Peppermint oil and the like can be mentioned, and can be used singly or in combination of two or more. Among them, l-menthol, dl-camphor, d-camphor, d-borneol, geraniol and eucalyptus oil are preferred.

The amount of component (B) in the ophthalmic composition is preferably 0.0001 w/v% or more, more preferably 0.0001-0.5 w/v%, more preferably 0.00015-0. 2 w/v % is more preferred, and 0.0002 to 0.1 w/v % is particularly preferred. If the blending amount is too large, the irritation at the time of instillation will be strong, and there is a possibility that the feeling of use may be impaired.

When blending (B-1) l-menthol as the cooling agent of the present invention, it is preferably 0.005 to 0.5 w/v%, more preferably 0.01 to 0.2 w/v%, and 0 0.02 to 0.1 w/v% is more preferred, 0.03 to 0.1 w/v% is particularly preferred, and 0.04 to 0.05 w/v% is most preferred. If the compounding amount is too large, the irritation at the time of instillation may be strong, and the feeling of use may be impaired.

When (B-2) camphor is blended as the cooling agent of the present invention, it is preferably 0.002 to 0.5 w/v%, more preferably 0.005 to 0.2 w/v%, and 0.01. ~0.1 w/v% is more preferred. If the compounding amount is too large, the irritation at the time of instillation may be strong, and the feeling of use may be impaired.

When (B-3) d-borneol or geraniol is blended as the cooling agent of the present invention, it is preferably 0.002 to 0.5 w/v%, more preferably 0.003 to 0.2 w/v%. , 0.005 to 0.1 w/v% is more preferred. If the compounding amount is too large, the irritation at the time of instillation may be strong, and the feeling of use may be impaired.

When (B-4) eucalyptus oil is blended as the cooling agent of the present invention, it is preferably 0.0005 to 0.5 w/v%, more preferably 0.001 to 0.2 w/v%, and 0.001 to 0.2 w/v%. 0015 to 0.1 w/v% is more preferred. If the compounding amount is too large, the irritation at the time of instillation may be strong, and the feeling of use may be impaired.

[(C) component]
Nonionic surfactants are not particularly limited as long as they are used in ophthalmic compositions, and may be used singly or in combination of two or more. For example, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester (POE sorbitan fatty acid ester) typified by polyoxyethylene (20) sorbitan oleate (polysorbate 80), and poloxamer. polyoxyethylene polyoxypropylene glycol (polyoxyethylene polyoxypropylene block copolymer, POEPOP glycol), polyethylene glycol monostearate represented by polyethylene glycol monostearate (10), and the like.

Polyoxyethylene castor oil (POE castor oil) is a compound obtained by addition polymerization of ethylene oxide (EO) to castor oil, and several types with different average number of added moles of ethylene oxide are known. . The average number of added moles of ethylene oxide in polyoxyethylene castor oil is not particularly limited, but is exemplified from 3 to 60 moles. Specifically, polyoxyethylene castor oil 3 (EO average addition mole number 3), polyoxyethylene castor oil 10 (EO average addition mole number 10), polyoxyethylene castor oil 20 (EO average addition mole number 20), poly Oxyethylene castor oil 35 (average number of EO addition moles 35), polyoxyethylene castor oil 40 (average number of EO addition moles 40), polyoxyethylene castor oil 50 (average number of EO addition moles 50), polyoxyethylene castor oil 60 (EO average added mole number 60) and the like.

Polyoxyethylene hydrogenated castor oil (POE hydrogenated castor oil) is a compound obtained by addition polymerization of ethylene oxide to hydrogenated castor oil, and several types with different average number of added moles of ethylene oxide are known. ing. The average number of moles of ethylene oxide added to the polyoxyethylene hydrogenated castor oil is not particularly limited, but is exemplified from 5 to 100 moles. Specifically, polyoxyethylene hydrogenated castor oil 5 (EO average addition mole number 5), polyoxyethylene hydrogenated castor oil 10 (EO average addition mole number 10), polyoxyethylene hydrogenated castor oil 20 (EO average addition mole number 20 ), polyoxyethylene hydrogenated castor oil 30 (EO average addition mole number 30), polyoxyethylene hydrogenated castor oil 40 (EO average addition mole number 40), polyoxyethylene hydrogenated castor oil 50 (EO average addition mole number 50), Polyoxyethylene hydrogenated castor oil 60 (EO average addition mole number 60), polyoxyethylene hydrogenated castor oil 80 (EO average addition mole number 80), polyoxyethylene hydrogenated castor oil 100 (EO average addition mole number 100), etc. be done.

Polyoxyethylene sorbitan fatty acid esters (POE sorbitan fatty acid esters) include polyoxyethylene (20) sorbitan monolaurate (polysorbate 20), polyoxyethylene (20) sorbitan monopalmitate (polysorbate 40), and polyoxyethylene monostearate. (20) Sorbitan (polysorbate 60), polyoxyethylene tristearate (20) sorbitan (polysorbate 65), polyoxyethylene monooleate (20) sorbitan (polysorbate 80).

Polyoxyethylene polyoxypropylene glycol (POEPOP glycol) is a block copolymer consisting of polyoxyethylene chains (POE) and polyoxypropylene chains (POP), the average of ethylene oxide (EO) and propylene oxide (PO) Several types with different number of added moles are known. The average number of added moles of ethylene oxide and propylene oxide in polyoxyethylene polyoxypropylene glycol is not particularly limited, but an average number of added moles of 5 to 200 is exemplified. Specifically, polyoxyethylene (200) polyoxypropylene (70) glycol (EO average addition mole number 200, PO average addition mole number 70), polyoxyethylene (196) polyoxypropylene (67) glycol (EO average addition Mole number 196, PO average addition mole number 67), polyoxyethylene (160) polyoxypropylene (30) glycol (EO average addition mole number 160, PO average addition mole number 30), polyoxyethylene (120) polyoxypropylene (40) glycol (average number of EO addition moles 120, average number of PO addition moles 40), polyoxyethylene (42) polyoxypropylene (67) glycol (average number of EO addition moles 42, average number of PO addition moles 67), poly Oxyethylene (54) polyoxypropylene (39) glycol (EO average addition mole number 54, PO average addition mole number 39), polyoxyethylene (20) polyoxypropylene (20) glycol (EO average addition mole number 20, PO average number of added moles 20) and the like.

Among them, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene (20) sorbitan oleate and polyoxyethylene polyoxypropylene glycol are preferred.

The blending amount of component (C) in the ophthalmic composition is preferably 0.001 to 5.0 w/v%, more preferably 0.001 to 2.0 w/v% when polyoxyethylene polyoxypropylene glycol is blended. is more preferred, and 0.001 to 1.0 w/v% is even more preferred. When blending other than polyoxyethylene polyoxypropylene glycol, it is preferably 0.001 to 0.5 w/v%, more preferably 0.001 to 0.3 w/v%, and 0.001 to 0.2 w/v%. is more preferred. If the blending amount of component (C) is too large, the cooling agent may be encapsulated in the activator micelle and volatilization may be suppressed. There is

[(D) component]
Component (D) is one or more components selected from dibutylhydroxytoluene (BHT), dibutylhydroxyanisole (BHA), propyl parahydroxybenzoate, butyl parahydroxybenzoate and chlorobutanol. Among them, dibutylhydroxytoluene is preferred. Component (D) may be used singly or in combination of two or more. Since component (D) has lower solubility than component (B) and is easily encapsulated in active agent micelles, volatilization of (B) the cooling agent is further accelerated, and (B) the odor masking effect of the cooling agent is enhanced. .

The amount of component (D) in the ophthalmic composition is preferably 0.001 w/v% or more, preferably 0.002 w/v% or more, from the viewpoint of masking effect when dibutylhydroxytoluene or dibutylhydroxyanisole is blended. is more preferable, and 0.003 w/v% or more is even more preferable. Although the upper limit is not particularly limited, it can be 0.01 w/v% or less.

When blending propyl parahydroxybenzoate and butyl parahydroxybenzoate, from the viewpoint of masking effect, it is preferably 0.03 w/v% or more, more preferably 0.05 w/v% or more, and 0.1 w/v% or more. More preferred. Although the upper limit is not particularly limited, it can be 1 w/v% or less.

When chlorobutanol is blended, it is preferably 0.03 w/v% or more, more preferably 0.05 w/v% or more, and even more preferably 0.1 w/v% or more, from the viewpoint of masking effect. Although the upper limit is not particularly limited, it can be 3 w/v% or less.

A preferred range of the compounding ratio (mass ratio) represented by (B)/(D) is as follows. Although this ratio is a w/v% ratio, it is the same as the mass ratio (same below). Component (D) is (D-I) dibutylhydroxytoluene or dibutylhydroxyanisole, (D-II) propyl parahydroxybenzoate or butyl parahydroxybenzoate, or (D-III) chlorobutanol will be explained separately.

(I) When the (D) component is dibutylhydroxytoluene (BHT) or dibutylhydroxyanisole (BHA), it is preferably 0.05 to 500, more preferably 0.1 to 200, and further 0.1 to 100 preferable.

When l-menthol is blended as component (B), it is preferably from 1.0 to 200, more preferably from 2.0 to 100, even more preferably from 3.0 to 50, and particularly preferably from 4.0 to 50.

When camphor (dl-camphor, d-camphor) is added as component (B), it is preferably 0.4 to 200, more preferably 1.0 to 100, even more preferably 2.0 to 50.

When d-borneol or geraniol is blended as component (B), it is preferably from 0.4 to 200, more preferably from 0.6 to 100, even more preferably from 1.0 to 50.

When eucalyptus oil is blended as component (B), it is preferably from 0.1 to 200, more preferably from 0.2 to 100, even more preferably from 0.3 to 50.

(II) When the component (D) is propyl parahydroxybenzoate or butyl parahydroxybenzoate, it is preferably 0.001 to 200, more preferably 0.003 to 100, even more preferably 0.01 to 50.

When l-menthol is blended as component (B), it is preferably from 0.1 to 100, more preferably from 0.2 to 50, even more preferably from 0.4 to 10.

When camphor (dl-camphor, d-camphor) is blended as component (B), it is preferably from 0.05 to 100, more preferably from 0.15 to 50, even more preferably from 0.2 to 10.

When d-borneol or geraniol is blended as component (B), it is preferably from 0.05 to 100, more preferably from 0.1 to 50, even more preferably from 0.15 to 10.

When eucalyptus oil is blended as component (B), it is preferably from 0.01 to 100, more preferably from 0.02 to 50, even more preferably from 0.05 to 10.

(III) When the component (D) is chlorobutanol, it is preferably 0.0001 to 100, more preferably 0.0003 to 50, and even more preferably 0.0005 to 20 or more.

When 1-menthol is blended as component (B), it is preferably from 0.01 to 50, more preferably from 0.02 to 20, even more preferably from 0.04 to 10.

When camphor (dl-camphor, d-camphor) is blended as component (B), it is preferably from 0.05 to 50, more preferably from 0.15 to 20, even more preferably from 0.2 to 10.

When d-borneol or geraniol is blended as component (B), it is preferably from 0.0005 to 50, more preferably from 0.001 to 20, and even more preferably from 0.0015 to 10.

When eucalyptus oil is blended as component (B), it is preferably from 0.001 to 50, more preferably from 0.002 to 20, and even more preferably from 0.005 to 10.

A preferred range of the compounding ratio (mass ratio) represented by ((B)+(D))/(C) is as follows. When the component (A) is vitamin A, when the component (C) is (C-I) polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil or polyoxyethylene sorbitan fatty acid ester, (C-II) The case of polyoxyethylene polyoxypropylene glycol is described separately.

(A) When the component is vitamin A, the blending ratio (mass ratio) represented by ((B) + (D)) / (C) is preferably 0.01 to 30, more preferably 0.02 to 10. preferable. If ((B) + (D)) / (C) is too small, the cooling agent may be included in the micelle and volatilization may be suppressed. may separate.

When component (C) is (C-I) polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil or polyoxyethylene sorbitan fatty acid ester, l-menthol is blended as component (B) and component (D) is added. , dibutylhydroxytoluene or dibutylhydroxyanisole, it is preferably from 0.05 to 15, more preferably from 0.1 to 10, and even more preferably from 0.15 to 5.

When camphor (d-camphor, dl-camphor) is blended as component (B) and dibutylhydroxytoluene or dibutylhydroxyanisole is blended as component (D), 0.04 to 5 is preferable, and 0.05 to 0.05 4 is more preferred, and 0.08 to 3 is even more preferred.

When d-borneol or geraniol is blended as component (B), and dibutylhydroxytoluene or dibutylhydroxyanisole is blended as component (D), 0.03 to 5 is preferred, and 0.04 to 4 is more preferred. 0.05 to 3 is more preferred, and 0.06 to 3 is particularly preferred.

When eucalyptus oil is blended as component (B) and dibutylhydroxytoluene or dibutylhydroxyanisole is blended as component (D), it is preferably 0.02 to 5, more preferably 0.03 to 3, and 0.04. ~3 is more preferred, and 0.045 to 3 is particularly preferred.

(C-II) In the case of polyoxyethylene polyoxypropylene glycol When l-menthol is blended as the component (B) and dibutylhydroxytoluene or dibutylhydroxyanisole is blended as the component (D), 0.005 to 1 0.5 is preferred, 0.015 to 1.0 is more preferred, and 0.025 to 0.5 is even more preferred.

When camphor (d-camphor, dl-camphor) is blended as component (B) and dibutylhydroxytoluene or dibutylhydroxyanisole is blended as component (D), 0.007 to 0.5 is preferred, and 0.007 to 0.5 is preferred. 01 to 0.4 is more preferred, and 0.015 to 0.3 is even more preferred.

When d-borneol or geraniol is blended as component (B), and dibutylhydroxytoluene or dibutylhydroxyanisole is blended as component (D), 0.007 to 0.5 is preferred, and 0.008 to 0.4 is preferred. is more preferred, and 0.01 to 0.3 is even more preferred.

When eucalyptus oil is blended as component (B) and dibutylhydroxytoluene or dibutylhydroxyanisole is blended as component (D), 0.005 to 0.5 is preferred, and 0.006 to 0.4 is more preferred. , 0.007 to 0.3 are more preferred.

In the above (B) / (D) ratio, the blending ratio represented by ((B) + (D)) / (C), when multiple components (B) are blended, the total amount of component (B) Treat as the concentration of each component. Since the masking effect is highest in the order of eucalyptus oil, geraniol, d-borneol, camphor (d-camphor, dl-camphor), and l-menthol, the above ratio is the highest masking effect component among the ingredients. follow the range. When multiple components (C) and (D) are blended, the total amount of each component is treated as the concentration of each component. The above ratios are in accordance with the ranges of the components with high loadings.

[Optional component]
The ophthalmic composition of the present invention may optionally contain various components used in the ophthalmic composition as long as the effects of the present invention are not impaired. Preferred ingredients include drugs, buffers, stabilizers, thickeners, tonicity agents, antioxidants, preservatives, pH adjusters, polyhydric alcohols and the like.

Drugs include, for example, decongestant components, ocular muscle modulator components, anti-inflammatory drug components or astringent drug components, antihistamine drug components or antiallergic drug components, amino acids, antibacterial drug components or bactericidal drug components, saccharides, polysaccharides or Derivatives thereof, local anesthetic components, steroid components, glaucoma therapeutic components, cataract therapeutic components, mydriatic components and the like can be mentioned. Specific examples are shown below.

decongestant components: e.g. α-adrenergic agonists such as imidazoline derivatives (naphazoline, tetrahydrozoline etc.), β-phenylethylamine derivatives (phenylephrine, epinephrine, ephedrine, methylephedrine etc.) and their pharmaceutically or physiologically acceptable salts (e.g., inorganic salts such as naphazoline hydrochloride, naphazoline nitrate, tetrahydrozoline hydrochloride, tetrahydrozoline nitrate, phenylephrine hydrochloride, epinephrine hydrochloride, ephedrine hydrochloride, methylephedrine hydrochloride; organic acid salts such as epinephrine hydrogen tartrate, etc. ) and the like.

Ingredients for ocular muscle modulators: Examples include cholinesterase inhibitors (eg, neostigmine methylsulfate, etc.) having an active center similar to that of acetylcholine, tropicamide, atropine sulfate, and the like.

Anti-inflammatory or astringent ingredients: e.g. pranoprofen, celecoxib, rofecoxib, indomethacin, diclofenac, diclofenac sodium, piroxicam, meloxicam, aspirin, mefenamic acid, indomethacin farnesyl, acemethacin, ibuprofen, tiaprofenic acid, loxoprofen sodium, tiaramide hydrochloride , zinc salts (e.g., zinc sulfate, zinc lactate, etc.), lysozyme, lysozyme chloride, methyl salicylate, allantoin, epsilon-aminocaproic acid, berberine chloride, berberine sulfate, glycyrrhizic acid and pharmacologically acceptable salts (e.g., glycyrrhizin dipotassium acid, ammonium glycyrrhizinate, etc.).

Antihistamine or antiallergic ingredients: for example, ketotifen, acitazanolast, chlorpheniramine, diphenhydramine, levocabastine, cromoglycic acid, tranilast, ibudilast, amlexanox, pemirolast, and pharmaceutically or physiologically acceptable salts thereof (diphenhydramine hydrochloride, ketotifen fumarate, sodium cromoglycate, etc.) and the like.

Amino acids: e.g. leucine, isoleucine, valine, methionine, threonine, alanine, phenylalanine, tryptophan, lysine, glycine, serine, proline, tyrosine, cysteine, histidine, ornithine, hydroxyproline, hydroxylysine, glycylglycine, γ-aminobutyric acid , glutamic acid, sodium aspartate, potassium aspartate, magnesium aspartate, aminoethylsulfonic acid (taurine) or salts thereof (eg, cysteine hydrochloride, etc.).

Antibacterial or bactericidal ingredients: e.g. sulfonamides (e.g. sulfamethoxazole, sulfisoxazole, sulfisomidine and pharmacologically acceptable salts (sulfamethoxazole sodium, sulfisomidine sodium, etc.), acrinol, alkylpolyaminoethylglycine, new quinolones (lomefloxacin, levofloxacin, ciprofloxacin, ofloxacin, norfloxacin, ciprofloxacin hydrochloride, etc.), β-lactam antimicrobials (sulbenicillin, cefmenoxime, etc.), aminoglycosides Antibacterial agents (kanamycin, gentamicin, tobramycin, sisomycin, dibekacin, bekanamycin, micronomycin, etc.), tetracycline antibacterial agents (oxytetracycline, etc.), macrolide antibacterial agents (erythromycin, etc.), chloramphenicol antibacterial agents ( chloramphenicol, etc.), polypeptide antibacterial agents (colistin, etc.), etc. Also, antiviral agents (idoxuridine, acyclovir, adenine arabinoside, ganciclovir, foscarnet, valacyclovir, trifluorothymidine, cidofovir, carbocyclic oxetanosine G, etc.), antifungal agents (pimaricin, fluconazole, itraconazole, miconazole, flucytosine, amphotericin B, etc.).

Sugars: Examples include lactulose, raffinose, pullulan, glucose, maltose, trehalose, sucrose, cyclodextrin, xylitol, mannitol, sorbitol and the like.

Polysaccharides or derivatives thereof: for example, gum arabic, karaya gum, xanthan gum, carob gum, guar gum, guaiac butter, quince seed, dammar gum, tragacanth, benzoin gum, locust bean gum, casein, agar, alginic acid, dextrin, dextran, carrageenan, gelatin, Collagen, pectin, starch, polygalacturonic acid (alginic acid), chitin and its derivatives, chitosan and its derivatives, elastin, hyaluronic acid, chondroitin sulfate or salts thereof (sodium alginate, sodium chondroitin sulfate, etc.) and the like.

Local anesthetic components: for example, lidocaine, oxybuprocaine, dipcaine, procaine, ethyl aminobenzoate, meprilcaine, mepivacaine, bupivacaine, cocaine, and salts thereof (lidocaine hydrochloride, oxybuprocaine hydrochloride, etc.), etc. .

Steroid components: Examples include hydrocortisone, prednisolone, cortisol, methylprednisolone, triamcinolone, paramethasone, betamethasone, salts thereof, and the like.

Glaucoma therapeutic ingredients: for example, distigmine bromide, timolol maleate, carteolol hydrochloride, betaxolol hydrochloride, latanoprost, isopropyl unoprostone, dipivefrin hydrochloride, apraclonidine hydrochloride, pilocarpine hydrochloride, carbachol, dorzolamide hydrochloride, acetazolamide , methazolamide, and salts thereof.

Cataract therapeutic ingredients: Examples include pirenoxine, glutathione, salivary gland hormones, thiopronin, dihydro azapentacene disulfonate and salts thereof (eg, Sodium 5,12-dihydro azapentacene disulfonate, etc.).

Mydriatic component: Examples include cyclopentolate hydrochloride and tropicamide.

When a drug is blended, the blending amount can be selected to be an effective and appropriate amount of each drug. It is preferably in the range of ~5 w/v%.

Examples of buffering agents include citric acid, sodium citrate, boric acid, borax, phosphoric acid, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, acetic acid, sodium acetate, glacial acetic acid, trometamol, Sodium carbonate, sodium hydrogencarbonate, etc. are mentioned. When blending a buffering agent, the blending amount thereof is preferably in the range of 0.003 to 4 w/v% in the ophthalmic composition.

Stabilizers include, for example, ethylenediamineacetic acid derivatives or salts thereof (e.g., edetic acid (ethylenediaminetetraacetic acid, etc.), sodium edetate (ethylenediaminetetraacetic acid sodium), etc.), α-cyclodextrin, β-cyclodextrin, γ- cyclodextrins and the like. When a stabilizer is blended, its blending amount is preferably in the range of 0.003 to 2 w/v% in the ophthalmic composition.

Examples of thickening agents include cellulose polymer compounds such as methyl cellulose, hypromellose and hydroxyethyl cellulose, polyvinyl polymer compounds such as povidone and polyvinyl alcohol, liquid paraffin, carboxyvinyl polymer, and polyethylene glycol. When a thickening agent is blended, its blending amount is preferably in the range of 0.003 to 3 w/v% in the ophthalmic composition.

Examples of isotonizing agents include potassium chloride, sodium chloride, calcium chloride, magnesium chloride, potassium acetate, sodium acetate, sodium carbonate, magnesium sulfate, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium hydrogen sulfite and the like. mentioned. When a tonicity agent is blended, its blending amount is preferably in the range of 0.001 to 3 w/v% in the ophthalmic composition.

Antioxidants include, for example, hydroquinone, propyl gallate, sodium hydrogen sulfite, and the like. When an antioxidant is blended, its blending amount is preferably in the range of 0.001 to 1 w/v% in the ophthalmic composition.

Examples of antiseptics include benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, sorbic acid, potassium sorbate, polydronium chloride, alkyldiaminoethylglycine hydrochloride, polyhexamethylene biguanide and the like. When an antiseptic is added, the amount of the antiseptic is preferably in the range of 0.001 to 0.5 w/v% in the ophthalmic composition.

Examples of pH adjusters include hydrochloric acid, sulfuric acid, phosphoric acid, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide and the like. The pH (20° C.) of the ophthalmic composition of the present invention is 3.5-8.0, preferably 5.0-7.5, more preferably 6.0-7.3. If the pH is too low or too high, the feeling of stimulation may become strong. The pH is measured at 20° C. using a pH osmometer (HSMO-1, Toa DKK Co., Ltd.). Sodium hydroxide, potassium hydroxide, hydrochloric acid and the like are preferable as the pH adjuster.

Polyhydric alcohols include, for example, glycerin, propylene glycol, butylene glycol, polyethylene glycol and the like.

[Production method]
The ophthalmic composition of the present invention can be produced, for example, by a known production method with the remainder being water. For example, after dissolving each of the above components in a mixed solvent with water such as sterilized purified water or ion-exchanged water, the pH is adjusted, and if necessary, the osmotic pressure and the like are appropriately adjusted using a pH adjuster and an isotonizing agent. can be obtained by adjusting

[Ophthalmic products]
The ophthalmic product of the present invention is contained in a container having a main body containing an ophthalmic composition and a cap, and the container is surrounded and sealed with an enclosure together with an iron-based oxygen absorber. and
The capacity of the main body is 1 to 25 mL,
The oxygen permeability of the main body is 10 cc/(m ² · 24 hr · atm) or more,
The volume of the space formed between the enclosure and the container is 200 V/V % or less with respect to the volume of the container.

The container comprises a body containing the ophthalmic composition and a cap. More specifically, the main body is provided with an eyedropper and has a screw-type, one-touch-type, or other cap that seals the main body. The main body may be provided with an inner plug having an eyedropper, the eyedropper may be provided in the cap, or the cap may be directly placed on the container so as to be sealed. Preferably, the main body is provided with an inner plug having an eyedropper. In the present invention, the term "container" refers to a state in which a cap is attached to a main body.

<Body>
The main body containing the ophthalmic composition has an oxygen permeability of 10 cc/(m ² ·24 hr·atm) or more in order to volatilize the cooling agent in the ophthalmic composition into the enclosure. Although the upper limit is not particularly limited, it may be 200 cc/(m ² ·24 hr·atm) or less. Specific examples of the body having such oxygen permeability include bodies made of materials such as polyethylene, polyethylene terephthalate, polypropylene, polybutylene, polycarbonate, polyarylate, and vinyl chloride. More specifically, a multi-dose eye drop container made of polyethylene terephthalate is highly stable and more suitable. The oxygen permeability can be measured by a method according to JIS-K7126-2 Plastic Film and Sheet - Gas Permeability Test Method B (Appendix B).

The volume of the main body (the volume when the main body is filled with the ophthalmic composition) is 1-25 mL, preferably 5-20 mL. Furthermore, the amount of the ophthalmic composition to be accommodated can be appropriately selected according to the product and its method of use. is more preferred. If the amount of the ophthalmic composition is too small, the volatilization amount of the cooling agent in the eye drop container may be insufficient, resulting in an insufficient odor masking effect.

<Cap, inner plug>
The inner stopper and the cap can be made of materials used for containers of known ophthalmic products. The material of the inner plug is preferably polyethylene or polypropylene having a melt flow rate of 2.0 or less, preferably 1.2 to 1.8. As a material for the cap, polyethylene and polypropylene are preferable.

The oxygen permeability of the container is preferably 0.01% or more, more preferably 0.1% or more, and even more preferably 0.2% or more. Although the upper limit is not particularly limited, it can be, for example, 5% or less. The method for measuring the oxygen permeability is the method described in Examples below. If the oxygen permeability is high, the cooling agent is easily volatilized, and a better odor masking effect can be obtained.

The filling ratio of the ophthalmic composition to the volume of the container (the volume ratio of the empty wall of the main body to the full amount of the container in a container fitted with a cap and an inner plug) is preferably 50% or more, more preferably 70% or more, and 80%. The above is more preferable. If the accommodation rate is too low, the cooling agent fills the inside of the cavity wall, and the effect of masking the odor inside the enclosure may be insufficient.

[Oxygen absorber]
The oxygen absorbent of the present invention is an iron-based oxygen absorbent, and specifically, Ageless (FX, SA, Z-PT, GL, G) manufactured by Mitsubishi Gas Chemical Company, Inc., Tokiwa Sangyo Vitalon, etc. manufactured by the company are commercially available. Use specs that can absorb enough oxygen in the enclosure. Oxygen absorbers are generally widely used in the pharmaceutical and food industries, so they can be used at low cost. The oxygen absorber to be used has the ability to absorb all the oxygen present in the pillow. If it is below the capacity, it will not be able to absorb oxygen sufficiently, and easily oxidized substances will be oxidatively decomposed.

[Enclosure]
The ophthalmic composition is enclosed and sealed in an envelope along with an oxygen absorber. Materials for the enclosure include, for example, polyethylene, polyethylene terephthalate, polypropylene, polybutylene, polycarbonate, polyester, nylon, cellophane, polyvinyl chloride film, aluminum foil or polyvinyl alcohol film deposited with aluminum, polyamide film, and alumina deposited. Polyethylene terephthalate coated with silicon oxide, polyethylene terephthalate deposited with silicon oxide, polyvinylidene chloride-coated film or laminated film, and composite and multilayer films thereof. Among them, polyethylene terephthalate/polyethylene multilayer film and alumina-deposited polyethylene terephthalate/polyethylene multilayer film are preferable. The oxygen permeability is preferably 10 cc/(m ² ·24 hr·atm) or less (that is, 0 to 10 cc/(m ² ·24 hr·atm)). The oxygen permeability of the enclosure is preferably lower than that of the main body, more preferably less than 10 cc/(m ² ·24 hr·atm), 0 to 3 cc/(m ² ·24 hr·atm), 0 ~ 1 cc/(m ² · 24 hr · atm), more preferably 0.01 to 0.3 cc / (m ² · 24 hr · atm), particularly 0.01 to 0.1 cc / (m ² · 24 hr · atm) Preferably, 0.01 to 0.02 cc/(m ² ·24 hr·atm) is most preferable.

The volume of the space (inner space) formed between the enclosure and the container (with the cap attached to the main body) is 200 V/V% or less and 150 V/V% or less of the volume of the container. is preferred, and 120 V/V % or less is more preferred. If it exceeds 200 V/V %, a sufficient odor masking effect cannot be obtained in the enclosure. Although the lower limit is not particularly limited, it can be 20 V/V % or more.

[Masking method]
The present invention
(A) easily oxidizable,
(B) a cooling agent;
(C) a nonionic surfactant, and (D) one or more components selected from dibutylhydroxytoluene, dibutylhydroxyanisole, propyl parahydroxybenzoate, butyl parahydroxybenzoate and chlorobutanol, wherein an ophthalmic composition comprising An ophthalmic product housed in a container comprising a main body containing an ophthalmic composition and a cap, wherein the container and an iron-based oxygen absorber are enclosed and sealed with an enclosure,
The capacity of the main body is 1 to 25 mL,
The oxygen permeability of the main body is 10 cc/(m ² · 24 hr · atm) or more,
Provided is a method for masking an odor when the envelope is opened, wherein the volume of the space formed between the envelope and the container is 200 V/V % or less with respect to the volume of the container. Preferred components, ranges, etc. are the same as above.

EXAMPLES Hereinafter, the present invention will be specifically described by showing examples and comparative examples, but the present invention is not limited to the following examples. In the following examples, unless otherwise specified, "%" in the composition indicates w/v% (g/100 mL), and ratio indicates mass ratio.

[Example, Comparative example]
An ophthalmic composition having the composition shown in the table below was produced according to a conventional method, placed in the container shown below, and then packed with an oxygen absorber (ageless (model number: Z-PT15), manufactured by Mitsubishi Gas Chemical Company, Inc.). The film was wrapped in an enclosure and sealed to obtain an ophthalmic product. This ophthalmic product was stored in an environment of 40° C. and 75% RH for 1 month. After storage, the film package was opened, and the following sensory evaluation of odor was carried out.

Except for Example 2, Comparative Example 3, Comparative Example 4 and Comparative Example 5, the following containers/enclosures were used.
<container>
・Body Material: Polyethylene terephthalate: Oxygen permeability 10cc/( ^m2・24hr・atm)
Body capacity: 17mL
・Cap screw type ・Inner plug <Enclosure>
Material: polyethylene terephthalate vapor-deposited with alumina/polyethylene multilayer film (oxygen permeability 0.2 cc/(m ² ·24 hr · atm))
Size: W9.0 x L6.5 (cm)

Conditions for using the container/enclosure described above are as follows.
- Amount of ophthalmic composition: 15 mL
・Container oxygen permeability: 0.7%
・Filling ratio of ophthalmic composition to container volume: 88%
・Container volume: 22 mL
- A space (inner space) formed between the enclosure and the container: 23 mL
・Ratio of inner space to container volume: 105%
In Example 2 and Comparative Example 4, the size of the enclosure was changed so that the ratio of the inner space to the volume of the container in the table was obtained. , and in Comparative Example 5, a non-oxygen-permeable main body was used.

[Method for measuring container oxygen permeability]
(1) An empty container was placed in the enclosure at room temperature (20-30°C). An inner stopper and a cap were attached to the container. As for the oxygen permeability of the enclosure, a low oxygen permeability enclosure having an oxygen permeability of 0.2 cc/(m ² ·24 hr·atm) or less was used. The size of the enclosure was 150×65 mm (inner dimensions).
(2) The space between the container and the enclosure was filled with nitrogen gas and sealed. The nitrogen substitution rate at this time was set to 90% by volume or more (oxygen concentration of 2% by volume or less).
(3) The envelope was divided into two spaces by heat sealing so that the size of the envelope was 85×65 mm (inner dimensions). The oxygen concentration in the space of the enclosure on the side without the container was measured and used as the initial value. A residual oxygen concentration meter (Iijima Electronics Co., Ltd.) was used for the oxygen concentration.
(4) It was stored under conditions of 40° C. and 75% RH for 3 days, taken out and allowed to stand at room temperature, and then the oxygen concentration in the enclosure was measured.
The value calculated by the following formula is defined as oxygen permeability.
Oxygen permeability formula:
Oxygen permeability (%) = oxygen concentration in enclosure after storage (%) - initial oxygen concentration in enclosure (%)

[Evaluation of Odor]
The odor was evaluated sensory by expert panelists according to the following four grades (n=6).
0: Very bad smell 1: Bad smell 2: Slight bad smell 3: Almost no bad smell 4: No bad smell at all 5: No bad smell, smell of cooling agent Results obtained ( average value) and the following evaluation criteria based thereon. ●, 〇, and ◎ are accepted.
<Evaluation criteria>
×: Less than 1.5 ●: 1.5 or more and less than 2.0 ○: 2.0 or more and less than 3.0 ◎: 3.0 or more

Similar results were obtained when the material of the envelope was changed to polyethylene (oxygen permeability 3 cc/(m ² ·24 hr·atm)).

The raw materials used in the above examples are shown below. In addition, unless otherwise specified, the amount of each component in the table is the amount in terms of pure content.
Retinol palmitate: (trade name: retinol palmitate, manufactured by DSM Nutrition Japan, 1,740,000 IU/g)
l-menthol: (trade name: l-menthol (mint brain), manufactured by Suzuki Mint load Co., Ltd.)
dl-camphor: (trade name: Japanese Pharmacopoeia dl-camphor, manufactured by Nippon Fine Chemical Co., Ltd.)
d-camphor (trade name: Japanese Pharmacopoeia d-camphor, manufactured by Nippon Fine Chemical Co., Ltd.)
d-borneol: (trade name: d-borneol, manufactured by Masami Yanagisawa Co., Ltd.)
Eucalyptus oil: (Product name: Japanese Pharmacopoeia eucalyptus oil, Ogawa Perfumery Co., Ltd.)
Geraniol: (trade name: Geraniol EX MIX, manufactured by Takasago International Corporation)
Polyoxyethylene hydrogenated castor oil 60: (trade name: HCO-60 (medical use), manufactured by Nippon Surfactant Kogyo Co., Ltd.)
Polyoxyethylene hydrogenated castor oil 40: (trade name: HCO-40 (medical use), manufactured by Nippon Surfactant Kogyo Co., Ltd.)
Polyoxyethylene (20) sorbitan oleate (polysorbate 80): (trade name: Rhodol TW-O120V, manufactured by Kao Corporation)
Polyoxyethylene polyoxypropylene glycol (polyoxyethylene (196) polyoxypropylene (67) glycol): (trade name: Kolliphor P407, manufactured by BASF Japan Ltd.)
Polyethylene glycol monostearate (polyoxyl 40 stearate): (trade name: NIKKOL MYS-40MV, manufactured by Nippon Surfactant Kogyo Co., Ltd.)
Dibutylhydroxytoluene: (trade name: dibutylhydroxytoluene, manufactured by Wako Pure Chemical Industries, Ltd.)
Propyl paraoxybenzoate: (trade name: Mekkin-P, manufactured by Ueno Pharmaceutical Co., Ltd.)
Butyl paraoxybenzoate: (trade name: Mekkins-B, manufactured by Ueno Pharmaceutical Co., Ltd.)
Chlorobutanol: (trade name: chlorobutanol, JSC Olainfarm)

Claims (6)

(A) easily oxidizable,
(B) a cooling agent;
(C) a nonionic surfactant, and (D) one or more components selected from dibutylhydroxytoluene, dibutylhydroxyanisole, propyl parahydroxybenzoate, butyl parahydroxybenzoate and chlorobutanol, wherein an ophthalmic composition comprising An ophthalmic product housed in a container comprising a main body containing an ophthalmic composition and a cap, the container being surrounded and sealed with an enclosure together with an iron-based oxygen absorber,
The capacity of the main body is 1 to 25 mL,
The oxygen permeability of the main body is 10 cc/(m ² · 24 hr · atm) or more,
An ophthalmic product, wherein the volume of the space formed between the enclosure and the container is 200 V/V % or less of the volume of the container. The ophthalmic product of Claim 1, wherein component (A) is vitamin A. The ophthalmic product according to claim 1 or 2, wherein component (B) is one or more selected from l-menthol, dl-camphor, d-camphor, d-borneol, geraniol and eucalyptus oil. The ophthalmic product according to any one of claims 1 to 3, wherein the amount of component (B) in the ophthalmic composition is 0.0001 w/v% or more. Component (C) is one or more selected from polyoxyethylene hydrogenated castor oil 60, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene (20) sorbitan oleate and polyoxyethylene polyoxypropylene glycol. 5. The ophthalmic product according to any one of 1-4. (A) easily oxidizable,
(B) a cooling agent;
(C) a nonionic surfactant, and (D) one or more components selected from dibutylhydroxytoluene, dibutylhydroxyanisole, propyl parahydroxybenzoate, butyl parahydroxybenzoate and chlorobutanol, wherein an ophthalmic composition comprising An ophthalmic product housed in a container comprising a main body containing an ophthalmic composition and a cap, wherein the container and an iron-based oxygen absorber are enclosed and sealed with an enclosure,
The capacity of the main body is 1 to 25 mL,
The oxygen permeability coefficient of the main body is 10 cc/(m ² · 24 hr · atm) or more,
A method of masking an odor when the envelope is opened, wherein the volume of the space formed between the envelope and the container is 200 V/V% or less of the volume of the container.