JP2003113078A - Ophthalmic preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a vitamin A-containing preparation whose vitamin A is stable during manufacturing and storage. SOLUTION: An ophthalmic preparation containing vitamin A is produced by filling an ophthalmic composition containing vitamin A (including a precursor of the same) in a resin-made container, and further closely wrapping the container with a wrapping material having an oxygen permeability coefficient of <=10 cc/m<2> /24 hr/atm. The preparation is characterized in that (1) the ophthalmic composition is prepared by adding a mixture of vitamin A, an oil-soluble oxidizing agent and a nonionic surfactant to an aqueous liquid to solubilize the mixture, (2) the ophthalmic composition is filled in a resin-made container with a head space of <=5%, and (3) the resin container is closely wrapped with a wrapping material having an oxygen permeability coefficient of <=10 cc/m<2> /24 hr/atm, and the space between the wrapping material and the container is filled with an inert gas having a concentration of >=50 vol.%.

Description

Description: BACKGROUND OF THE INVENTION 1. Field of the Invention
The present invention relates to a vitamin A-containing ophthalmic preparation having good qualitative properties. BACKGROUND OF THE INVENTION Vitamin A is particularly susceptible to oxidative degradation
In addition, in the state of solution dissolved in water, etc.
Easy and stable during storage of the preparation, including during the production of aqueous preparations
Maintaining sex was an issue. JP-A-62-138438 describes
After filling such containers that easily oxidize into a container,
Stabilization methods for sealing with oxygen scavengers have been proposed.
However, there was a problem that the cost was expensive. [0002] The present invention relates to a method for manufacturing
Vitamin that maintains stability during production and storage of Tamine A
It is intended to provide an A-containing preparation. [0003] The present inventors have solved the above problems.
As a result of studying to solve the problem, a specific composition and manufacturing method
With the specified ophthalmic composition and a specific packaging form
By doing so, the present inventors have found that the above problems can be solved, and
completed. That is, the present invention relates to vitamin A, fat-soluble acid
Ophthalmic composition containing a non-ionic surfactant and a nonionic surfactant
A resin container is filled, and the container has an oxygen permeability coefficient of 1
0cc / m ² / 24hr / atm or less sealed
Ophthalmic preparations, wherein (1) the ophthalmic composition comprises vitamins
A mixture of fats-soluble oxidizing agent and nonionic surfactant
A composition added to an aqueous liquid and solubilized, and (2) the eye
Medical composition with less than 5% headspace in resin container
(3) The resin container has an oxygen permeability coefficient of 10
cc / m ² / 24hr / atm or less sealed
Between the package and the container.
Vitamin characterized by being filled with active gas
A class A-containing ophthalmic preparation is provided. [0004] The ophthalmic preparation of the present invention comprises an essential component
As vitamin A, fat-soluble oxidizing agent, nonionic surfactant
Agent. As vitamin A, vitamin A
In addition to itself, vitamin A containing mixtures such as vitamin A oil,
Vitamins such as retinol palmitate and retinol acetate
Includes vitamin A derivatives such as fatty acid A esters
You. Vitamin A precursor is administered in vivo after administration to the human body.
A substance that converts to Mines A, such as pantothenic acid or
And their salts. Vitamin A is, for example,
1.7 million retinol palmitate international
(IU) are commercially available. [0005] Vitamin A is usually present in eye drop compositions.
0.003-0.2g / 100mL
And preferably from 0.01 to 0.1 weight g / 100 mL
Range. In addition, as vitamin A international units,
It is preferably at 200,000 units / 100 mL.
Is not particularly limited. The fat-soluble antioxidant of the present invention includes Vitamin
E, dibutylhydroxytoluene, butylhydroxy
Cyanisole. Vitamin Es are, for example,
Vitamin E acetate, vitamin E succinate
You. Vitamin E is available from Riken Vitamin Co., Ltd.
Acetate α, BHT manufactured by Yoshitomi Fine Chemical Co., Ltd.
"Takeda" and the like are commercially available. [0007] Vitamin E is usually present in eye drop compositions.
0.001 to 0.5 weight g / 100mL
And preferably in the range of 0.01 to 0.1 g / 100 mL
It is. Dibutylhydroxytoluene, butylhydroxy
Cyanisole is usually present in the eye drop composition at 0.0001 to 0.0001.
0.05g / 100mL can be blended, preferably
Is in the range of 0.001 to 0.01 g / 100 mL. [0008] Nonionic surfactants include water-soluble surfactants.
Higher fatty acid esters such as reoxyethylene hydrogenated castor oil
, Polyoxyethylene sorbitan higher fatty acid ester
And sucrose fatty acid esters.
Oxyethylene (p = 60) hydrogenated castor oil, polyoxy
Ethylene (p = 20) sorbitan monooleate
You. Here, p represents the average number of moles of ethylene oxide added.
You. Specifically, Nikkor H manufactured by Nikko Chemicals Co., Ltd.
CO-40, HCO-50, HCO-60, TO-10
Etc. are commercially available. [0009] The nonionic surfactant is usually used as an ophthalmic composition.
0.01 to 1.0% by weight in
Or 0.05 to 0.5% by weight. The content composition of the ophthalmic preparation of the present invention includes
Other than the essential components described, unless the effects of the present invention are hindered,
Various additives commonly used in ordinary ophthalmic preparations, examples
For example, drugs, preservatives, tonicity agents, thickeners, buffers, stabilization
Agents, chelating agents, solubilizers, pH adjusters, fresheners, etc.
Can be further contained, and these can be used alone or
Two or more kinds can be used in appropriate combination. As the drug, for example, glycyrrhizic acid
Dipotassium, epsilon-aminocaproic acid, allant
In, berberine chloride, sodium azulene sulfonate
Anti-inflammatory agents such as vitamins, zinc sulfate, lysozyme chloride, vitamins
B2, vitamin B6, vitamin B12, panthenol,
Calcium pantothenate, sodium pantothenate, etc.
Vitamins, diphenhydramine hydrochloride, maleic acid
Antihistamines such as lorpheniramine, epinef hydrochloride
Phosphorus, naphazoline hydrochloride, tetrahydrozoline hydrochloride, etc.
Decongestant, potassium L-aspartate, LA
Magnesium spraginate, aminoethyl sulfonic acid
Which amino acids, chondroitin sodium sulfate, here
Acid mucopolysaccharides such as sodium luronate, sulfa drugs,
Sulfur, isopropylmethylphenol, hinokithio
Fungicides, lidocaine, lidocaine hydrochloride, pro-hydrochloride
Local anesthetics such as caine and dibucaine hydrochloride, methyl sulfate
Other active ingredients such as ostigmine are included. Compounding amount
May be mixed with an appropriate effective amount of each drug. As preservatives, benzalkonium chloride,
Benzethonium chloride, chlorhexidine gluconate,
Rubic acid, potassium sorbate, paraoxybenzoic acid
Steal and the like. As tonicity agents, potassium chloride, sodium chloride
Thorium, calcium chloride, magnesium sulfate, propylene
Examples include lenglycol and glycerin. As the thickener, polyvinyl alcohol,
Polyvinylpyrrolidone, carboxyvinyl polymer,
Polyvinyl polymer compound such as vinyl methyl ether
Product: methylcellulose, hydroxyethylcellulose,
Hydroxypropyl methylcellulose, hydroxyethyl
Cellulose, hydroxypropylcellulose, ethyl
Cellulose such as cellulose and carboxymethylcellulose
Polymer compounds; polyethylene glycol, polypropylene
Examples include polyalkylene glycols such as pyrene glycol.
I can do it. As a buffer, for example, boric acid or its acid
Salt (borax, etc.), citric acid or its salt (sodium citrate)
), Phosphoric acid or its salts (sodium monohydrogen phosphate)
Etc.), tartaric acid or its salts (such as sodium tartrate), glue
Conic acid or its salt (sodium gluconate, etc.), trome
Tamol, acetic acid or its salt (sodium acetate, etc.), various
Amino acids and the like or a combination thereof are exemplified. As the chelating agent and the stabilizer, for example,
Sodium edetate, sodium citrate, cyclodex
String, sulfite, citric acid or a salt thereof and the like.
You. As a solubilizing agent, polyethylene glycol
And propylene glycol. As the pH adjuster, for example, hydrochloric acid,
Acid or a salt thereof, boric acid or a salt thereof, phosphoric acid or a salt thereof,
Acetic acid or its salt, tartaric acid or its salt, sodium hydroxide
, Potassium hydroxide, sodium carbonate, sodium hydrogen carbonate
And the like. The pH of the present invention is in the range of 4-9.
It is more preferably, and more preferably from 5 to 8.5.
Outside of the above range, the stability of vitamin A decreases.
And so on. As the cooling agent, d-camphor, dl-
Camphor, geraniol, d-borneol, dl-bo
Luneol, l-menthol, linalool, cineau
, Anethole, peppermint oil, bergamot oil, eucalyptus
Oil, rose oil, lavender oil, spearmint oil, wiki
Cherry oil and the like. The method for producing the ophthalmic composition of the present invention is characterized in that
Preparing Min A and fat-soluble antioxidants and nonionic surfactants
Mixed, homogeneously dissolved in the range of 20 to 90 ° C, and stirred.
While gradually adding to 20-90 ° C aqueous liquid
An ophthalmic preparation containing various vitamin A compounds is prepared. In the present invention, the blending of the above essential components,
Other than the production method, that is, regarding the blending of other components, the present invention
Can be blended in any way as long as the effect of
Wear. For example, vitamins such as vitamin A acetate
Vitamin Es such as min A and vitamin E acetate
With non-ionic such as polyoxyethylene hydrogenated castor oil 60
After homogeneously dissolving in a surfactant and solubilizing in water,
Drugs such as epsilon-aminocaproic acid,
Buffering agents such as acid, preservatives such as benzalkonium chloride,
Solubilizing agents such as propylene glycol, sodium chloride
Etc .; stabilizers such as sodium edetate;
Viscosity agents such as roxypropyl methylcellulose, citric acid
And then add hydrochloric acid or sodium hydroxide
The pH is adjusted to 4 to 9, preferably to 5 using a pH adjusting agent such as
8.5 Adjustment impairs the stability of vitamin A
Preparing ophthalmic preparations containing vitamin A without licking
Can be. In addition, other drugs, preservatives, isotonic
Agents, thickeners, buffers, stabilizers, chelating agents,
Purified water (p) obtained by adding auxiliary agents, pH adjusters, fresheners, etc. to water
H4-9, preferably 5-8.5), wherein
Vitamin A and fat-soluble oxidizing agent
Homogeneously dissolved in non-ionic surfactants such as castor oil 60
A solution may be added and solubilized. As the container used in the ophthalmic preparation of the present invention
Is preferably an oxygen-permeable container, and as its material,
For example, polyethylene, polypropylene, polycarbonate
, Polyvinyl chloride, polyethylene terephthalate, etc.
A container made of a material is exemplified. These polymers have U
1-20% by mass of polymer, tinuvin, anthraquinone
Yellow dye, monoazo yellow dye, cyanine blue, acid
0.1-10 pigments such as iron oxide, zinc oxide and titanium oxide
Materials kneaded by mass% can also be preferably used. Oxygen transmission
Among these, the oxygen permeability coefficient is particularly high
Material, especially oxygen permeability coefficient is 10cc / m2 · 24hr ·
Atm or more are preferable. In such a container,
Fill the contents so that the space is 5% or less.
Apply cap. Examples of specific enclosure materials are listed below.
You. Polyethylene terephthalate, polyethylene
Ren, polypropylene, polycarbonate, polyvinyl chloride
Nyl, acrylonitrile resin polyethylene naphthalate / polyethylene terephthale
1%, 3%, 5%, 10% U polymer as a mixed resin additive of 1/99 to 20/80
Cyanine blue, tinuvin, and anthrax as polyethylene terephthalate additives
Non-system yellow dye, monoazo system yellow dye, iron oxide, suboxide
Polyethylene kneaded with 0.5% each of lead and titanium oxide
5% U polymer as terephthalate additive and 0.1% pigment each.
Polyethylene terephthalate kneaded with 5% kneaded polyethylene
Propylene, polycarbonate, polyvinyl chloride,
Acrylonitrile resin, a resin filled with a container,
Seal. As the enclosure, those which are particularly impermeable to oxygen
Preferably, for example, aluminum foil, aluminum
Polyvinyl alcohol, Polyamide, Polyvinyl chloride
Simple or composite films such as dencoat are mentioned,
It is not limited to these. Especially for long-term stabilization
Means that the oxygen permeability coefficient is 10 cc / m2 / 24 hr / atm
The following (that is, 0 to 10 cc / m2 / 24 hr / atm)
(JIS-K7126 plastic film and sheet
Gas permeability test method B, test conditions: 23 ° C, 90%
An oxygen impermeable envelope of RH) is preferred. Concrete siege
Examples of body materials are listed below. Polyethylene terephthalate / polychlorinated
Vinylidene / polyethylene / ethylene vinyl acetate
Composite film polyethylene terephthalate / silica / polyethylene
/ Ethylene vinyl acetate composite film Polyethylene terephthalate / Aluminum oxide / Poly
Polyethylene / ethylene vinyl acetate composite film (10) Nylon / silica / polyethylene / ethylene bi
Nyl acetate composite film (11) Polyethylene terephthalate / silica / ex
Tolusion coated polyethylene / linear low density
Polyethylene composite film (12) Polyethylene terephthalate / aluminum oxide
/ Extrusion coated polyethylene / Linear low
Density polyethylene composite film [13] Nylon / silica / extrusion
Coat Polyethylene / Linear Low Density Polyester
Tylene composite film (14) Aluminum foil (15) Polyvinyl alcohol deposited with aluminum (16) Polyamide (17) Polyvinylidene chloride coat The ophthalmic preparation of the present invention comprises the above sealed container.
50% by volume between vessel and enclosure (inner space)
The above inert gas is filled. As an inert gas
Is a gas such as nitrogen, helium, neon, argon, etc.
Is mentioned. The inert gas concentration in the inner space is low.
Must be at least 50 vol% or more
At least 75 vol%, particularly preferably 90 vol%
Preferably, there is. Inert gas replacement rate is 50 vol%
If less, the stabilizing effect is inferior, and the object of the present invention may be achieved.
I can't do that. Further, as the volume of the inner space becomes larger,
The smaller the container capacity, the higher the stabilizing effect.
The inner space volume must be equal to or greater than the container volume.
desirable. In addition, the enclosure must be completely sealed.
There must be no pinholes. This sealing method
As a method, a method using heat sealing is simple and suitable.
, But is not limited to this. EXAMPLES Examples 1 to 4 and Comparative Examples 1 to 3 are shown below.
Prepared and packaged by the method. Evaluation: About vitamin A content
And measured by HPLC immediately after production and after storage at 50 ° C for 2 months
did. The results are summarized and shown at the end. Example 1 Vitamin A palmitate 0.25 g (1.7 million international unit
Mixed with 0.05 g of dibutylhydroxytoluene
And polyoxyethylene (20) sorbitan mono
Mixed with 2 g of oleate (Nikkor TO-10)
And dissolved in 800 mL of water. Add tetrahydrochloride
Zoline 0.5 g, benzethonium chloride 0.1 g, l-meth
0.05 g, propylene glycol 5 g, ara
1 g of pantoin, 0.2 g of panthenol, epsilon-A
Minocaproic acid 10 g, ethylenediaminetetraacetic acid dinatto
0.1 g of lithium and mixed with sodium hydroxide
After adjusting to 7.0, the total volume was adjusted to 1000 mL with purified water.
And sterile-filtered and 15 mL of polyethylene terephthalate
Into an eyedropper made from a glass. This is called polyethylene
Tarate / polyvinylidene chloride / polyethylene / ethylene
Covered with an envelope of vinyl acetate composite film
Heat sealed in a raw gas atmosphere (inner
Pace volume: about 35cm ³ , Inert gas replacement rate: 75
%). Example 2 Vitamin E acetate 0.5 g, Vitamin A palmitate
0.2g (1.7 million international units)
Ethylene (60) hydrogenated castor oil (Nikkor HCO-6
0) After mixing with 1.8g, dissolve in 800mL of warm water
You. Add 10g of boric acid, 2g of borax, naphazoli hydrochloride
0.3 g, 10 g of benzalkonium chloride solution 0.5 g, l
-Menthol 0.05 g, d-borneol 0.05
g, propylene glycol 5 g, neostig methyl sulfate
0.05 g of min, 0.5 g of pyridoxine hydrochloride, asparagus
Potassium formate 10g, ethylenediaminetetraacetic acid dinatto
0.03 g of lithium was mixed, and the pH was adjusted to 6.5 with dilute hydrochloric acid.
After adjusting the volume, make up the total volume to 1000 mL with purified water and sterile filter.
10mL polyethylene terephthalate eyedropper
Fill. This is polyethylene terephthalate / poly
Vinylidene chloride / polyethylene / ethylene vinyl acetate
Coated with an enclosure of heat-resistant composite film in a nitrogen gas atmosphere.
Heat sealed (inner space volume: approx.
35cm ³ , Inert gas replacement rate: 85%). Comparative Example 1 Vitamin E acetate 0.5 g, Vitamin A palmitate
0.2g (1.7 million international units)
Ethylene (60) hydrogenated castor oil (Nikkor HCO-6
0) After mixing with 1.8g, dissolve in 800mL of warm water
You. Add 10g of boric acid, 2g of borax, naphazoli hydrochloride
0.3 g, 10 g of benzalkonium chloride solution 0.5 g, l
-Menthol 0.05 g, d-borneol 0.05
g, propylene glycol 5 g, neostig methyl sulfate
0.05 g of min, 0.5 g of pyridoxine hydrochloride, asparagus
Potassium formate 10g, ethylenediaminetetraacetic acid dinatto
0.03 g of lithium was mixed, and the pH was adjusted to 6.5 with dilute hydrochloric acid.
After adjusting the volume, make up the total volume to 1000 mL with purified water and sterile filter.
10mL polyethylene terephthalate eyedropper
Fill. This is polyethylene terephthalate / poly
Vinylidene chloride / polyethylene / ethylene vinyl acetate
Coated with an enclosure of a composite film and purged with inert gas.
Without heat sealing.
Volume: about 35cm ³ ). Comparative Example 2 Vitamin E acetate 0.5 g and Vitamin A palmitate
0.2 g (1.7 million international units) of a mixture of 800 m
L, and then cured with polyoxyethylene (60)
Add 1.8 g of castor oil (Nikkor HCO-60)
Was. Add 10g of boric acid, 2g of borax, naphazoli hydrochloride
0.3 g, 10 g of benzalkonium chloride solution 0.5 g, l
-Menthol 0.05 g, d-borneol 0.05
g, propylene glycol 5 g, neostig methyl sulfate
0.05 g of min, 0.5 g of pyridoxine hydrochloride, asparagus
Potassium formate 10g, ethylenediaminetetraacetic acid dinatto
0.03 g of lithium was mixed, and the pH was adjusted to 6.5 with dilute hydrochloric acid.
After adjusting the volume, make up the total volume to 1000 mL with purified water and sterile filter.
10mL polyethylene terephthalate eyedropper
Fill. This is polyethylene terephthalate / poly
Vinylidene chloride / polyethylene / ethylene vinyl acetate
Coated with an enclosure of heat-resistant composite film in a nitrogen gas atmosphere.
Heat sealed (inner space volume: approx.
35cm ³ , Inert gas substitution rate: 75%). Comparative Example 3 Vitamin E acetate 0.5 g and Vitamin A palmitate
0.2 g (1.7 million international units) of a mixture of 800 m
L, and then cured with polyoxyethylene (60)
Add 1.8 g of castor oil (Nikkor HCO-60)
Was. Add 10g of boric acid, 2g of borax, naphazoli hydrochloride
0.3 g, 10 g of benzalkonium chloride solution 0.5 g, l
-Menthol 0.05 g, d-borneol 0.05
g, propylene glycol 5 g, neostig methyl sulfate
0.05 g of min, 0.5 g of pyridoxine hydrochloride, asparagus
Potassium formate 10g, ethylenediaminetetraacetic acid dinatto
0.03 g of lithium was mixed, and the pH was adjusted to 6.5 with dilute hydrochloric acid.
After adjusting the volume, make up the total volume to 1000 mL with purified water and sterile filter.
10mL polyethylene terephthalate eyedropper
Fill. This is polyethylene terephthalate / poly
Vinylidene chloride / polyethylene / ethylene vinyl acetate
Coated with an enclosure of a composite film and purged with inert gas.
Without heat sealing.
Volume: about 35cm ³⁾ . Example 3 Vitamin E succinate 0.5 g, Vitamin A palmite
0.2 g (1.7 million international units)
Reoxyethylene (40) hydrogenated castor oil (Nikkor H
After mixing 1.4 g of CO-40), the mixture was heated to 70 ° C.
Dissolve in 850 mL of water. To this, trometamol 15
g, chlorpheniramine maleate 0.3 g, 10% salt
1 g of benzalcodium bromide solution, 0.05 g of l-menthol,
dl-camphor 0.03 g, propylene glycol 5
g, neostigmine methyl sulfate 0.05 g, pyrido hydrochloride
0.5 g of toxin, 10 g of potassium aspartate, ethyl
Mix 0.05 g of disodium diaminetetraacetic acid,
After adjusting the pH to 7.0 with dilute hydrochloric acid, the total amount was adjusted to 1 with purified water.
5,000 mL, sterile filtered and 15 mL of polypropylene
Aseptically filled eye drops. This is polyethylene
Covered with an envelope of a composite film as the main material, nitrogen gas
(Tokai Sangyo nitrogen: 99.99 v / v% or more) nozzle
Heat sealed while spraying from inside (inner
Space volume: about 35cm ³ , Nitrogen gas replacement rate: 90
%). Example 4 Vitamin E acetate 0.5 g, Vitamin A palmitate
0.25 g (1.7 million international units), dibutyl hydroxy
Mix 0.05 g of toluene and further add polyoxyethylene.
Ren (60) hydrogenated castor oil (Nikkor HCO-60)
After mixing 1.5 g, this was heated to 50 ° C. for purification.
Dissolve in water. Add 10g of trometamol, malein
Chlorpheniramine acid 0.3g, Tetrahydrozori hydrochloride
0.2 g, 10 g of benzalkonium chloride solution 0.3 g, l
-Menthol 0.08 g, d-borneol 0.05
g, propylene glycol 5 g, neostig methyl sulfate
0.05 g of min, 0.5 g of pyridoxine hydrochloride, hydroxy
2 g of propyl methylcellulose, ethylenediamine 4
Mix 0.05 g of disodium acetate and adjust the pH with dilute hydrochloric acid.
After adjusting to 7.2, the total volume was adjusted to 1000 mL with purified water.
And sterile-filtered, 15 mlL polyethylene terephthalate
Aseptically filled in eye drop containers made of This is polyethylene
Phthalate / silica / polyethylene / ethylene vinyl
Cover with an acetate composite film enclosure and place in a nitrogen gas atmosphere.
Heat sealed with air (sealed inner space)
Product: about 35cm ³ , Inert gas replacement rate: 70%). <Evaluation> Production of vitamin A
Immediately after and after storage at 50 ° C. for 2 months, measurement was performed by HPLC. <Results> VA content (%) immediately after production VA content (%) after storage at 50 ° C. for 2 months Example 1 99 85 Example 2 100 84 Comparative Example 1 99 49 Comparative Example 2 85 71 Comparative Example 3 85 40 Example Example 3 99 86 Example 4 100 86 Comparative Example 1: Inner space was inert gas
Without substitution, the stability of vitamin A is significantly reduced. Comparative Example 2: Addition of a mixture of vitamin A and a fat-soluble antioxidant
Vitamin A content decreases immediately after production by changing the method
You. Comparative Example 3: Vitamin A addition method was changed to
By not performing inert gas replacement of the pace,
The VA content immediately after production is low, and the stability after storage is low.
It decreases significantly. Further, each eye having the composition shown in Examples 5 to 52
The pharmaceutical preparation was produced by the following method. (1) Vitamin A and fat-soluble antioxidant are mixed, and
Mix the nonionic surfactant at 50 ° C. 800 g of purified water obtained by heating (2) to 50 ° C.
200 rpm (diameter: 12 cm)
Add little by little while stirring with a stirring blade) and dissolve. (3) After mixing other components with (2), sodium hydroxide
Adjust the pH to 7.2 with water or diluted hydrochloric acid. (4) Make up to 1000 mL with purified water. (5) Sterile filtration, 15 ml L polyethylene terephthalate
Aseptic filling of rate ophthalmic containers with 2% headspace
You. (6) Replace (5) with a tubular polyethylene placed under a nitrogen stream.
Lenterephthalate / silica / polyethylene / ethylene
Installed in vinyl acetate composite film and heat-sealed
And heat-sealed (inners
Pace volume: about 35cm ³ , Inert gas replacement rate: 95
%) [Table 1] Examples 5, 6, 7, 8, 9, 10
Nzarkonium 0.003% replaced by sorbic acid 0.1%
Example 11, 12, 13, 14, 15, 16
An agent was manufactured. [Table 2] Examples 17, 18, 19, 20, 21, 2
2 benzalkonium chloride 0.003% potassium sorbate
Examples 23, 24, 25, 2 in which 0.1% of Li was replaced
6, 27 and 28 eye drops were prepared. [Table 3] Embodiments 29, 30, 31, 32, 33, 3
4 benzalkonium chloride 0.003%
Examples 35, 36, 37, and 3 in which 0.05% of Li was used.
8, 39 and 40 eyewashes were produced. [Table 4] Embodiments 41, 42, 43, 44, 45, 4
6 benzalkonium chloride 0.003% 5 sorbic acid
Examples 47, 48, 49, 5 in which potassium was changed to 0.1%
0, 51 and 52 contact lens mounting solutions were produced. In Examples 5 to 52, after storage at 50 ° C. for 2 months,
Both have retinol palmitate content of 85% or more
Met. Further, the material of the container is specifically described in this specification.
The invention of the present invention by replacing containers of the listed materials
Was prepared. (PEN / PET = 10/9
0) Further, the enclosure is specifically referred to as a column in this specification.
Ophthalmic use according to the present invention in place of the described envelope material-(17)
An agent was manufactured. According to the present invention, the stability of vitamin A is improved.
Formulation can be prepared without loss and long term
Vitamin A can be kept stable over
You.

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Claims (1)

Ophthalmic composition containing Claims 1. A vitamin A (including precursors) are filled in a resin container, further the resin vessel is oxygen permeability coefficient 10cc ^/ m 2 / 24hr / At
An ophthalmic agent sealed in a package of not more than m
The ophthalmic composition is a composition obtained by adding a mixture of vitamin A, a fat-soluble oxidizing agent, and a nonionic surfactant to an aqueous liquid and solubilizing the composition. (2) The ophthalmic composition is not more than 5% in a resin container filled with headspace and, (3) the resin container is sealed to the oxygen permeability coefficient 10cc ^/ m 2 / 24hr / atm or less of the package, the concentration between the package and the container 5
An ophthalmic preparation containing vitamin A, which is filled with 0 vol% or more of an inert gas.