JP2008154810A - Ophthalmic agent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an ophthalmic agent containing a medicine unstable under light, especially berberine, and exerting favorable stability of the medicine. <P>SOLUTION: This ophthalmic agent is formed by filling a resin container with absorbance of 0.5 or more at wavelength 400 nm or less with ophthalmic components containing the medicine unstable under the light. It is preferable to use a resin container with the absorbance of 1.0 or less at the wavelength of 600 nm. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to an ophthalmic agent containing a photolabile drug.

Drugs that are unstable to light, such as berberine chloride, are usually stored in a well-shielded container to ensure stability. However, it is essential that the ophthalmic agent is transparent so that a foreign matter test can be performed, and since light is transmitted, decomposition gradually proceeds and it is difficult to maintain stability.
In order to raise the said stability, in WO91-1718, the light stabilization method which mix | blends a boric acid and a polyhydric alcohol is proposed, However, The decomposition | disassembly suppression by light cannot be ensured depending on a drug.
In addition, a colored container may be used, but the colored container is not always effective in light stability.

WO91-1718

  An object of the present invention is to provide an ophthalmic agent containing a photolabile drug and having good stability of the drug.

By using a resin-made container body having a specific absorbance, the present inventors have provided storage stability (decomposition by light) of an ophthalmic preparation composition containing a light-labile drug, particularly berberine. It has been found that suppression is good, and has led to the present invention.
That is, the present invention

<1> An ophthalmic agent comprising an ophthalmic composition containing a photolabile drug filled in a resin container having an absorbance at a wavelength of 400 nm or less of 0.5 or more.
<2> The ophthalmic agent according to <1>, wherein the container is a resin container having an absorbance at a wavelength of 600 nm of 1.0 or less.
<3> The container was made of polyethylene, polypropylene, polyethylene terephthalate, polyethylene naphthalate, polyarylate, acrylonitrile styrene, acrylonitrile butadiene styrene, a copolymer polyester thereof, or a mixture of two or more. The ophthalmic agent according to <1> or <2>, which is a container.
<4> The material of the container is a resin containing 0.00001 to 0.5% by mass of a dye selected from an azo dye, a phthalocyanine dye, and an anthraquinone dye and / or an ultraviolet absorber. The ophthalmic preparation according to <1> to <3>.
<5> The ophthalmic agent according to <1> to <4>, wherein the hue of the colored container is yellow to green, or brown to brown.
Is to provide.

  By adopting the above-described constitution of the present invention, an ophthalmic agent containing a light-labile drug such as berberine and having good storage stability (inhibition of decomposition of the drug by light) can be obtained.

(1) Ophthalmic solution composition <Photolabile drug>
The photolabile drug used in the present invention is preferably berberine.
Berberine is a drug having an effect of enhancing the antiseptic effect by blending as a natural product-derived anti-inflammatory agent, and examples thereof include berberine chloride and berberine sulfate.
The compounding quantity of berberine is 0.0001-0.1g / 100mL in an ophthalmic composition, Preferably it is 0.0003-0.05g / 100mL, More preferably, it is 0.0005-0.025g / 100mL. Within this range, the solubility, effectiveness, antiseptic effect enhancing effect and the like are excellent, and the light stability when filled in the container of the present invention is also good.

In addition to berberines, vitamins A (retinol palmitate, retinol acetate, etc.), pyridoxines (pyridoxine hydrochloride, etc.), azulene (sodium azulenesulfonate, etc.), cobalamin (cyanocobalamin, mecobalamin, etc.) , Pranoprofen and the like, and these can also be used suitably.

<Other optional components>
In the present invention, in addition to the photolabile drug, drugs and additives other than those described above can be contained.

Examples of the drug include the following.
・ Antihistamines: chlorpheniramine maleate, diphenhydramine hydrochloride, levocabastine hydrochloride, etc. ・ Anti-inflammatory agents: dipotassium glycyrrhizinate, lysozyme chloride, epsilon-aminocaproic acid, allantoin, zinc sulfate, zinc lactate, etc. ・ Antiallergic agents: cromoglycate sodium, Ketotifen fumarate, tranilast, acitazanolast, etc./antihypertensive agent ... tetrahydrozoline hydrochloride, naphazoline hydrochloride, naphazoline nitrate, etc./vitamins...natural vitamin E, tocopherol acetate, panthenol, sodium pantothenate, calcium pantothenate, FAD, ascorbine Acids, amino acids ... L-potassium aspartate, L-magnesium aspartate, magnesium-potassium L-aspartate, aminoethylsulfonic acid (taurine), etc. Membrane protective agent ... Sodium chondroitin sulfate, sodium hyaluronate, etc., sulfa drugs ... Sulfamethoxazole, sulfamethoxazole sodium, sulfisoxazole, sulfisomidine sodium, etc., local anesthetics ... chlorobutanol, inorganic salts ... sodium chloride, potassium chloride, calcium chloride, sodium bicarbonate, sodium carbonate, magnesium sulfate, etc.

Additives that can be blended into ophthalmic agents include the following components.
・ Refreshing agents, fragrances: menthol, camphor, borneol, eucalyptus oil, caffeine, mint oil, mint water, lavender oil, rosemary oil, bergamot oil, agate, geraniol, etc. Preservatives: benzalkonium chloride, benzethonium chloride , Cetylpyridinium chloride, alkylaminoethylglycine, parabens, sorbic acid, chlorhexidine gluconate, butylhydroxytoluene, butylhydroxyanisole, phenylethyl alcohol, alkylpolyaminoethylglycine, benzyl alcohol, etc., buffering agent, pH regulator ... boric acid , Borax, trometamol, phosphoric acid, sodium phosphate, sodium hydrogen phosphate, sodium acetate, hydrochloric acid, sodium hydroxide, etc. Stabilizers ... Sodium edetate, polyethylene glycol, glycerin , Propylene glycol, etc./polymer compounds ... polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, etc. These may be contained in an amount ophthalmologically acceptable without impairing the effects of the present invention. it can.

The ophthalmic preparation composition of the present invention preferably has the following physical properties.
-PH ... 4-9, preferably 5-8, more preferably 6-8
-Osmotic pressure ratio: 0.6-3, preferably 0.8-2, more preferably 0.85-1.55
・ Viscosity ・ ・ ・ 1-50mPa ・ s

(2) Container In the ophthalmic preparation of the present invention, the ophthalmic composition is filled in a container (main body) having a mouth, and an inner plug having an eye drop is further installed in the mouth of the eye drop container. (Screw type or one-touch type). Alternatively, a cap having an eye drop may be installed directly on the container so that it can be sealed.

<Container>
In order to improve the light stability of a light-unstable drug such as berberine, a resin container having a specific absorbance is used in the present invention.
Specifically, the absorbance of the container of the present invention is such that the absorbance at a wavelength of 400 nm or less is 0.5 or more, preferably 1.0 or more. When the absorbance at a wavelength of 400 nm or less is less than 0.5, the stability of a drug such as berberine is deteriorated. More preferred is a resin having an absorbance at a wavelength of 600 nm of 1.0 or less, particularly 0.5 or less. When a container having an absorbance in this range is used, it is possible to obtain a container having good stability of the drug and transparency which allows easy foreign substance inspection.

Such a container can be obtained by using a resin containing a pigment or an ultraviolet absorber.
Preferred resins for the ophthalmic preparation container body of the present invention include polyethylene (PE), polypropylene (PP), polyethylene terephthalate (PET), polyethylene naphthalate (PEN), and poly from the viewpoints of transparency, moldability, and usability. Examples include arylate (AR), acrylonitrile styrene (AS), acrylonitrile butadiene styrene (ABS), and copolymers and mixtures thereof. Of these, polyethylene, polypropylene, and polyethylene terephthalate are more preferable.

  Specific means for setting the absorbance of the resin to the above-mentioned absorbance include means for blending a dye and an ultraviolet absorber into the resin, means for winding a colored film around the container by shrink wrap processing, etc., vapor deposition of silica, zinc oxide, titanium oxide, etc. There is a means for coating with, for example, a means for mixing a dye, an ultraviolet absorber, etc. directly in a container. Hydrophobic dyes are preferred as the pigment that can be kneaded into the resin to ensure transparency. The types of dyes are nitro, benzeneazo, naphthaleneazo, azo, stilbene, triphenylmethane, xanthene, quinoline, polymethine, azomethine, thiazole, quinoneimine, anthraquinone, indigoid And phthalocyanine-based hydrophobic dyes. Specifically, phthalocyanine dyes (mainly blue to purple), azo dyes (mainly yellow to red), anthraquinone dyes (mainly yellow to purple), and the like can be preferably used.

Blue 404 as the phthalocyanine dye, Yellow 205, Yellow 401, Yellow 404, Yellow 405, Yellow 5, Yellow 406, Yellow 4, Yellow 402, Yellow 407 as the azo dye , Orange color 203, orange color 401, orange color 403, orange color 205, orange color 402, orange color 204, red 221, 228, 404, 225, 501, 505, 202, 203, 204, 205, 206, 207, 208, 219, 220, 405, 2, 102, 201, 227, 502, 503, 504 506, brown 201.
Examples of anthraquinone dyes include Blue No. 204, Blue No. 403, Purple No. 401, Purple No. 201, Green No. 201 and Green No. 202.

It is preferable to adjust these colors so that the hues are yellow, yellowish green, green, brown and brown.
The total amount of the dyes is preferably 0.00001 to 0.5% by mass, more preferably 0.0001 to 0.2% by mass, and particularly preferably 0.0005 to 0.00. 1%. Within this range, the photostability and transparency of the drug are particularly good.

Examples of ultraviolet absorbers include salicylic acid derivatives such as phenyl salicylate, 4-t-butyl salicylate, p-octylphenyl salicylate, 2-hydroxy-4-octoxybenzophenone, 2-hydroxy-4-octade. Benzophenone derivatives such as siloxybenzophenone, 2-hydroxy-4-dodecyloxybenzophenone, 2-hydroxy-5-chlorobenzophenone, 2,4-dibenzoylresorcinol, 4,6-dibenzoylresorcinol, 2- (2'-hydroxy -5'-methylphenyl) benzotriazole, 2- (3 ', 5'-tert-butyl-2'-hydroxy-5'-methylphenyl) -5-chlorobenzotriazole, 2- (2'-hydroxy-3 Benzotriazole derivatives such as', 5'-tert-amylphenyl) benzotriazole, aromatic ester compounds, hindered amine light stabilizers, represented by the trade name Tinuvin (R) For fat added UV absorbers, such as light stabilizers and the like.
The total amount of the ultraviolet absorber is 0.01% to 5%, preferably 0.1 to 3%, based on the entire resin. If the amount is too large, there may be safety problems such as elution from the container surface.

<Inner plug, cap>
The inner plug and cap used for the ophthalmic agent container of the present invention can be a cap made of a material used for a known ophthalmic agent container, but for the purpose of the present invention, it has a light shielding property. It is preferable to use a translucent or opaque material.
As the material for the inner plug, polyethylene or polypropylene having a melt flow rate of 2.0 or less, preferably 1.2 to 1.8 is preferably used.
As the material of the cap, polyethylene and polypropylene are preferably used.
These resins are kneaded with titanium oxide, zinc oxide, dyes, pigments, UV inhibitors, antistatic agents, plasticizers, etc., and paint, vapor deposition, coating, clothing, etc., so that light is not easily transmitted. The material processed into is preferably used.

The eye drop composition described in Table 1 was filled in the container shown in Table 2, and the storage stability of berberine chloride was evaluated.
<Storage conditions> Sun exposure 1 month
<Method for measuring residual rate of berberine chloride>
The berberine chloride concentration before and after storage was quantified by liquid chromatography to determine the residual rate.
<Container absorbance measurement method>
The container was placed in an absorptiometer so that the thinnest and smoothest surface of the container was perpendicular to the light beam, and the absorption spectrum at a wavelength of 400 nm or less and the absorbance at a wavelength of 600 nm were measured. In the containers measured in this test, the minimum absorbance value at a wavelength of 400 nm or less was observed at a wavelength of 400 nm. Therefore, the absorbance values at 400 nm were described in the following examples.
<Transparency evaluation criteria>
Judgment was made according to the second method of transparency test of the Japanese Pharmacopoeia “Plastic Drug Container Testing Method”.

Other examples of the present invention are shown in Tables 3 and 4.

ヒドロキシプロピルメチルセルロース：信越化学工業（株）製 メトローズ６０ＳＨ−４０００
ポリビニルピロリドン：BASF社製 Kollidon９０F
ヒドロキシエチルセルロース：HERCULES社製 NATROSOL 250 G Pharm
ベルベリン安定性：◎…99%以上，○…95%〜99%未満，△…90%〜95%未満，×…90%未満

Hydroxypropyl methylcellulose: Metrows 60SH-4000 manufactured by Shin-Etsu Chemical Co., Ltd.
Polyvinylpyrrolidone: BASF Kollidon90F
Hydroxyethyl cellulose: NATROSOL 250 G Pharm manufactured by HERCULES
Berberine stability: ◎… 99% or more, ○… 95% to less than 99%, △… 90% to less than 95%, ×… less than 90%

About the ophthalmic preparation composition of composition 16, after storing for 1 week under fluorescent light (1500 lux), the amount of pranoprofen was quantified by liquid chromatography and the residual amount was determined. As shown in Table 6, When the container 1 was filled, the residual ratio was about 60%, whereas when the containers 2, 3, and 5 were filled, the residual ratio was 90% or more, and the stability was good.

Claims (6)

An ophthalmic composition comprising an ophthalmic composition containing a photolabile drug filled in a resin container having an absorbance at a wavelength of 400 nm or less of 0.5 or more. The ophthalmic agent according to claim 1, wherein the container is a resin container having an absorbance at a wavelength of 600 nm of 1.0 or less. The container is made of polyethylene, polypropylene, polyethylene terephthalate, polyethylene naphthalate, polyarylate, acrylonitrile styrene and acrylonitrile butadiene styrene, a copolymer polyester thereof, or a mixture of two or more thereof. The ophthalmic agent according to claim 1 or 2. The material of the container is a resin containing 0.00001 to 0.5% by mass of a dye selected from an azo dye, a phthalocyanine dye, and an anthraquinone dye and / or an ultraviolet absorber. The ophthalmic agent according to -3. The ophthalmic agent according to any one of claims 1 to 4, wherein the hue of the colored container is yellow to green, or brown to brown. The ophthalmic preparation according to claim 1, wherein the photolabile drug is berberine.