JP2008120764A - Prostaglandin aqueous ophthalmic solution - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To improve the solubility of prostaglandins such as latanoprost and isopropyl unoprostone in water without using a surface active agent in the prostaglandin aqueous ophthalmic solution. <P>SOLUTION: The aqueous ophthalmic solution comprises a prostaglandin compound or its derivative as an active ingredient. The aqueous ophthalmic solution comprises a 1-4C monohydric alcohol as a dissolution auxiliary and a chemical stabilizer for the active ingredient. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to an aqueous eye drop containing prostaglandins (including prostaglandin compounds and derivatives thereof) as an active ingredient (main ingredient).

  Here, representative latanoprost and isopropyl unoprostone will be described as examples of prostaglandins, but the prostaglandins are not limited thereto.

  The chemical name of “latanoprost” is “isopropyl- (Z) -7 [(1R, 2R, 3R, 5S) 3,5-dihydroxy-2-[(3R) -3-hydroxy-5-phenylpentyl]”. Cyclopentyl] -5-heptanoate ".

  The chemical name of “isopropyl unoprostone” is “(+)-isopropyl (Z) -7 [(1R, 2R, 3R, 5S) -3,5-dihydroxy-2- (3-oxodecyl) cyclopentyl] hepta- 5-enoate ".

  Latanoprost and isopropyl unoprostone are common in that they are prostaglandin compounds having a medicinal effect of reducing intraocular pressure by promoting the outflow of aqueous humor and their glaucoma therapeutic agents.

  Prostaglandin-based glaucoma drugs have low water solubility and are generally unstable (thermal, light, and oxidative degradation over time), and have the property of being easily adsorbed to containers. It is known.

In order to solve these problems, various methods have been proposed. For example,
1) Patent Document 1 discloses a method for improving chemical stability using polyethoxylated castor oil as a solubilizer,
2) Patent Document 2 discloses a method of solubilizing using a surfactant such as PEG-2 to PEG-200 castor oil; and PEG-5 to PEG-200 hydrogenated castor oil, and filling a polypropylene container.
3) Patent Document 3 includes a method of blending a nonionic surfactant and an antioxidant to improve solubility and prevent decomposition, and suppress adsorption to a container.
4) Patent Document 4 includes a method using benzethonium chloride having 12 carbon atoms and using a surfactant and / or nonionic isotonicity.
5) Patent Document 5 discloses a method for storing at room temperature by adding pH of 5.0 to 6.25 or ε-aminocaproic acid.
Each has been proposed.

  As described above, surfactants are conventionally blended for the purpose of preventing adsorption to solubilizers or containers. On the other hand, some surfactants are known to cause corneal epithelial damage.

  In addition, preservatives are added to most eye drops from the viewpoint of safety in that aqueous eye drops prevent microbial (bacterial) contamination during use. On the other hand, it is known that preservatives cause corneal epithelial damage as well as surfactants.

  In addition, glaucoma treatment has a problem that it is necessary to take instillation for a long time, and the disorder is likely to appear.

  In addition, as will be described later, ophthalmic solution (eye drops) is usually contained in a container and used dropwise, but at this time, the dropped body volume is reduced and air is sucked in and replaced. This inhalation of air makes latanoprost and isopropyl unoprostone susceptible to oxidative degradation. The present inventors do not know about reports on this problem and proposals for improvement.

The applicants of the present application have proposed a delamination container, which is a sterile eye drop container, in Patent Documents 6 and 7 and the like.
JP 11-500122 A (summary etc.) Japanese translation of PCT publication No. 2002-523068 (claims 1 and 5 etc.) JP 2002-161037 A (summary etc.) JP 2004-123729 A (summary etc.) JP 2004-182719 A (summary etc.) JP 2002-80055 A (summary etc.) JP 2004-262470 A (summary etc.)

  In view of the above, the present invention aims to improve the solubility of prostaglandins in water and suppress decomposition in an aqueous solution without using a surfactant in an aqueous prostaglandin eye drop. And

  Another object of the present invention is to provide a prostaglandin aqueous eye drop that can suppress adsorption to a plastic container after filling.

  Still another object of the present invention is to provide a prostaglandin aqueous eye drop that can be of a preservative-less type.

  As a result of various studies, the present inventors have found that prostaglandins, which are active ingredients, are practically effective by using specific alcohols, and have sufficient solubility and action / effect to suppress decomposition in an aqueous solution. Further, the inventors have found that the adsorption of the main agent to the plastic container is suppressed by adopting the surfactant-less type, and have arrived at one of the present invention.

  Further, the present invention has found that the adsorption of the main agent to the plastic container can be further suppressed by blending one or more selected from the group of polyvinyl pyrrolidone, polyvinyl alcohol, and polyethylene glycol from a nonionic water-soluble polymer. I came up with another one.

  Furthermore, the present inventors have conceived another aspect of the present invention by focusing on the fact that if these aqueous eye drops are filled in a sterile eye drop container capable of ensuring sterility, the preservative can be eliminated.

  Each configuration of the group of the present invention is as follows.

A water-based eye drop containing a prostaglandin compound and a derivative thereof as an active ingredient (main ingredient),
It contains a monohydric alcohol having 1 to 4 carbon atoms as a dissolution aid and stabilizer (subagent) for the main agent.

  In the above configuration, the main agent may be latanoprost or isopropyl unoprostone.

  In the above-described configuration, the non-ionic water-soluble substance selected from the group of polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA), and solid polyethylene glycol (solid PEG) as an adsorption inhibitor (adjunct) of the main agent for the plastic container One kind or two or more kinds of polymers can be contained in combination.

  Each composition of the present invention is expressed in terms of composition as follows.

A water-based eye drop containing a prostaglandin compound and a derivative thereof as an active ingredient (main ingredient),
The content of the active ingredient is 0.0010 to 0.20% (W / V),
A composition containing monohydric alcohols having 1 to 4 carbon atoms in a total content of 0.05 to 10% (W / V) and a composition ratio of 0.25 to 10000 parts by mass with respect to 1.0 part by mass of the active ingredient; Become.

  The active ingredient is latanoprost or isopropyl unoprostone.

  Further, as an auxiliary agent, it further contains one or two or more kinds selected from the group of nonionic water-soluble polymers such as polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), and solid polyethylene glycol (solid PEG). Amount: 0.010 to 2.5% (W / V), with a composition ratio of 0.050 to 2500 parts by mass with respect to 1.0 part by mass of the active ingredient.

  As the monohydric alcohol, ethanol or isopropyl alcohol can be used. As the PVP, a K value (viscosity characteristic value) in the range of 12 to 100, and as the PVA, a saponification degree: 70 to As the solid PEG, those in the range of 98 mol%, those having a number average molecular weight (Mn) in the range of 900 to 10,000 can be used.

  Furthermore, the aqueous eye drops having the above-mentioned constitutions can contain the preservative or surfactant in an amount of 0% (W / V) or less than an amount that does not cause corneal epithelial damage.

  In addition, the aqueous eye drop of each of the above constitutions can be filled in a sterile eye drop container that can ensure the sterility of the drug solution even after opening, and the sterile eye drop container is formed on the inner surface of the outer layer from the outer layer. A laminate peeling container formed by laminating a peelable inner layer and a stopper attached to the mouth of the laminate peeling container, the outer layer is for introducing outside air between the inner layer and the outer layer Ventilation holes are provided, a discharge path for discharging the ophthalmic solution contained in the inner layer is provided, and a filter and a check valve are provided in the discharge path.

  Hereinafter, the prostaglandin aqueous eye drop of the present invention will be described in further detail. In the following description, “%” indicating the concentration means “% (W / V)” (mass (g) / volume (mL) percentage ”unless otherwise specified.“ Part ”indicating the number of blended parts. Means parts by mass.

  The aqueous eye drop of the present invention is premised on using a prostaglandin compound and a derivative thereof as an active ingredient (main ingredient).

  Here, the active ingredient is latanoprost or isopropyl unoprostone.

  The concentration of the active ingredient (latanoprost or isopropyl unoprostone) is, for example, about 0.0010 to 0.20%, and particularly preferably about 0.0050 to 0.12%, which is a clinical dose.

  (1) The aqueous eye drop of the present invention has a characteristic configuration containing a monohydric alcohol having 1 to 4 carbon atoms as an auxiliary agent (dissolution aid and chemical stabilizer).

  Examples of the monohydric alcohol having 1 to 4 carbon atoms include methanol, ethanol, propanol, isopropanol, butanol and the like. Of these, ethanol and isopropanol, which have relatively low eye irritation, are preferred.

  The content (blending amount) of monohydric alcohols is an amount that has the effect of stably dissolving an active ingredient (latanoprost or isopropyl unoprostone), and the specific content varies slightly depending on the type and concentration of the active ingredient. .

  For example, when the content of the active ingredient is about 0.0010 to 0.20%, the monohydric alcohol is contained in a composition having a total content of about 0.050 to 10.0% and a blending ratio of about 0.25 to 10000 parts with respect to 1.0 part of the active ingredient. It is preferable.

  When the content of the active ingredient is preferably about 0.0050 to 0.12%, the composition of monohydric alcohols is about 0.20 to 1.0% in total content, and the mixing ratio is about 1.7 to 200 parts with respect to 1.0 part of the active ingredient It is preferable to contain.

  If the monohydric alcohol is too small, it is difficult to dissolve the prostaglandins. If the monohydric alcohol is excessive, an increase in the dissolving action cannot be expected any more and eye irritation tends to occur.

  (2) The aqueous eye drop of the present invention further contains a nonionic water-soluble polymer selected from the group of polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), and solid polyethylene glycol (solid PEG) as a main agent for plastic containers. It is another characteristic constitution to contain as an adsorption inhibitor.

  The molecular weight of the nonionic water-soluble polymer varies depending on the type of the water-soluble polymer.

  For example, in the case of PVP, it is preferable to appropriately select from a commercially available K value (viscosity characteristic value): about 12 to 100, and further about 25 to 90. Specifically, those commercially available from various companies with grades of PVPK-15, PVPK-17, PVPK-25, PVPK-30, PVPK-60, and PVPK-90 can be used.

  Here, the “K value” is a viscosity characteristic value that correlates with the molecular weight, and is calculated by applying a relative viscosity value (25 ° C.) to the following Fikentscher's equation using a capillary viscometer.

ＰＶＡの場合、ケン化度：約７０〜９８mol％、更には約７８〜９６mol％の範囲にあるものから適宜選定することが好ましい。

In the case of PVA, the degree of saponification is preferably appropriately selected from those in the range of about 70 to 98 mol%, more preferably about 78 to 96 mol%.

  In the case of solid PEG, it is preferable to select the number average molecular weight (Mn) from about 900 to 10,000, more preferably from about 2600 to 9300. Specifically, products marketed by each company in grades of “PEG1000, PEG1540, PEG4000, PEG6000” can be used.

  Here, the reason why the adsorption inhibitor is used for the plastic container is that it is necessary to mold the inner container with a flexible plastic in order to obtain at least the inner container contraction type delamination container described later.

  The content of these water-soluble polymers varies depending on the type and concentration of the active ingredient, and is the minimum amount that exerts an adsorption inhibiting action on the plastic container.

  For example, when the content of the active ingredient is about 0.0010 to 0.20%, the water-soluble polymer is contained in a composition having a total content of about 0.010 to 2.5% and a blending ratio of about 0.050 to 2500 parts with respect to 1.0 part of the active ingredient It is preferable to make it.

  When the content of the active ingredient is preferably about 0.0050 to 0.12%, the water-soluble polymer may be contained at a total content of about 0.10 to 2.0% and a composition ratio of about 0.83 to 400 parts with respect to 1.0 part of the active ingredient. preferable.

  Here, if the content of the water-soluble polymer is too small, the effect of suppressing the adsorption to the plastic container is not observed, and if it is too much, the viscosity becomes high and the practical use becomes difficult in terms of the dropability of eye drops (eye drops).

  The aqueous eye drop of the present invention can ensure sufficient solubility and chemical stability (against heat, light, and oxidative degradation) and further suppress adsorption to a plastic container by adopting the configuration as described above. can do.

  In the case of eye drops, an osmotic pressure, a pH adjuster and the like are blended in order to suppress eye irritation, but in the present invention, they can be prepared using a known pharmaceutical technique.

  For example, examples of the osmotic pressure adjusting agent include propylene glycol, glycerin, aminoethylsulfonic acid, sorbitol, mannitol, creatinine, sodium chloride, potassium chloride, and calcium chloride.

  pH adjusters include hydrochloric acid, sulfuric acid, acetic acid, lactic acid, citric acid, tartaric acid, malic acid, phosphoric acid, boric acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, monoethanolamine, trometamol (tris (hydroxymethyl) aminomethane), diethylamine, ammonia and salts thereof.

  The prostaglandin aqueous eye drop of the present invention has a composition that contains substantially no content of the following chemical stabilizer, preservative, and surfactant (content: 0%) due to the constitution containing the alcohols. ). However, small amounts of the following chemical stabilizers, preservatives, and surfactants may be used as appropriate. At this time, the content of the preservative and the surfactant needs to be not more than an amount that does not cause corneal epithelial damage.

    1) Stabilizer: Examples include sodium edetate, sodium sulfite, sodium hydrogen sulfite, sodium thiosulfate, dibutylhydroxytoluene, tocopherol and the like.

    2) As preservatives, paraoxybenzoic acid ester, chlorobutanol, phenylethyl alcohol, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, alkylpolyaminoethylglycines, sorbic acid, and the like.

    3) Surfactant: quaternary amine surfactants such as benzethonium chloride and benzalkonium chloride, polyoxyethylene higher alcohol ethers, polyoxyethylene sorbitan fatty acid esters, glycerin fatty acid esters, polyoxyethylene cured castor Nonionic interfaces such as oil, polyoxyethylene fatty acid ester, polyoxyethylene nonyl phenyl ether, polyoxyethylene octyl phenyl ether, sorbitan fatty acid ester, propylene glycol fatty acid ester, fatty acid polyethylene glycol, polyglycerin fatty acid ester, sucrose fatty acid ester Active agents, etc.

  The prostaglandin aqueous eye drop of the above-described constitution of the present invention is preferably used as a container-filled eye drop filled in a sterile eye drop container capable of ensuring a sterile solution even after opening.

  By adopting such a configuration, a formulation (formulation) that does not contain a corneal epithelial disorder preservative that is usually blended can be realized. A corneal epithelial disorder preservative is formulated for the purpose of preventing bacteria and fungi from contaminating the liquid medicine in the eye drop container when the eye drop container nozzle comes into contact with the eyeball or tears during patient use. Examples thereof include benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, chlorobutanol, benzyl alcohol, phenylethyl alcohol, and paraoxybenzoic acid esters.

  The aseptic eye drop container is preferably one having a structure as described in Patent Documents 6 and 7 previously proposed by the applicants of the present application.

  As an example, a sterile eye drop container shown in Patent Document 6 is shown in FIG.

  The aseptic eye drop container includes a laminated peeling container (container body) 15 formed by laminating an inner layer 13 that can be peeled from the outer layer 11 on the inner surface of the outer layer 11, and a plug 17 attached to the mouth of the container main body 15. The outer layer 11 is provided with a vent hole 19 for introducing outside air between the inner layer 13 and the outer layer 11, and a discharge path for discharging ophthalmic solution contained in the inner layer 13. 21 is provided, and a filter 23 and a check valve 25 are provided in the discharge passage 21. Reference numeral 27 denotes a screw type protective cap.

  Here, it is preferable to use the filter 23 having pores (for example, 0.2 μm or less) through which bacteria (bacterial width: 0.2 to 10 μm) cannot pass.

  Furthermore, as a feature of this container, when the contents liquid is discharged at the time of instillation, the volume of the contents liquid remaining in the container is reduced by the discharge volume, and the peelable inner layer of the laminated peeling container is peeled off from the outer layer, and the volume change Therefore, there is no suction of air in contact with the liquid content from the discharge path. As a result, no oxidative degradation occurs, and the use of the delamination container for the eye drop of the present invention greatly improves the chemical stability of the active ingredient.

  Examples and comparative examples performed for confirming the effects of the present invention will be described.

  The technical scope of the present invention is not limited to the following examples, but extends to various embodiments within the scope of the claims.

<Solubility measurement test>
Each component was weighed according to the formulation shown in Table 1, and purified water was added to prepare an aqueous solution with a total volume of 100 mL.

そして、２５℃で３日間放置したのち、遠心分離機を用いて3000rpm ５分間遠心し、水相中の有効成分（主剤）の濃度をＨＰＬＣ（高速液体クロマトグラフィー：high precission liquid chromatography）にて測定し、溶解度を算出した。ＨＰＬＣは、市販のＯＤＳカラム（固定相：シリカゲルにＣ１８を結合させた化学結合充填剤）を使用した。

Then, after standing at 25 ° C. for 3 days, centrifuge for 5 minutes at 3000 rpm, and measure the concentration of the active ingredient (main agent) in the aqueous phase by HPLC (High Precission Liquid Chromatography). The solubility was calculated. For HPLC, a commercially available ODS column (stationary phase: a chemically bonded packing material in which C18 was bonded to silica gel) was used.

  The solubility measurement results are shown in Table 2.

比較例１・２の場合、精製水に対する溶解度は約0.0001％前後以下でほとんど溶解しないが、アルコールを配合した実施例１〜４は約100倍以上の溶解性を示した。また、アルコールの配合量が多くなるほど溶解性を増大し、第４級カチオン性界面活性剤や非イオン性界面活性剤を実質的に必要としない溶解性であることが判明した。
＜温度安定性試験１＞
表３の処方で各成分を量りとり精製水で全量１００ｍLとして調製し、ガラス製バイアルに充填した。

In Comparative Examples 1 and 2, the solubility in purified water was about 0.0001% or less and hardly dissolved, but Examples 1 to 4 containing alcohol showed a solubility of about 100 times or more. Further, it was found that the solubility increases as the blending amount of the alcohol increases, and the solubility does not substantially require a quaternary cationic surfactant or a nonionic surfactant.
<Temperature stability test 1>
Each component was weighed with the formulation shown in Table 3 and prepared with purified water to a total volume of 100 mL, and filled into a glass vial.

そして６０℃で４週間保存し、残存量を、ＨＰＬＣを用いて測定した。

And it preserve | saved for 4 weeks at 60 degreeC, and the residual amount was measured using HPLC.

  The residual rate was calculated using the following formula.

Residual rate (%) = measured value / initial value × 100
The test results of temperature stability (residual rate) are shown in FIG.

実施例５〜７は、４週間後においても約８０％以上の残存率であった。一方比較例５・６は大きく残存率が低下した。このことから、第４級カチオン性界面活性剤や非イオン性界面活性剤を用いた場合に比して、エタノール（１価アルコール）の配合によって化学的に安定化されていることが判明した。なお配合量が多いほど安定化に寄与することが示された。
＜温度安定性試験２＞
表５の処方で各成分を量りとり、１Ｎ塩酸を加えｐＨを6.5に調製した後、精製水を加え全量１００ｍLとして水溶液を調製しガラス製バイアル（vial）に充填した。

In Examples 5 to 7, the residual ratio was about 80% or more even after 4 weeks. On the other hand, in Comparative Examples 5 and 6, the residual ratio was greatly reduced. From this, it became clear that it was chemically stabilized by blending ethanol (monohydric alcohol) as compared with the case where a quaternary cationic surfactant or a nonionic surfactant was used. In addition, it was shown that it contributes to stabilization, so that there are many compounding quantities.
<Temperature stability test 2>
Each component was weighed according to the formulation of Table 5, 1N hydrochloric acid was added to adjust the pH to 6.5, purified water was added to prepare an aqueous solution with a total volume of 100 mL, and the solution was filled in a glass vial.

そして、６０℃で４週間保存し、残存量を、ＨＰＬＣを用いて測定した。

And it preserve | saved for 4 weeks at 60 degreeC, and the residual amount was measured using HPLC.

  The residual rate was calculated using the following formula.

Residual rate (%) = measured value / initial value × 100
The test results of temperature stability (residual rate) are shown in FIG.

各実施例は、何れも、エタノール（１価アルコール）の濃度に依存して化学的安定性が改善された。比較例は、何れも、残存率が低く、また、塩化ベンザルコニウムの濃度を増やしても安定性に変化なかった。
＜吸着試験１＞
表７の処方で各成分を量りとり、精製水を加え全量100ｍL(ｐＨ6.5)として水溶液を調製しラタノプロストあるいはイソプロピルウノプロストン濃度をＨＰＬＣを用いて測定した。この液をポリプロピレン製、ポリエチレン製、ＰＥＴ製、ガラスアンプルの４種類の容器に充填し密封した。

In each example, chemical stability was improved depending on the concentration of ethanol (monohydric alcohol). In all of the comparative examples, the residual ratio was low, and the stability did not change even when the concentration of benzalkonium chloride was increased.
<Adsorption test 1>
Each component was weighed according to the formulation shown in Table 7, purified water was added to prepare an aqueous solution with a total volume of 100 mL (pH 6.5), and the latanoprost or isopropyl unoprostone concentration was measured using HPLC. This liquid was filled into four types of containers of polypropylene, polyethylene, PET, and glass ampule and sealed.

各容器に充填後、蓋をして密閉し４０℃の温度条件下１４日後、各溶液中のラタノプロストあるいはイソプロピルウノプロストン量を測定し、以下の式に従い吸着率を求めた。

After filling each container, it was sealed with a lid, and after 14 days at a temperature of 40 ° C., the amount of latanoprost or isopropyl unoprostone in each solution was measured, and the adsorption rate was determined according to the following formula.

Adsorption rate (%) = (main agent concentration immediately after adjustment−drug concentration after 14 days storage) / drug concentration immediately after adjustment × 100
The results of these adsorption tests are shown in Table 8.

ガラス容器を用いた場合約１％程度の吸着であり、各実施例、比較例ともに差は認められなかったが、プラスチック容器に対する吸着率について、実施例と比較例で差が認められた。比較例では約１０〜１３％の吸着率であったが、本実施例では約４〜６％と吸着率を１/２に抑制することができた。このことから、エタノールは、界面活性剤レスにする処方となり、プラスチックに対する吸着抑制にも働くことが判った。
＜吸着試験２＞
表９の処方で各成分を量りとり、精製水を加え全量100ｍL(ｐＨ6.5)として水溶液を調製しラタノプロスト濃度をＨＰＬＣを用いて測定した。この液をポリプロピレン製、ポリエチレン製、ＰＥＴ製、ガラスアンプルの4種類の容器に充填し密封した。

When the glass container was used, the adsorption was about 1%, and no difference was observed in each of the examples and the comparative examples, but the difference in the adsorption rate for the plastic container was recognized between the examples and the comparative examples. In the comparative example, the adsorption rate was about 10 to 13%, but in this example, the adsorption rate was about 4 to 6% and could be suppressed to 1/2. From this, it was found that ethanol is a formulation that does not require a surfactant, and also acts to suppress adsorption to plastic.
<Adsorption test 2>
Each component was weighed according to the formulation shown in Table 9, purified water was added to prepare an aqueous solution with a total volume of 100 mL (pH 6.5), and the latanoprost concentration was measured using HPLC. This liquid was filled into four types of containers of polypropylene, polyethylene, PET, and glass ampule and sealed.

各容器に充填後、蓋をして密閉し４０℃の温度条件下１４日後、各溶液中のラタノプロスト量を測定し、以下の式に従い吸着率を求めた。

After filling each container, it was sealed with a lid, and after 14 days at a temperature of 40 ° C., the amount of latanoprost in each solution was measured, and the adsorption rate was determined according to the following formula.

Adsorption rate (%) = (main agent concentration immediately after preparation−drug concentration after 14 days storage) / drug concentration immediately after preparation × 100
Table 10 shows the results of these adsorption tests.

実施例１５〜１８におけるプラスチック容器への吸着率は、約１％以下となり、先の実施例１２〜１４の結果（吸着率約４〜６％）と比較して更に約１/２の吸着抑制効果を示した。
＜無菌容器を用いた安定性試験＞
表１１の処方で各成分を量りとり、１Ｎ塩酸を加えｐＨを6.5に調製した後、精製水を加え全量１００ｍLとして水溶液を調製した。

The adsorption rate to the plastic container in Examples 15 to 18 is about 1% or less, and the adsorption suppression is about 1/2 as compared with the results of Examples 12 to 14 (adsorption rate of about 4 to 6%). Showed the effect.
<Stability test using sterile container>
Each component was weighed according to the formulation of Table 11, 1N hydrochloric acid was added to adjust the pH to 6.5, and then purified water was added to make a total volume of 100 mL to prepare an aqueous solution.

実施例２０は、当該無菌容器に充填した。比較例１３はポリプロピレン製点眼容器に充填した。充填直後のラタノプロスト濃度を測定し初期値とした。その後室温にて保存し、１週間に１回１滴滴下したのちキャップを閉め再度保存した。８週間後の残存液中のラタノプロスト濃度を、ＨＰＬＣを用いて測定した。

In Example 20, the aseptic container was filled. Comparative Example 13 was filled in a polypropylene eye drop container. The latanoprost concentration immediately after filling was measured and used as the initial value. Thereafter, it was stored at room temperature, and after one drop was dropped once a week, the cap was closed and stored again. The latanoprost concentration in the remaining solution after 8 weeks was measured using HPLC.

  The residual rate was calculated using the following formula.

Residual rate (%) = measured value / initial value × 100
The test results are shown in Table 12.

Although the aseptic container used in Example 20 did not absorb air, decomposition of the main agent was suppressed, but the general eye dropper container used in Comparative Example 13 caused an inflow (mixture) of air when the liquid was dropped. Therefore, the stability is considered to have decreased.
<Eye irritation test>
Each component was weighed according to the formulation of Table 13, 1N hydrochloric acid was added to adjust the pH to 6.5, and then purified water was added to make a total volume of 100 mL to prepare an aqueous solution (aqueous eye drop).

健常人（パネラー）２０名を対象に眼刺激性試験を実施した。方法は、被験者の片眼に上記で調製した各実施例試料及び対照比較例試料の試験液を１滴づつ点眼し、そのときの刺激性と結膜の充血による発赤を下記４段階で評価し、スコア化し、平均値で比較した。

An eye irritation test was conducted on 20 healthy persons (panelists). The method is to apply one drop of the test solution of each example sample and the control comparative example sample prepared above to one eye of a subject, and evaluate the irritation and redness due to conjunctival redness in the following four stages, Scored and compared by mean.

No irritation: 0 points Weak irritation: 1 point Irritation: 2 points Strong irritation: 3 points Table 12 shows the results.

各実施例試料は極めて刺激係数及び充血の度合いが低いことがわかる。

It can be seen that each example sample has a very low stimulation coefficient and degree of hyperemia.

It is sectional drawing which shows an example of a sterile eye drop container. It is a graph which shows the time-dependent change of the active ingredient residual ratio in the temperature stability test 1. It is a graph which shows the time-dependent change of the active ingredient residual ratio in the temperature stability test 2.

Explanation of symbols

11 outer layer of delamination container 13 inner layer of delamination container 15 delamination container (container body)
17 Plug body 27 Protective cap

Claims (13)

A water-based eye drop containing a prostaglandin compound and a derivative thereof as an active ingredient (main ingredient),
A prostaglandin aqueous eye drop containing monohydric alcohol having 1 to 4 carbon atoms as a solubilizing agent and chemical stabilizer (adjunct) of the active ingredient.   The prostaglandin aqueous eye drop according to claim 1, wherein the active ingredient is latanoprost or isopropyl unoprostone.   1 as a nonionic water-soluble polymer selected from the group consisting of polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), and solid polyethylene glycol (solid PEG) The prostaglandin aqueous eye drop according to claim 1 or 2, comprising a seed or a combination of two or more kinds. A water-based eye drop containing a prostaglandin compound and a derivative thereof as an active ingredient (main ingredient),
The content of the active ingredient is 0.0010 to 0.20% (W / V),
Containing monohydric alcohols having 1 to 4 carbon atoms in a total content of 0.05 to 10% (W / V) and a composition ratio of 0.25 to 10000 parts by mass with respect to 1.0 part by mass of the active ingredient. Prostaglandin aqueous eye drops.   The prostaglandin aqueous eye drop according to claim 4, wherein the active ingredient is latanoprost or isopropyl unoprostone.   Furthermore, one or more of nonionic water-soluble polymers selected from the group of polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), and solid polyethylene glycol (solid PEG), the total content: 0.010 to 2.5% The aqueous prostaglandin eye drop according to claim 5, wherein the composition is (W / V) and has a composition of 0.050 to 2500 parts by mass with respect to 1.0 part by mass of the main agent.   The prostaglandin aqueous eye drop according to any one of claims 1 to 6, wherein the monohydric alcohol is ethanol or isopropyl alcohol.   The prostaglandin aqueous eye drop according to claim 3 or 6, wherein the PVP has a K value (viscosity characteristic value) in a range of 12 to 100.   The prostaglandin aqueous eye drop according to claim 3 or 6, wherein the PVA has a saponification degree in a range of 70 to 98 mol%.   The prostaglandin aqueous eye drop according to claim 3 or 6, wherein the solid PEG is in the range of number average molecular weight (Mn): 900-10000.   The prostaglandin aqueous ophthalmic solution according to any one of claims 1 to 10, wherein the content of the preservative or the surfactant is 0% (W / V) or less than an amount that does not cause corneal epithelial disorder. Agent.   The prostaglandin aqueous eye drop according to claim 11, which is filled in a sterile eye drop container capable of securing a chemical solution in a sterile state even after opening.   The aseptic eye drop container comprises a laminate release container formed by laminating an inner layer that can be peeled off from the outer layer on the inner surface of the outer layer, and a stopper attached to the mouth of the laminate release container. A vent hole for introducing outside air is provided between the inner layer and the outer layer, and a discharge passage for discharging the eye drops contained in the inner layer is provided, and a filter and a check valve are provided in the discharge passage. 13. The prostaglandin aqueous eye drop according to claim 12, wherein the composition is provided.

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