TW201705948A - Ophthalmic composition - Google Patents
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- TW201705948A TW201705948A TW105106856A TW105106856A TW201705948A TW 201705948 A TW201705948 A TW 201705948A TW 105106856 A TW105106856 A TW 105106856A TW 105106856 A TW105106856 A TW 105106856A TW 201705948 A TW201705948 A TW 201705948A
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
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Abstract
Description
本發明係關於一種眼科用組成物、抑制眼科用組成物之動黏度之經時變化及/或高度維持防腐力或保存效力之方法。 The present invention relates to an ophthalmic composition, a method for inhibiting the temporal change of the dynamic viscosity of an ophthalmic composition, and/or a method for maintaining a high degree of antiseptic or preservation efficacy.
玻尿酸或其鹽係作為乾眼症之治療劑而眾所周知，例如於日本被廣泛用作滴眼液。滴眼液為了持續多次使用，而大多使用可自由地進行利用蓋之開封及再封之多劑量型。另一方面，多劑量型之滴眼液由於以長時間使用為前提，故而必須事先添加防腐劑。 Hyaluronic acid or a salt thereof is known as a therapeutic agent for dry eye, and is widely used as an eye drop, for example, in Japan. In order to continue to use a plurality of times, the eye drops are often used in a multi-dose type in which the lid can be opened and resealed freely. On the other hand, since the multi-dose type eye drops are premised for long-term use, it is necessary to add a preservative in advance.
作為眼科用防腐劑，以往氯化苄烷銨眾所周知。近年來，提出使用洛赫西定(chlorhexidine)類代替上述氯化苄烷銨(例如專利文獻1)。又，廣泛調配乙二胺四乙酸鹽類作為滴眼液之穩定劑(例如專利文獻2)。 As an ophthalmic preservative, the conventional benzalkonium chloride is well known. In recent years, it has been proposed to use chlorhexidine instead of the above-described benzalkonium chloride (for example, Patent Document 1). Further, ethylenediaminetetraacetate is widely used as a stabilizer for eye drops (for example, Patent Document 2).
[先前技術文獻] [Previous Technical Literature]
[專利文獻] [Patent Literature]
[專利文獻1]國際公開第2008/050776號 [Patent Document 1] International Publication No. 2008/050776
[專利文獻2]日本專利特開2003-327530號公報 [Patent Document 2] Japanese Patent Laid-Open Publication No. 2003-327530
然而，根據本發明者等人之研究，關於含有玻尿酸或其鹽與洛赫西定類之滴眼液，發現滴眼液之動黏度隨時間降低之不良情況。 However, according to the study by the inventors of the present invention, regarding the ophthalmic solution containing hyaluronic acid or its salt and loceceptine, it was found that the dynamic viscosity of the ophthalmic solution was lowered with time.
本發明之目的在於高度維持含有玻尿酸或其鹽之滴眼液等眼科用組成物之動黏度的保持率。 An object of the present invention is to maintain the retention of the dynamic viscosity of an ophthalmic composition such as an eye drop containing hyaluronic acid or a salt thereof.
本發明者等人發現，藉由於含有玻尿酸或其鹽與洛赫西定類之滴眼液等眼科用組成物中調配丙二醇，並且將乙二胺四乙酸鹽類之調配濃度設為0.015%(w/v)以下，而可持續長期地且穩定地保持眼科用組成物之動黏度，從而完成本發明。具體而言，本發明提供以下者。 The present inventors have found that propylene glycol is formulated by an ophthalmic composition containing hyaluronic acid or a salt thereof and an eye drop of lohexidine, and the concentration of ethylenediaminetetraacetate is set to 0.015% ( w/v) below, and the dynamic viscosity of the ophthalmic composition can be maintained for a long period of time and stably, thereby completing the present invention. Specifically, the present invention provides the following.
[1]一種眼科用組成物，其含有0.001~0.5%(w/v)之玻尿酸或其鹽、0.0005~0.02%(w/v)之洛赫西定類、0.03~1.5%(w/v)之丙二醇及0.015%(w/v)以下之乙二胺四乙酸鹽類。 [1] An ophthalmic composition comprising 0.001 to 0.5% (w/v) of hyaluronic acid or a salt thereof, 0.0005 to 0.02% (w/v) of Lohcetin, 0.03 to 1.5% (w/v) And propylene glycol and 0.015% (w/v) or less of ethylenediaminetetraacetate.
[2]如[1]記載之眼科用組成物，其中，上述玻尿酸或其鹽為0.01~0.3%(w/v)。 [2] The ophthalmic composition according to [1], wherein the hyaluronic acid or a salt thereof is 0.01 to 0.3% (w/v).
[3]如[1]記載之眼科用組成物，其中，上述洛赫西定類為0.0007~0.008%(w/v)。 [3] The ophthalmic composition according to [1], wherein the loceceptine is 0.0007 to 0.008% (w/v).
[4]如[1]記載之眼科用組成物，其中，上述丙二醇為0.05~1.0%(w/v)。 [4] The ophthalmic composition according to [1], wherein the propylene glycol is 0.05 to 1.0% (w/v).
[5]如[1]記載之眼科用組成物，其中，上述乙二胺四乙酸鹽類為0.01%(w/v)以下。 [5] The ophthalmic composition according to [1], wherein the ethylenediaminetetraacetate is 0.01% (w/v) or less.
[6]如[1]至[5]中任一項記載之眼科用組成物，其pH值為5.5~8。 [6] The ophthalmic composition according to any one of [1] to [5] wherein the pH is 5.5 to 8.
[7]如[1]至[6]中任一項記載之眼科用組成物，其滲透壓為0.4~1.1。 [7] The ophthalmic composition according to any one of [1] to [6] wherein the osmotic pressure is from 0.4 to 1.1.
[8]如[1]至[7]中任一項記載之眼科用組成物，其係醫藥用滴眼液、軟性隱形眼鏡用滴眼液或軟性隱形眼鏡用濕潤液。 [8] The ophthalmic composition according to any one of [1] to [7], which is a medical eye drop, a soft contact lens eye drop or a soft contact lens wet liquid.
再者，上述[1]至[8]之各構成可任意選擇2種以上進行組合。 In addition, each of the above [1] to [8] can be arbitrarily selected by combining two or more types.
[9]一種抑制眼科用組成物之動黏度之經時變化之方法，其藉由使含有玻尿酸或其鹽及洛赫西定類之眼科用組成物含有丙二醇與乙二胺四乙酸鹽類而抑制眼科用組成物之動黏度之經時變化。 [9] A method for inhibiting temporal change of dynamic viscosity of an ophthalmic composition, which comprises propylene glycol and ethylenediaminetetraacetate by using an ophthalmic composition containing hyaluronic acid or a salt thereof and loceceptine The temporal change of the dynamic viscosity of the ophthalmic composition is suppressed.
[10]一種抑制眼科用組成物之動黏度之經時變化之方法，其藉由使含有玻尿酸或其鹽及洛赫西定類之眼科用組成物含有0.03~1.5%(w/v)之丙二醇與0.015%(w/v)以下之乙二胺四乙酸鹽類而抑制眼科用組成物之動黏度的經時變化。 [10] A method for inhibiting temporal change of dynamic viscosity of an ophthalmic composition, which comprises 0.03 to 1.5% (w/v) of an ophthalmic composition containing hyaluronic acid or a salt thereof and loceceptine Propylene glycol and 0.015% (w/v) or less of ethylenediaminetetraacetate inhibit the temporal change of the dynamic viscosity of the ophthalmic composition.
[11]一種高度維持眼科用組成物之防腐力或保存效力之方法，其藉由使含有玻尿酸或其鹽及洛赫西定類之眼科用組成物含有丙二醇與乙二胺四乙酸鹽類而高度維持眼科用組成物之防腐力或保存效力。 [11] A method for highly maintaining the antiseptic or preservative efficacy of an ophthalmic composition, which comprises propylene glycol and ethylenediaminetetraacetate by using an ophthalmic composition containing hyaluronic acid or a salt thereof and loceceptine Highly maintains the antiseptic or preservation efficacy of ophthalmic compositions.
[12]一種高度維持眼科用組成物之防腐力或保存效力之方法，其藉由使含有玻尿酸或其鹽及洛赫西定類之眼科用組成物含有0.03~1.5%(w/v)之丙二醇與0.015%(w/v)以下之乙二胺四乙酸鹽類而高度維持眼科用組成物之防腐力或保存效力。 [12] A method for highly maintaining the antiseptic or preservative efficacy of an ophthalmic composition, which comprises 0.03 to 1.5% (w/v) of an ophthalmic composition containing hyaluronic acid or a salt thereof and loceceptine Propylene glycol and 0.015% (w/v) or less of ethylenediaminetetraacetate to maintain the antiseptic or preservative efficacy of the ophthalmic composition.
[13]一種抑制眼科用組成物之動黏度之經時變化，且高度維持防腐力或保存效力之方法，其藉由使含有玻尿酸或其鹽及洛赫西定類之眼科用組成物含有丙二醇與乙二胺四乙酸鹽類而抑制眼科用組成物之動黏度之經時變化，且高度維持防腐力或保存效力。 [13] A method for suppressing temporal changes in dynamic viscosity of an ophthalmic composition, and highly maintaining antiseptic or preservative efficacy, which comprises propylene glycol by an ophthalmic composition containing hyaluronic acid or a salt thereof and loceceptine It inhibits the change of the dynamic viscosity of the ophthalmic composition with ethylenediaminetetraacetate and maintains the antiseptic or preservation efficacy.
[14]一種抑制眼科用組成物之動黏度之經時變化，且高度維持防腐力或 保存效力之方法，其藉由使含有玻尿酸或其鹽及洛赫西定類之眼科用組成物含有0.03~1.5%(w/v)之丙二醇與0.015%(w/v)以下之乙二胺四乙酸鹽類而抑制眼科用組成物之動黏度之經時變化，且高度維持防腐力或保存效力。 [14] A time-dependent change in the dynamic viscosity of an ophthalmic composition, and maintaining a high degree of antiseptic or A method for preserving efficacy by containing 0.03 to 1.5% (w/v) of propylene glycol and 0.015% (w/v) or less of ethylenediamine by using an ophthalmic composition containing hyaluronic acid or a salt thereof and loceceptine The tetraacetate inhibits the temporal change of the dynamic viscosity of the ophthalmic composition and maintains the antiseptic or preservation efficacy to a high degree.
[15]一種抑制劑，其係含有丙二醇及乙二胺四乙酸鹽類的眼科用組成物之動黏度之經時變化之抑制劑，且該眼科用組成物含有玻尿酸或其鹽及洛赫西定類。 [15] An inhibitor comprising an inhibitor of the dynamic viscosity of an ophthalmic composition comprising propylene glycol and ethylenediaminetetraacetate, and the ophthalmic composition comprising hyaluronic acid or a salt thereof and Lohsi Class.
[16]一種含有丙二醇及乙二胺四乙酸鹽類之組成物，其用於抑制含有玻尿酸或其鹽及洛赫西定類之眼科用組成物之動黏度之經時變化。 [16] A composition comprising propylene glycol and ethylenediaminetetraacetate for suppressing temporal changes in dynamic viscosity of an ophthalmic composition containing hyaluronic acid or a salt thereof and rocetaxel.
[17]一種防腐劑或保存劑，其係將含有丙二醇及乙二胺四乙酸鹽類的眼科用組成物之防腐力或保存效力高度維持之防腐劑或保存劑，且該眼科用組成物含有玻尿酸或其鹽及洛赫西定類。 [17] A preservative or preservative which is a preservative or preservative containing a high-preservation or preservation efficacy of an ophthalmic composition containing propylene glycol and ethylenediaminetetraacetate, and the ophthalmic composition contains Hyaluronic acid or its salt and lohcetin.
[18]一種含有丙二醇及乙二胺四乙酸鹽類之組成物，其用於將含有玻尿酸或其鹽及洛赫西定類之眼科用組成物之防腐力或保存效力高度維持。 [18] A composition comprising propylene glycol and ethylenediaminetetraacetate for highly maintaining the antiseptic or preservation efficacy of an ophthalmic composition containing hyaluronic acid or a salt thereof and loceceptine.
[19]一種含有丙二醇及乙二胺四乙酸鹽類之組成物，其用於抑制含有玻尿酸或其鹽及洛赫西定類之眼科用組成物之動黏度之經時變化，且高度維持防腐力或保存效力。 [19] A composition comprising propylene glycol and ethylenediaminetetraacetate for suppressing temporal changes in dynamic viscosity of an ophthalmic composition containing hyaluronic acid or a salt thereof and loceceptine, and maintaining a high degree of preservation Force or save effectiveness.
再者，上述[9]至[19]之各構成之成分濃度可依據本發明之實施形態，以較佳之範圍及組合適當進行限定。 Further, the component concentrations of the respective configurations of the above [9] to [19] can be appropriately limited in accordance with the embodiment of the present invention, and are preferably defined in a preferred range and combination.
根據本發明，含有玻尿酸或其鹽與洛赫西定類之滴眼液等眼科用組成物可抑制其動黏度之經時變化，且可高度維持防腐力或保存效力。 According to the present invention, an ophthalmic composition containing hyaluronic acid or a salt thereof and an eye drop of lohexidine can suppress temporal change of its dynamic viscosity, and can highly maintain antiseptic or preservation efficacy.
以下，對本發明之實施形態詳細地進行說明。 Hereinafter, embodiments of the present invention will be described in detail.
本實施形態之眼科用組成物含有玻尿酸或其鹽、洛赫西定類及丙二醇，且含有0.015%(w/v)以下之乙二胺四乙酸鹽類。於本實施形態中發現，雖以往乙二胺四乙酸鹽類作為眼科用組成物之穩定劑而被廣泛調配，但於將其調配量設為極微量(0.015%以下)之情形時，可穩定地保持滴眼液之動黏度。即，本實施形態之眼科用組成物可含有0.001~0.5%(w/v)之玻尿酸或其鹽、0.0005~0.02%(w/v)之洛赫西定類、0.03~1.5%(w/v)之丙二醇及0.015%(w/v)以下之乙二胺四乙酸鹽類。 The ophthalmic composition of the present embodiment contains hyaluronic acid or a salt thereof, lohwidine and propylene glycol, and contains 0.015% (w/v) or less of ethylenediaminetetraacetate. In the present embodiment, it has been found that ethylenediaminetetraacetate is widely used as a stabilizer for ophthalmic compositions, but it can be stabilized when the amount is adjusted to a very small amount (0.015% or less). Maintain the dynamic viscosity of the eye drops. That is, the ophthalmic composition of the present embodiment may contain 0.001 to 0.5% (w/v) of hyaluronic acid or a salt thereof, 0.0005 to 0.02% (w/v) of Lohcetin, 0.03 to 1.5% (w/ v) propylene glycol and 0.015% (w/v) or less of ethylenediaminetetraacetate.
以下，對各成分逐個進行說明。 Hereinafter, each component will be described one by one.
玻尿酸或其鹽 Hyaluronic acid or its salt
本實施形態中之玻尿酸係下述通式(1)所表示之化合物。 The hyaluronic acid in the present embodiment is a compound represented by the following formula (1).
[式中，n表示自然數] [where n is a natural number]
作為本實施形態中之「玻尿酸」，較佳為平均分子量為50萬~390萬之玻尿酸，進而較佳為平均分子量為50萬~120萬之玻尿酸。 The "hyaluronic acid" in the present embodiment is preferably hyaluronic acid having an average molecular weight of 500,000 to 3.9 million, and more preferably hyaluronic acid having an average molecular weight of 500,000 to 1,200,000.
作為玻尿酸之鹽，只要為醫藥上所容許之鹽則並無特別限制，可列舉：與鹽酸、氫溴酸、氫碘酸、硝酸、硫酸、磷酸等無機酸之鹽；與乙酸、反丁烯二酸、順丁烯二酸、丁二酸、檸檬酸、酒石酸、己二酸、葡萄糖酸、葡庚糖酸、葡糖醛酸、對苯二甲酸、甲磺酸、乳酸、馬尿酸、1,2-乙二磺酸、羥乙磺酸、乳糖酸、油酸、雙羥萘酸、聚半乳糖醛酸、硬脂酸、鞣酸、三氟甲磺酸、苯磺酸、對甲苯磺酸、硫酸月桂酯、硫酸甲酯、萘磺酸、磺基水楊酸等有機酸之鹽；與溴甲烷、碘甲烷等之四級銨鹽；與溴離子、氯離子、碘離子等鹵離子之鹽；與鋰、鈉、鉀等鹼金屬之鹽；與鈣、鎂等鹼土金屬之鹽；與鐵、鋅等之金屬鹽；與氨之鹽；與三伸乙基二胺、2-胺基乙醇、2,2-亞胺基雙(乙醇)、1-去氧-1-(甲基胺基)-2-D-山梨醇、2-胺基-2-(羥基甲基)-1,3-丙二醇、普魯卡因、N,N-雙(苯基甲基)-1,2-乙二胺等有機胺之鹽等。 The salt of hyaluronic acid is not particularly limited as long as it is a pharmaceutically acceptable salt, and examples thereof include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, and phosphoric acid; and acetic acid and fubutene. Diacid, maleic acid, succinic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptonic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, lactic acid, hippuric acid, 1 ,2-ethanedisulfonic acid, isethionethane, lactobionic acid, oleic acid, pamoic acid, polygalacturonic acid, stearic acid, citric acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluene a salt of an organic acid such as an acid, a lauryl sulfate, a methyl sulfate, a naphthalenesulfonic acid or a sulfosalicylic acid; a quaternary ammonium salt with a methyl bromide or a methyl iodide; and a halogen ion such as a bromide ion, a chloride ion or an iodide ion; a salt; an alkali metal salt such as lithium, sodium or potassium; a salt with an alkaline earth metal such as calcium or magnesium; a metal salt such as iron or zinc; a salt with ammonia; and an ethylenediamine and a 2-amino group Ethanol, 2,2-iminobis(ethanol), 1-deoxy-1-(methylamino)-2-D-sorbitol, 2-amino-2-(hydroxymethyl)-1, 3-propanediol, procaine, N, N- A salt of an organic amine such as bis(phenylmethyl)-1,2-ethanediamine or the like.
作為本實施形態中之「玻尿酸之鹽」，較佳為下述通式(2)所表示之鈉鹽(以下，亦稱為「玻尿酸鈉」)。 The "salt of hyaluronic acid" in the present embodiment is preferably a sodium salt represented by the following formula (2) (hereinafter also referred to as "sodium hyaluronate").
[式中，m表示自然數] [where m represents a natural number]
本實施形態中之「玻尿酸或其鹽」可採用水合物或溶劑合物之形態。 The "hyaluronic acid or a salt thereof" in the present embodiment may be in the form of a hydrate or a solvate.
於玻尿酸中存在幾何異構物或光學異構物之情形時，上述異構物或該等之鹽亦包含於本發明之範圍內。又，於玻尿酸中存在質子互變異構物之情形時，上述互變異構物或該等之鹽亦包含於本發明之範圍內。 In the case where geometric isomers or optical isomers are present in hyaluronic acid, the above isomers or such salts are also included in the scope of the present invention. Further, in the case where a proton tautomer is present in hyaluronic acid, the above tautomer or such a salt is also included in the scope of the present invention.
於玻尿酸或其鹽、水合物或溶劑合物中存在多晶形及多晶形群(多晶形系統)之情形時，該等多晶形體及多晶形群(多晶形系統)亦包含於本發明之範圍內。此處，多晶形群(多晶形系統)意指根據該等結晶之製造、晶化、保存等之條件及狀態(再者，本狀態亦包含製劑化之狀態)而晶形發生變化之情形時之各階段中的各種晶形及其過程整體。 When polymorphic forms and polymorphic groups (polymorphic systems) are present in hyaluronic acid or a salt, hydrate or solvate thereof, such polymorphs and polymorphs (polymorphic systems) are also included in the scope of the present invention. Inside. Here, the polymorphic group (polymorphic system) means a case where the crystal form changes depending on conditions and conditions of production, crystallization, storage, and the like of the crystals (further, the state also includes a state of formulation). Various crystal forms and their processes as a whole in each stage.
「玻尿酸或其鹽」可依據有機合成化學之領域中之通常方法而進行製造，亦可依據日本特開平1-115902號公報所記載之方法而進行製造。又，「玻尿酸或其鹽」亦可使用由Sigma公司等市售者，例如，「玻尿酸鈉」係由Sigma公司市售(目錄編號：H5388)。 "Hypouric acid or a salt thereof" can be produced by a usual method in the field of organic synthetic chemistry, and can also be produced according to the method described in JP-A-1-115902. Further, "hyaluronic acid or a salt thereof" can also be used by a commercially available person such as Sigma, for example, "sodium hyaluronate" is commercially available from Sigma (Cat. No. H5388).
本實施形態之眼科用組成物可含有「玻尿酸或其鹽」作為唯一之有效成分，又，亦可含有「玻尿酸或其鹽」以外之有效成分。本實施態樣之眼科用組成物例如可不含有色甘酸或其鹽、普拉洛芬(pranoprofen)作為「玻尿酸或其鹽」以外之有效成分。本發明中所謂有效成分」意指藥理學上有效果之成分。 The ophthalmic composition of the present embodiment may contain "hyaluronic acid or a salt thereof" as the only active ingredient, and may contain an active ingredient other than "hyaluronic acid or a salt thereof". The ophthalmic composition of the present embodiment may contain, for example, cromolyn or a salt thereof or pranoprofen as an active ingredient other than "hyaluronic acid or a salt thereof". The term "active ingredient" as used in the present invention means a pharmacologically effective ingredient.
關於本實施形態之眼科用組成物中之「玻尿酸或其鹽」之濃度，作為下限值，較佳為0.001%(w/v)，更佳為0.01%(w/v)，進而較佳為0.05%(w/v)，作為上限值，較佳為0.5%(w/v)，更佳為0.3%(w/v)。 The concentration of "hyaluronic acid or a salt thereof" in the ophthalmic composition of the present embodiment is preferably 0.001% (w/v), more preferably 0.01% (w/v), and further preferably 0.01% (w/v). It is 0.05% (w/v), and as an upper limit, it is preferably 0.5% (w/v), more preferably 0.3% (w/v).
洛赫西定類 Lochite
作為洛赫西定類，例如可列舉：葡萄糖酸洛赫西定、乙酸洛赫西定、鹽酸洛赫西定等，較佳為葡萄糖酸洛赫西定。關於洛赫西定類之濃度，作為下限值，較佳為0.0005%(w/v)，更佳為0.0007，進而較佳為0.0008%(w/v)，作為上限值，較佳為0.02%(w/v)，更佳為0.01%(w/v)，進而較佳為0.008%(w/v)。 Examples of the lohside can be listed as lohexidine gluconate, loceceptine acetate, loceceptine hydrochloride, etc., and preferably lohcetin gluconate. The concentration of the lohexidine is preferably 0.0005% (w/v), more preferably 0.0007, still more preferably 0.0008% (w/v), as the upper limit, preferably 0.02% (w/v), more preferably 0.01% (w/v), still more preferably 0.008% (w/v).
本實施形態之眼科用組成物亦可含有洛赫西定類以外之防腐劑，例如可含有氯化苄烷銨，作為其濃度，較佳為0.002%(w/v)以下，更佳為0.0015%(w/v)以下。然而，本實施形態之眼科用組成物較佳為不含有氯化苄烷銨，更佳為含有洛赫西定類作為唯一之防腐劑。 The ophthalmic composition of the present embodiment may contain a preservative other than rocetaxel, and may, for example, contain benzalkonium chloride, and the concentration thereof is preferably 0.002% (w/v) or less, more preferably 0.0015. %(w/v) or less. However, the ophthalmic composition of the present embodiment preferably does not contain benzalkonium chloride, and more preferably contains loceceptine as the sole preservative.
丙二醇 Propylene glycol
關於本實施形態之眼科用組成物中之丙二醇之濃度，作為下限值，較佳為0.03%(w/v)，更佳為0.05%(w/v)，作為上限值，較佳為1.5%(w/v)，更佳為1.0%(w/v)。 The concentration of propylene glycol in the ophthalmic composition of the present embodiment is preferably 0.03% (w/v), more preferably 0.05% (w/v), and the upper limit is preferably the upper limit. 1.5% (w/v), more preferably 1.0% (w/v).
乙二胺四乙酸鹽類 Ethylenediaminetetraacetate
本實施形態之眼科用組成物中之乙二胺四乙酸鹽類係乙二胺四乙酸或其鹽，可為水合物之形態，又，亦可混合酸與鹽而使用。作為乙二胺四乙酸之鹽，例如可列舉：乙二胺四乙酸鈉、乙二胺四乙酸二鈉、乙二胺四乙酸四鈉等鹼金屬類，作為水合物，例如可列舉：乙二胺四乙酸二鈉之二水合物等乙二胺四乙酸鈉水合物。 The ethylenediaminetetraacetate in the ophthalmic composition of the present embodiment is ethylenediaminetetraacetic acid or a salt thereof, and may be in the form of a hydrate, or may be used by mixing an acid and a salt. Examples of the salt of ethylenediaminetetraacetic acid include alkali metals such as sodium ethylenediaminetetraacetate, disodium ethylenediaminetetraacetate, and tetrasodium ethylenediaminetetraacetate. Examples of the hydrate include ethylene glycol. Sodium ethylenediaminetetraacetate hydrate such as disodium diamine tetraacetate.
本實施形態之眼科用組成物中之乙二胺四乙酸鹽類之濃度為0.015%(w/v)以下，較佳為0.01%(w/v)以下，可為0.003%(w/v)以 下，亦可為0.001%(w/v)以下。進而，本實施形態之眼科用組成物可完全不含有乙二胺四乙酸鹽類。 The concentration of the ethylenediaminetetraacetate in the ophthalmic composition of the present embodiment is 0.015% (w/v) or less, preferably 0.01% (w/v) or less, and may be 0.003% (w/v). Take Next, it may be 0.001% (w/v) or less. Further, the ophthalmic composition of the present embodiment may contain no ethylenediaminetetraacetate at all.
關於本實施形態之眼科用組成物之pH值，作為下限值，較佳為5.5，更佳為6，進而較佳為超過6，作為上限值，較佳為8，更佳為7.5，進而較佳為7。若為上述pH值之範圍，則一面使眼科用組成物中之玻尿酸或其鹽穩定，一面作為眼科用組成物為低刺激性等，而可較佳地使用。 The pH value of the ophthalmic composition of the present embodiment is preferably 5.5, more preferably 6, more preferably more than 6, as the upper limit, and is preferably 8, more preferably 7.5. More preferably, it is 7. In the range of the pH value, the hyaluronic acid or a salt thereof in the ophthalmic composition is stabilized, and the ophthalmic composition is preferably low in irritation or the like.
緩衝劑 Buffer
本實施形態之眼科用組成物為了調整為上述較佳之範圍之pH值，較佳為進而含有緩衝劑。作為緩衝劑，可列舉：ε-胺基己酸、磷酸鈉、磷酸氫鈉、磷酸二氫鈉、乙酸鈉等。若可將本實施形態之眼科用組成物之pH值調整為上述較佳之範圍，則緩衝劑之添加量(濃度)並無特別限定。 The ophthalmic composition of the present embodiment preferably further contains a buffering agent in order to adjust the pH to the above preferred range. Examples of the buffering agent include ε-aminohexanoic acid, sodium phosphate, sodium hydrogen phosphate, sodium dihydrogen phosphate, and sodium acetate. When the pH of the ophthalmic composition of the present embodiment can be adjusted to the above preferred range, the amount (concentration) of the buffering agent is not particularly limited.
其他添加劑 Other additives
本實施形態之眼科用組成物為了調整為上述較佳之範圍之pH值，亦可進而含有pH值調節劑。作為pH值調節劑，只要為可調節本實施形態之眼科用組成物之pH值者則並無特別限定，作為具體例，可列舉：稀鹽酸、氫氧化鈉等。若可將本實施形態之眼科用組成物之pH值調整為上述較佳之範圍，則pH值調節劑之添加量(濃度)並無特別限定。 The ophthalmic composition of the present embodiment may further contain a pH adjuster in order to adjust the pH to the above preferred range. The pH adjusting agent is not particularly limited as long as it can adjust the pH of the ophthalmic composition of the present embodiment, and specific examples thereof include dilute hydrochloric acid and sodium hydroxide. When the pH of the ophthalmic composition of the present embodiment is adjusted to the above preferred range, the amount (concentration) of the pH adjuster is not particularly limited.
本實施形態之眼科用組成物之滲透壓只要為作為眼科用組成物所容許之範圍則並無特別限制，作為下限值，較佳為0.4，更佳為0.6，進而較佳為超過0.9，作為上限值，較佳為1.3，更佳為1.2，進而較佳為1.1以下。於本說明書中，滲透壓係藉由日本藥典第十六修訂版之滲透壓測定法(滲透壓莫耳濃度測定法)所記載之方法而測得之值。 The osmotic pressure of the ophthalmic composition of the present embodiment is not particularly limited as long as it is a range acceptable for the ophthalmic composition, and is preferably 0.4, more preferably 0.6, still more preferably 0.9, as the lower limit. The upper limit is preferably 1.3, more preferably 1.2, still more preferably 1.1 or less. In the present specification, the osmotic pressure is a value measured by the method described in the osmotic pressure measuring method (osmotic pressure molar concentration measuring method) of the sixteenth revised edition of the Japanese Pharmacopoeia.
本實施形態之眼科用組成物較佳為水性組成物。於本發明中，所謂「水性組成物」意指以水為基劑之組成物。本實施形態之眼科用組成物作為水性組成物較佳為至少含有上述玻尿酸或其鹽、洛赫西定類及丙二醇的水溶液，例如可採用下述滴眼液作為滴眼液。 The ophthalmic composition of the present embodiment is preferably an aqueous composition. In the present invention, the "aqueous composition" means a composition based on water. The ophthalmic composition of the present embodiment is preferably an aqueous solution containing at least the above hyaluronic acid or a salt thereof, loxetidine or propylene glycol. For example, the following eye drops can be used as the eye drop.
於本實施形態之眼科用組成物中，可視需要添加製藥學上所容許之添加劑。 In the ophthalmic composition of the present embodiment, a pharmaceutically acceptable additive may be added as needed.
本實施形態之眼科用組成物例如可藉由慣例進行製備，例如可使玻尿酸或其鹽、洛赫西定類及丙二醇、以及視需要調配之乙二胺四乙酸鹽類、緩衝劑、pH值調節劑等溶解於水中，並視需要進而添加pH值調節劑等，藉此調整pH值而獲得。 The ophthalmic composition of the present embodiment can be prepared, for example, by a conventional method, for example, hyaluronic acid or a salt thereof, lohwidine and propylene glycol, and optionally ethylenediaminetetraacetate, a buffer, and a pH. The regulator or the like is dissolved in water, and if necessary, a pH adjuster or the like is added thereto to adjust the pH.
本實施形態之眼科用組成物可較佳地用作醫藥用、隱形眼鏡用等之滴眼液，除此以外，亦可用作隱形眼鏡用濕潤液。尤其於不含有氯化苄烷銨之情形時，可較佳地用作軟性隱形眼鏡用滴眼液或濕潤液。作為醫藥用途，例如，不僅可用於伴隨乾眼症(乾眼綜合症)、休格連氏症候群、史蒂芬-瓊森症候群等內源性疾病之角結膜上皮損傷之治療，亦可用於伴隨因術後、藥劑性、外傷、隱形眼鏡配戴等引起之外源性疾病之角結膜上皮損傷之治療。 The ophthalmic composition of the present embodiment can be preferably used as an eye drop for medical use, contact lenses, and the like, and can also be used as a wet liquid for contact lenses. Particularly, in the case where it does not contain benzalkonium chloride, it can be preferably used as an eye drop or a wetting liquid for soft contact lenses. For medical use, for example, it can be used not only for the treatment of corneal epithelial damage associated with endogenous diseases such as dry eye syndrome (dry eye syndrome), Hugh's syndrome, and Stephen Johnson syndrome, but also for accompanying surgery. Post-treatment, pharmacy, trauma, contact lens wear, etc. cause the treatment of corneal epithelial damage of exogenous diseases.
本實施形態之眼科用組成物可將動黏度之經時變化抑制為較低，例如即便於50~70℃、具代表性之60℃靜置2週之苛刻試驗之條件下，亦可將動黏度之經時變化抑制為較低。具體而言，關於本實施形態之眼科用組成物，例如於60℃靜置2週之前及之後，分別藉由下述之動黏度測定試驗對動黏度進行測定，作為所測定之動黏度之保持率之下限值，較 佳為70%，更佳為75%，進而較佳為77%，作為上限值，較佳為100%，但例如即便為95%、90%、85%等，亦可較佳地用於上述用途。 The ophthalmic composition of the present embodiment can suppress the temporal change of the dynamic viscosity to a low level, for example, even under the conditions of a severe test at 50 to 70 ° C and a representative 60 ° C for 2 weeks. The change in viscosity over time is suppressed to a low level. Specifically, the ophthalmic composition of the present embodiment is measured for the dynamic viscosity by the following dynamic viscosity measurement test before and after standing at 60 ° C for 2 weeks, for example, as the measured dynamic viscosity. Lower limit Preferably, it is 70%, more preferably 75%, further preferably 77%, and as the upper limit, preferably 100%, but for example, even 95%, 90%, 85%, etc., can be preferably used for The above uses.
本實施形態之眼科用組成物如上述般具有動黏度之較高之保持率，可認為其原因在於：實現了作為其有效成分之玻尿酸或其鹽的穩定化、較佳為持續長期之穩定化。推測本實施形態之眼科用組成物中之玻尿酸或其鹽之穩定化係藉由反倒將以往作為眼科用組成物之穩定劑而廣泛調配之乙二胺四乙酸鹽類抑制為0.015%(w/v)以下之調配濃度而實現。 The ophthalmic composition of the present embodiment has a high retention of the dynamic viscosity as described above, and is considered to be because stabilization of hyaluronic acid or a salt thereof as an active ingredient thereof is achieved, and stabilization of the long-term stability is preferred. . It is estimated that the stabilization of hyaluronic acid or a salt thereof in the ophthalmic composition of the present embodiment suppresses the ethylenediaminetetraacetate which has been conventionally formulated as a stabilizer for ophthalmic compositions to 0.015% (w/). v) The following blending concentrations are achieved.
本實施形態之眼科用組成物可藉由所調配之洛赫西定類而維持優異之防腐效果。具體而言，關於藉由下述之保存效力試驗對本實施形態之眼科用組成物進行測定之保存效力(於本說明書中，亦稱為「防腐力」)，就大腸桿菌(E.coli)、綠膿桿菌(P.aeruginosa)或金黃色葡萄球菌(S.aureus)而言，於保存2週或4週時為3.0以上，就白色念珠菌(C.albicans)或巴西麯黴(A.brasiliensis)而言，於保存2週或4週時細菌未增加。 The ophthalmic composition of the present embodiment can maintain an excellent antiseptic effect by the formulated lohexidine. Specifically, the storage efficiency (also referred to as "preservative power" in the present specification) of the ophthalmic composition of the present embodiment by the following storage efficacy test is E. coli, For P. aeruginosa or S. aureus, it is 3.0 or more at 2 weeks or 4 weeks of storage, and it is C. albicans or A. brasiliensis. In other words, the bacteria did not increase at 2 weeks or 4 weeks of storage.
本發明之眼科用組成物由於如上述般動黏度之保持率較高，進而可高度維持防腐力或保存效力，故而作為眼科用組成物、例如作為多劑量型之眼科用組成物，亦可穩定地發揮上述醫藥用、隱形眼鏡用等各用途所需之藥效等效果。 Since the ophthalmic composition of the present invention has a high retention rate of the kinetic viscosity as described above, and can highly maintain the antiseptic property or the preservation effect, it can be stabilized as an ophthalmic composition, for example, as a multi-dose ophthalmic composition. The effects of the above-mentioned medicines, contact lenses, and the like are exhibited.
藉由使含有玻尿酸或其鹽及洛赫西定類之眼科用組成物(以下，於本說明書中，有時稱為「對象眼科用組成物」)含有丙二醇與乙二胺四乙酸鹽類，而可抑制目標眼科用組成物之動黏度之經時變化，又，可高度維持目標眼科用組成物之防腐力或保存效力，又，亦可抑制目標眼科用組成物之動黏度之經時變化，且高度維持防腐力或保存效力。 The ophthalmic composition containing hyaluronic acid or a salt thereof and loceceptine (hereinafter, referred to as "the target ophthalmic composition" in the present specification) contains propylene glycol and ethylenediaminetetraacetate. It can suppress the temporal change of the dynamic viscosity of the target ophthalmic composition, and can highly maintain the antiseptic or preservation efficacy of the target ophthalmic composition, and can also suppress the temporal change of the dynamic viscosity of the target ophthalmic composition. And maintain a high degree of anti-corrosion or preservation effectiveness.
又，如上述般抑制對象眼科用組成物之動黏度之經時變化之方法、高度維持對象眼科用組成物之防腐力或保存效力之方法、又抑制對象眼科用組成物之動黏度之經時變化，且高度維持防腐力或保存效力之方法亦為本發明之一。 Further, as described above, the method of suppressing the temporal change of the dynamic viscosity of the target ophthalmic composition, the method of highly maintaining the antiseptic property or the preservation effect of the ophthalmic composition, and the time lapse of the dynamic viscosity of the ophthalmic composition of the subject are suppressed. A method of changing, and maintaining a high degree of antiseptic or preservation efficacy is also one of the inventions.
該等各方法較佳為於在對象眼科用組成物中添加有丙二醇與乙二胺四乙酸鹽類之情形時，以成為對象眼科用組成物、丙二醇與乙二胺四乙酸鹽類之合計之0.03~1.5%(w/v)之濃度含有丙二醇，且以成為該合計之0.015%(w/v)以下之濃度含有乙二胺四乙酸鹽類。 In the case where propylene glycol and ethylenediaminetetraacetate are added to the ophthalmic composition of the subject, the method is preferably a combination of the ophthalmic composition, propylene glycol and ethylenediaminetetraacetate. The concentration of 0.03 to 1.5% (w/v) contains propylene glycol, and ethylenediaminetetraacetate is contained in a concentration of 0.015% (w/v) or less.
含有丙二醇及乙二胺四乙酸鹽類之組成物可用於抑制含有玻尿酸或其鹽及洛赫西定類之眼科用組成物(對象眼科用組成物)之動黏度的經時變化，又，可用於高度維持對象眼科用組成物之防腐力或保存效力，又，亦可用於抑制對象眼科用組成物之動黏度之經時變化，且高度維持防腐力或保存效力。上述含有丙二醇及乙二胺四乙酸鹽類之組成物較佳為如下組成物，即於該組成物與添加該組成物之對象眼科用組成物之合計中，含有0.03~1.5%(w/v)之丙二醇及0.015%(w/v)以下之乙二胺四乙酸鹽類。 The composition containing propylene glycol and ethylenediaminetetraacetate can be used for suppressing the temporal change of the dynamic viscosity of the ophthalmic composition (the ophthalmic composition) containing hyaluronic acid or its salt and loceceptine, and is also available. It can also maintain the anti-corrosion or preservation efficacy of the ophthalmic composition of the subject, and can also be used to suppress the temporal change of the dynamic viscosity of the ophthalmic composition of the subject, and maintain the antiseptic or preservation efficacy to a high degree. The composition containing propylene glycol and ethylenediaminetetraacetate is preferably a composition containing 0.03 to 1.5% (w/v) of the composition of the composition and the ophthalmic composition to which the composition is added. And propylene glycol and 0.015% (w/v) or less of ethylenediaminetetraacetate.
含有丙二醇及乙二胺四乙酸鹽類之組成物可作為含有玻尿酸或其鹽及洛赫西定類之眼科用組成物(對象眼科用組成物)之動黏度之經時變化的抑制劑發揮作用，又，可作為高度維持含有玻尿酸或其鹽及洛赫西定類之眼科用組成物之防腐力或保存效力的防腐劑或保存劑發揮作用。 The composition containing propylene glycol and ethylenediaminetetraacetate can function as an inhibitor of the temporal viscosity change of the ophthalmic composition (the ophthalmic composition of the object) containing hyaluronic acid or its salt and loceceptine. Further, it can function as a preservative or preservative which highly maintains the antiseptic or preservative efficacy of the ophthalmic composition containing hyaluronic acid or its salt and lohexidine.
又，此種含有丙二醇及乙二胺四乙酸鹽類之抑制劑及防腐劑或保存劑 亦為本發明之一。 Also, such inhibitors and preservatives or preservatives containing propylene glycol and ethylenediaminetetraacetate It is also one of the inventions.
上述抑制劑及防腐劑或保存劑較佳為於將各者添加至對象眼科用組成物中之情形時，以成為抑制劑或防腐劑或保存劑與對象眼科用組成物之合計之0.03~1.5%(w/v)之濃度含有丙二醇，且以成為該合計之0.015%(w/v)以下之濃度含有乙二胺四乙酸鹽類。 Preferably, the inhibitor, the preservative or the preservative is added to the ophthalmic composition of the subject, and is 0.03 to 1.5 in total as an inhibitor or a preservative or a preservative and a subject ophthalmic composition. The concentration of % (w/v) contains propylene glycol, and ethylenediaminetetraacetate is contained in a concentration of 0.015% (w/v) or less of the total.
[實施例] [Examples]
針對作為本發明之眼科用組成物之一實施態樣之滴眼液，以下列舉配方例及試樣製備例進一步具體地進行說明，但本發明並不僅限定於該等配方例及試樣製備例。 The eye drops which are one embodiment of the ophthalmic composition of the present invention are further specifically described below in the formulation examples and sample preparation examples, but the present invention is not limited to the formulation examples and the sample preparation examples. .
[配方例] [Formulation example]
配方例1 Formulation example 1
滴眼液(0.3%(w/v))100mL中 Eye drops (0.3% (w/v)) in 100mL
玻尿酸鈉0.3g Sodium Hyaluronate 0.3g
葡萄糖酸洛赫西定鹽0.005g Roxicildine Gluconate 0.005g
磷酸氫二鈉0.2g Disodium hydrogen phosphate 0.2g
磷酸二氫鈉0.04g Sodium dihydrogen phosphate 0.04g
氯化鈉0.6g Sodium chloride 0.6g
丙二醇0.4g Propylene glycol 0.4g
稀鹽酸 適量 Dilute hydrochloric acid
氫氧化鈉 適量 Sodium hydroxide
殺菌精製水 適量 Bactericidal refined water
於殺菌精製水中加入玻尿酸鈉及其以外之上述成分，將該等充分地進 行混合，藉此可製備0.3%(w/v)玻尿酸鈉滴眼液。 Adding sodium hyaluronic acid and the above-mentioned components to the sterilized purified water, and fully advancing the above The mixture was mixed, whereby 0.3% (w/v) sodium hyaluronate eye drops were prepared.
配方例2 Formulation example 2
滴眼液(0.1%(w/v))100mL中 Eye drops (0.1% (w/v)) in 100mL
玻尿酸鈉0.1g Sodium Hyaluronate 0.1g
葡萄糖酸洛赫西定鹽0.002g Roxicildine Gluconate 0.002g
磷酸氫二鈉0.2g Disodium hydrogen phosphate 0.2g
磷酸二氫鈉0.04g Sodium dihydrogen phosphate 0.04g
氯化鈉0.5g Sodium chloride 0.5g
丙二醇0.75g Propylene glycol 0.75g
乙二胺四乙酸鈉水合物0.001g Sodium ethylenediaminetetraacetate hydrate 0.001g
稀鹽酸 適量 Dilute hydrochloric acid
氫氧化鈉 適量 Sodium hydroxide
殺菌精製水 適量 Bactericidal refined water
於殺菌精製水中加入玻尿酸鈉及其以外之上述成分，將該等充分地進行混合，藉此可製備0.1%(w/v)玻尿酸鈉滴眼液。 0.1% (w/v) sodium hyaluronate eye drops can be prepared by adding sodium hyaluronic acid and the above-mentioned components to the sterilized purified water and mixing them sufficiently.
配方例3 Formulation example 3
滴眼液(0.3%(w/v))100mL中 Eye drops (0.3% (w/v)) in 100mL
玻尿酸鈉0.3g Sodium Hyaluronate 0.3g
葡萄糖酸洛赫西定鹽0.001g Lohcetin gluconate salt 0.001g
ε-胺基己酸0.2g ε-Aminocaproic acid 0.2g
氯化鈉0.6g Sodium chloride 0.6g
丙二醇0.5g Propylene glycol 0.5g
稀鹽酸 適量 Dilute hydrochloric acid
氫氧化鈉 適量 Sodium hydroxide
殺菌精製水 適量 Bactericidal refined water
於殺菌精製水中加入玻尿酸鈉及其以外之上述成分，將該等充分地進行混合，藉此可製備0.3%(w/v)玻尿酸鈉滴眼液。 The sodium hyaluronate and the above-mentioned components other than the above-mentioned components were added to the sterilized purified water, and these were sufficiently mixed, whereby 0.3% (w/v) sodium hyaluronate eye drops were prepared.
配方例4 Formulation example 4
滴眼液(0.2%(w/v))100mL中 Eye drops (0.2% (w/v)) in 100mL
玻尿酸鈉0.2g Sodium Hyaluronate 0.2g
葡萄糖酸洛赫西定鹽0.0025g Roxicildine Gluconate 0.0025g
ε-胺基己酸0.2g ε-Aminocaproic acid 0.2g
氯化鈉0.7g Sodium chloride 0.7g
丙二醇0.25g Propylene glycol 0.25g
乙二胺四乙酸鈉水合物0.002g Sodium ethylenediaminetetraacetate hydrate 0.002g
稀鹽酸 適量 Dilute hydrochloric acid
氫氧化鈉 適量 Sodium hydroxide
殺菌精製水 適量 Bactericidal refined water
於殺菌精製水中加入玻尿酸鈉及其以外之上述成分，將該等充分地進行混合，藉此可製備0.2%(w/v)玻尿酸鈉滴眼液。 The sodium hyaluronate and the above-mentioned components other than the above-mentioned components were added to the sterilized purified water, and these were sufficiently mixed, whereby 0.2% (w/v) sodium hyaluronate eye drops were prepared.
配方例5 Formulation example 5
滴眼液(0.005%(w/v))100mL中 Eye drops (0.005% (w/v)) in 100mL
玻尿酸鈉0.005g Sodium Hyaluronate 0.005g
葡萄糖酸洛赫西定鹽0.001g Lohcetin gluconate salt 0.001g
ε-胺基己酸0.1g Ε-aminohexanoic acid 0.1g
氯化鈉0.7g Sodium chloride 0.7g
丙二醇0.3g Propylene glycol 0.3g
稀鹽酸 適量 Dilute hydrochloric acid
氫氧化鈉 適量 Sodium hydroxide
殺菌精製水 適量 Bactericidal refined water
於殺菌精製水中加入玻尿酸鈉及其以外之上述成分，將該等充分地進行混合，藉此可製備0.005%(w/v)玻尿酸鈉滴眼液，但亦可進而含有其他有效成分。 The sodium hyaluronate and the other components other than the above-mentioned components are added to the sterilized purified water, and 0.005% (w/v) of sodium hyaluronate eye drops can be prepared, but further may contain other active ingredients.
配方例6 Formulation example 6
滴眼液(0.05%(w/v))100mL中 Eye drops (0.05% (w/v)) in 100mL
玻尿酸鈉0.05g Sodium hyaluronate 0.05g
葡萄糖酸洛赫西定鹽0.001g Lohcetin gluconate salt 0.001g
ε-胺基己酸0.1g Ε-aminohexanoic acid 0.1g
氯化鈉0.7g Sodium chloride 0.7g
丙二醇0.3g Propylene glycol 0.3g
乙二胺四乙酸鈉水合物0.015g Ethylenediaminetetraacetic acid sodium hydrate 0.015g
稀鹽酸 適量 Dilute hydrochloric acid
氫氧化鈉 適量 Sodium hydroxide
殺菌精製水 適量 Bactericidal refined water
於殺菌精製水中加入玻尿酸鈉及其以外之上述成分，將該等充分地進行混合，藉此可製備0.05%(w/v)玻尿酸鈉滴眼液，但亦可進而含有其他 有效成分。 The sodium hyaluronic acid and the other components other than the above-mentioned components are added to the sterilized purified water, and these are sufficiently mixed to prepare 0.05% (w/v) sodium hyaluronate eye drops, but may further contain other Active ingredients.
配方例7 Formulation Example 7
滴眼液(0.1%(w/v))100mL中 Eye drops (0.1% (w/v)) in 100mL
玻尿酸鈉0.1g Sodium Hyaluronate 0.1g
葡萄糖酸洛赫西定鹽0.001g Lohcetin gluconate salt 0.001g
ε-胺基己酸0.1g Ε-aminohexanoic acid 0.1g
氯化鈉0.7g Sodium chloride 0.7g
丙二醇0.3g Propylene glycol 0.3g
乙二胺四乙酸鈉水合物0.01g Sodium ethylenediaminetetraacetate hydrate 0.01g
稀鹽酸 適量 Dilute hydrochloric acid
氫氧化鈉 適量 Sodium hydroxide
殺菌精製水 適量 Bactericidal refined water
於殺菌精製水中加入玻尿酸鈉及其以外之上述成分，將該等充分地進行混合，藉此可製備0.1%(w/v)玻尿酸鈉滴眼液，但亦可進而含有其他有效成分。 The sodium hyaluronate and the other components other than the above-mentioned components are added to the sterilized purified water, and 0.1% (w/v) of sodium hyaluronate eye drops can be prepared, but further may contain other active ingredients.
配方例8 Formulation Example 8
滴眼液(0.3%(w/v))100mL中 Eye drops (0.3% (w/v)) in 100mL
玻尿酸鈉0.3g Sodium Hyaluronate 0.3g
葡萄糖酸洛赫西定鹽0.001g Lohcetin gluconate salt 0.001g
ε-胺基己酸0.1g Ε-aminohexanoic acid 0.1g
氯化鈉0.7g Sodium chloride 0.7g
丙二醇0.3g Propylene glycol 0.3g
乙二胺四乙酸鈉水合物0.015g Ethylenediaminetetraacetic acid sodium hydrate 0.015g
稀鹽酸 適量 Dilute hydrochloric acid
氫氧化鈉 適量 Sodium hydroxide
殺菌精製水 適量 Bactericidal refined water
於殺菌精製水中加入玻尿酸鈉及其以外之上述成分，將該等充分地進行混合，藉此可製備0.3%(w/v)玻尿酸鈉滴眼液，但亦可進而含有其他有效成分。 The sodium hyaluronate and the above-mentioned components are added to the sterilized purified water, and these are sufficiently mixed to prepare a 0.3% (w/v) sodium hyaluronate eye drop, but may further contain other active ingredients.
[試樣製備例] [Sample preparation example]
實施例1~3 Example 1~3
使玻尿酸鈉0.3g、葡萄糖酸洛赫西定鹽0.005g、丙二醇0.25g、氯化鈉0.7g、磷酸氫二鈉0.2g及磷酸二氫鈉0.04g溶解於水中而獲得100mL之滴眼液。將於該滴眼液中添加稀鹽酸及/或氫氧化鈉而成為pH值6.5者設為實施例1，將成為pH值7.0者設為實施例2，將成為pH值7.5者設為實施例3。 0.3 g of sodium hyaluronic acid, 0.005 g of locetaxet gluconate salt, 0.25 g of propylene glycol, 0.7 g of sodium chloride, 0.2 g of disodium hydrogen phosphate, and 0.04 g of sodium dihydrogen phosphate were dissolved in water to obtain 100 mL of an eye drop. The addition of dilute hydrochloric acid and/or sodium hydroxide to the ophthalmic solution to obtain a pH of 6.5 is referred to as Example 1, and the pH of 7.0 is referred to as Example 2, and the pH is 7.5 as an example. 3.
實施例4~6 Example 4~6
使玻尿酸鈉0.3g、葡萄糖酸洛赫西定鹽0.005g、丙二醇0.25g、乙二胺四乙酸鈉水合物0.001g、氯化鈉0.7g、磷酸氫二鈉0.2g及磷酸二氫鈉0.04g溶解於水中而獲得100mL之滴眼液。將於該滴眼液中添加稀鹽酸及/或氫氧化鈉而成為pH值6.5者設為實施例4，將成為pH值7.0者設為實施例5，將成為pH值7.5者設為實施例6。 0.3 g of sodium hyaluronate, 0.005 g of locetaxet gluconate, 0.25 g of propylene glycol, 0.001 g of sodium edetate hydrate, 0.7 g of sodium chloride, 0.2 g of disodium hydrogen phosphate, and 0.04 g of sodium dihydrogen phosphate. Dissolved in water to obtain 100 mL of eye drops. The addition of dilute hydrochloric acid and/or sodium hydroxide to the ophthalmic solution to obtain a pH of 6.5 is referred to as Example 4, and the pH is 7.0 as Example 5, and the pH is 7.5 as an example. 6.
實施例7~9 Examples 7-9
使玻尿酸鈉0.3g、葡萄糖酸洛赫西定鹽0.0008g、丙二醇0.25g、氯化鈉0.7g、磷酸氫二鈉0.2g及磷酸二氫鈉0.04g溶解於水中而獲得100mL 之滴眼液。將於該滴眼液中添加稀鹽酸及/或氫氧化鈉而成為pH值6.5者設為實施例7，將成為pH值7.0者設為實施例8，將成為pH值7.5者設為實施例9。 0.3 mL of sodium hyaluronic acid, 0.0008 g of lohexidine gluconate salt, 0.25 g of propylene glycol, 0.7 g of sodium chloride, 0.2 g of disodium hydrogen phosphate, and 0.04 g of sodium dihydrogen phosphate were dissolved in water to obtain 100 mL. Eye drops. The addition of dilute hydrochloric acid and/or sodium hydroxide to the ophthalmic solution to obtain a pH of 6.5 is referred to as Example 7, and the pH of 7.0 is referred to as Example 8, and the pH is 7.5 as an example. 9.
實施例10~12 Example 10~12
使玻尿酸鈉0.3g、葡萄糖酸洛赫西定鹽0.0008g、丙二醇0.25g、乙二胺四乙酸鈉水合物0.001g、氯化鈉0.7g、磷酸氫二鈉0.2g及磷酸二氫鈉0.04g溶解於水中而獲得100mL之滴眼液。將於該滴眼液中添加稀鹽酸及/或氫氧化鈉而成為pH值6.5者設為實施例10，將成為pH值7.0者設為實施例11，將成為pH值7.5者設為實施例12。 0.3 g of sodium hyaluronate, 0.0008 g of lohexidine gluconate salt, 0.25 g of propylene glycol, 0.001 g of sodium edetate hydrate, 0.7 g of sodium chloride, 0.2 g of disodium hydrogen phosphate, and 0.04 g of sodium dihydrogen phosphate. Dissolved in water to obtain 100 mL of eye drops. The addition of dilute hydrochloric acid and/or sodium hydroxide to the ophthalmic solution to obtain a pH of 6.5 is shown in Example 10, and the pH is 7.0 as Example 11, and the pH is 7.5 as an example. 12.
比較例1~3 Comparative example 1~3
使玻尿酸鈉0.3g、葡萄糖酸洛赫西定鹽0.005g、乙二胺四乙酸鈉水合物0.1g、氯化鉀0.15g、氯化鈉0.7g、磷酸氫二鈉0.2g及磷酸二氫鈉0.04g溶解於水中而獲得100mL之滴眼液。將於該滴眼液中添加稀鹽酸及/或氫氧化鈉而成為pH值6.5者設為比較例1，將成為pH值7.0者設為比較例2，將成為pH值7.5者設為比較例3。 0.3 g of sodium hyaluronate, 0.005 g of locetaxet gluconate salt, 0.1 g of sodium edetate sodium hydrate, 0.15 g of potassium chloride, 0.7 g of sodium chloride, 0.2 g of disodium hydrogen phosphate and sodium dihydrogen phosphate 0.04 g was dissolved in water to obtain 100 mL of eye drops. The addition of dilute hydrochloric acid and/or sodium hydroxide to the ophthalmic solution to obtain a pH of 6.5 was set as Comparative Example 1, and the pH was 7.0 as Comparative Example 2, and the pH was 7.5 as a comparative example. 3.
比較例4 Comparative example 4
使玻尿酸鈉0.3g、葡萄糖酸洛赫西定鹽0.005g、丙二醇0.25g、乙二胺四乙酸鈉水合物0.1g、氯化鈉0.7g、磷酸氫二鈉0.2g及磷酸二氫鈉0.04g溶解於水中而獲得100mL之滴眼液。將於該滴眼液中添加稀鹽酸及/或氫氧化鈉而成為pH值7.5者設為比較例4。 0.3 g of sodium hyaluronate, 0.005 g of lohexidine gluconate salt, 0.25 g of propylene glycol, 0.1 g of sodium edetate hydrate, 0.7 g of sodium chloride, 0.2 g of disodium hydrogen phosphate, and 0.04 g of sodium dihydrogen phosphate. Dissolved in water to obtain 100 mL of eye drops. Comparative Example 4 was prepared by adding dilute hydrochloric acid and/or sodium hydroxide to the ophthalmic solution to have a pH of 7.5.
<試驗方法> <Test method>
針對實施例1~12及比較例1~4中所製備之各含玻尿酸之滴眼液，如 下述般進行試驗。 For each of the hyaluronic acid-containing eye drops prepared in Examples 1 to 12 and Comparative Examples 1 to 4, The test was carried out as follows.
[動黏度測定試驗] [Dynamic Viscosity Measurement Test]
依據「日本藥典第十六修訂版 一般試驗法 黏度測定法 第1法 毛細管黏度計法」，對測定溫度30℃時之動黏度進行測定，藉此進行動黏度測定試驗，而確認各滴眼液之動黏度穩定化效果。 According to the "Japanese Pharmacopoeia, the sixteenth revised version of the general test method viscosity measurement method, the first method capillary viscosity meter method", the dynamic viscosity at a temperature of 30 ° C is measured, thereby performing the dynamic viscosity measurement test, and confirming each eye drop Dynamic viscosity stabilization effect.
將結果示於表1~3。再者，表1~3中之各調配成分之單位為%(w/v)，各滴眼液之動黏度之單位為mm2/s，動黏度之保持率之單位為%。 The results are shown in Tables 1 to 3. Further, the units of the respective components in Tables 1 to 3 are % (w/v), the unit of the dynamic viscosity of each eye drop is mm 2 /s, and the unit of the retention of the dynamic viscosity is %.
[保存效力試驗] [preservation effectiveness test]
為了確認丙二醇對玻尿酸滴眼液之保存效力所造成之影響，而對實施例7~12中所製備之各含玻尿酸之滴眼液進行保存效力試驗。 In order to confirm the effect of propylene glycol on the preservation efficacy of hyaluronic acid eye drops, the storage efficacy tests of each of the hyaluronic acid-containing eye drops prepared in Examples 7 to 12 were carried out.
保存效力試驗係依據日本藥典第十六修訂版(以下，亦簡稱為「日本藥典」)之保存效力試驗法而進行。於本試驗中，使用大腸桿菌(Esherichia Coli)(E.coli；表2中為「EC」)、綠膿桿菌(Pseudomonas aeruginosa)(P.aeruginosa；表2中為「PA」)、金黃色葡萄球菌(Staphylococcus aureus)(S.aureus；表2中為「SA」)、白色念珠菌(Candida albicans)(C.albicans；表2中為「CA」)及巴西麯黴(Aspergillus brasiliensis)(A.niger；表2中為「AB」)作為試驗細菌。 The preservation efficacy test was carried out in accordance with the preservation efficacy test method of the 16th revised edition of the Japanese Pharmacopoeia (hereinafter also referred to as "Japanese Pharmacopoeia"). In this test, Escherichia Coli (E. coli; "EC" in Table 2), Pseudomonas aeruginosa (P. aeruginosa; "PA" in Table 2), golden yellow grapes were used. Staphylococcus aureus (S. aureus; "SA" in Table 2), Candida albicans (C. albicans; "CA" in Table 2) and Aspergillus brasiliensis (A. niger) ; "AB" in Table 2) as test bacteria.
將結果示於表2。表2中，「ND」係表示未檢測到細菌之情況。 The results are shown in Table 2. In Table 2, "ND" indicates that no bacteria were detected.
(探討) (discussion)
如表1~2所示，於在含有洛赫西定類之玻尿酸滴眼液中調配丙二醇，且調配0.015%(w/v)以下、具體而言為0.001%(w/v)以下之乙二胺四乙酸鈉水合物之情形時，於60℃保存2週後之動黏度保持率均為77.0%以上。 As shown in Tables 1-2, propylene glycol was formulated in hyaluronic acid eye drops containing lohexidine, and formulated to be 0.015% (w/v) or less, specifically 0.001% (w/v) or less. In the case of sodium diaminetetraacetate hydrate, the dynamic viscosity retention after storage at 60 ° C for 2 weeks was 77.0% or more.
相對於此，如表3所示，於不調配丙二醇之情形時或調配0.1%(w/v)之乙二胺四乙酸鈉水合物之情形時，於60℃保存2週後之動黏度保持率均為69.7%以下。 On the other hand, as shown in Table 3, when the propylene glycol was not formulated or when 0.1% (w/v) of sodium edetate hydrate was formulated, the dynamic viscosity retention after storage at 60 ° C for 2 weeks was maintained. The rate is below 69.7%.
因此，與於含有洛赫西定類之玻尿酸滴眼液中含有丙二醇，且乙二胺四乙酸鹽類之調配濃度為0.015%(w/v)以下之情形(亦包括不含有乙二胺四乙酸鹽類之情形)、不含有丙二醇之情形、或含有丙二醇但調配0.1%(w/v)以上之乙二胺四乙酸鈉水合物之情形相比，具有改善該滴眼液之動黏度穩定性之效果。 Therefore, the hyaluronic acid eye drops containing the lohexidine type contain propylene glycol, and the blending concentration of the ethylenediaminetetraacetate is 0.015% (w/v) or less (including the absence of ethylenediamine IV). In the case of acetates, when propylene glycol is not contained, or when propylene glycol is contained but 0.1% (w/v) or more of sodium edetate sodium hydrate is blended, the dynamic viscosity of the eye drops is improved. The effect of sex.
又，如表2所示，於在含有洛赫西定類之玻尿酸滴眼液中調配丙二醇，且調配0.015%(w/v)以下、具體而言為0.001%(w/v)以下之 乙二胺四乙酸鈉水合物之情形時，關於保存效力，就大腸桿菌(E.coli)、綠膿桿菌(P.aeruginosa)而言，保存1週以後為ND，就金黃色葡萄球菌(S.aureus)而言，保存1週以後為2.6以上，保存2週以後為ND，就白色念珠菌(C.albicans)而言，保存1週後為3.8以上，保存2週以後為ND，就巴西麯黴(A.brasiliensis)而言，均為0.0以上，未見明顯之增加。 Further, as shown in Table 2, propylene glycol was blended in a hyaluronic acid eye drop containing roxicilidine, and formulated to be 0.015% (w/v) or less, specifically, 0.001% (w/v) or less. In the case of sodium edetate hydrate, regarding the preservation efficiency, in the case of Escherichia coli (E. coli) and P. aeruginosa, it is ND after 1 week of storage, and Staphylococcus aureus (S) .aureus) is 2.6 or more after 1 week of storage, and ND after 2 weeks of storage. For C. albicans, it is 3.8 or more after 1 week of storage, and ND after 2 weeks of storage. For Aspergillus (A. brasiliensis), both were above 0.0, and no significant increase was observed.
因此，於在含有洛赫西定類之玻尿酸滴眼液中含有丙二醇，且乙二胺四乙酸鹽類之調配濃度為0.015%(w/v)以下之情形時，具有將該滴眼液之保存效力保持為較高之效果。藉此，確認到於含有洛赫西定類之玻尿酸滴眼液中，丙二醇對玻尿酸滴眼液之保存效力所造成之影響實質上不存在或為可忽視之程度。 Therefore, when the hyaluronic acid eye drops containing the lohexidine type contain propylene glycol and the compound concentration of the ethylenediaminetetraacetate is 0.015% (w/v) or less, the eye drops are provided. The preservation effect remains high. Thereby, it was confirmed that the effect of propylene glycol on the preservation efficacy of hyaluronic acid eye drops in the hyaluronic acid eye drops containing lohexidine was substantially absent or negligible.
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| JPH115744A (en) * | 1997-06-16 | 1999-01-12 | Toa Yakuhin Kk | Aqueous solution preparation for external use containing hyaluronic acid |
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