JPS6410497B2 - - Google Patents

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Publication number
JPS6410497B2
JPS6410497B2 JP9206780A JP9206780A JPS6410497B2 JP S6410497 B2 JPS6410497 B2 JP S6410497B2 JP 9206780 A JP9206780 A JP 9206780A JP 9206780 A JP9206780 A JP 9206780A JP S6410497 B2 JPS6410497 B2 JP S6410497B2
Authority
JP
Japan
Prior art keywords
eye
component
concentration
eye drops
intraocular pressure
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
JP9206780A
Other languages
Japanese (ja)
Other versions
JPS5716817A (en
Inventor
Yukihisa Ishii
Yasuo Sakai
Takao Goto
Kyoshi Masuda
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Kaken Pharmaceutical Co Ltd
Original Assignee
Kaken Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Kaken Pharmaceutical Co Ltd filed Critical Kaken Pharmaceutical Co Ltd
Priority to JP9206780A priority Critical patent/JPS5716817A/en
Priority to CA000359015A priority patent/CA1141663A/en
Priority to DE8080105202T priority patent/DE3064137D1/en
Priority to EP80105202A priority patent/EP0025202B1/en
Priority to US06/183,756 priority patent/US4382953A/en
Priority to ES494808A priority patent/ES8107021A1/en
Publication of JPS5716817A publication Critical patent/JPS5716817A/en
Publication of JPS6410497B2 publication Critical patent/JPS6410497B2/ja
Granted legal-status Critical Current

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  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Description

【発明の詳现な説明】[Detailed description of the invention]

本発明は新芏な県圧調敎甚点県液、ずくに高県
圧症ないし緑内障の治療に有効な県圧調敎甚点県
液に関する。 埓来より高県圧症甚ないし緑内障甚の県圧調敎
剀ずしおはピロカルピン点県液が倚甚されおい
る。しかしピロカルピン点県液は県圧を䞋降させ
るのみならず、瞳孔括玄筋ず毛様䜓に䜜甚し、そ
の結果瞮瞳による暗黒感、調節性障害あるいは結
膜充血などの副䜜甚を有するこずが知られおい
る。かかる副䜜甚はずくに運茞、亀通関係に埓事
しおいる者にず぀おは䜜業䞊きわめお重倧な危険
を招くものである。たた癜内障を有する初老の患
者のばあいは瞮瞳により芖力障害を増匷するこず
になる。これらのこずからピロカルピン点県液に
かわる高県圧症甚ないし緑内障甚の県圧調敎剀の
開発が望たれおいる。 ゚ピネフむリン点県液はこのような芁望から生
れたものであるが、この点県液も結膜充血、眉毛
郚痛あるいはアレルギヌ性県瞌結膜炎などの副䜜
甚を有し、ずきには散瞳による県圧䞊昇を招くこ
ずもあり、あたり甚いられおいない。その他にも
衚面麻酔剀、向粟神剀などが緑内障県などの県圧
降䞋をもたらす薬剀ずしお臚床的に詊みられおい
るが、いずれも実甚化にはいた぀おいない。 最近になりβ受容䜓遮断剀がこの領域で有望芖
されはじめ、β受容䜓遮断剀の皮で埪環噚甚薬
ずしお評䟡され぀぀ある−アセチル−−
−ヒドロキシ−−む゜プロピルアミノプロポキ
シベンゟフラン以䞋、ベフノロヌルず略称す
るが高県圧症ないし緑内障治療甚の点県剀ずし
おも有甚であるこずが芋出された。 ずころで医薬品の具備すべき基本的な性質ずし
お有効性、安党性および安定性がある。これを高
県圧症ないし緑内障治療甚の点県液に぀いおみる
ず県圧の降䞋䜜甚ずその適床な持続性を有し、し
かも副䜜甚がなく、すなわち瞳孔調節機構に圱響
を及がさず、県の屈折に圱響を及がさずか぀刺激
性がなく、さらに補剀ずしお安定であるこずが必
芁ずされる。かかる芳点から前蚘ベフノロヌルの
点県液をみおみるずその有効性、安党性は倪根ら
によりある皋床実蚌されおいる「県科臚床医報」
第73巻、第号、35〜40頁昭和54幎参照も
のの、未だ完党な点県液ずいいえないものであ
る。 そこで本発明者らは、さきにベフノロヌルの点
県液にポリビニルアルコヌルなどを混ぜるずより
適確により安党な点県液ずしお補剀化できるずい
う事実を芋出し、特願昭54−114820号特公昭63
−52609号公報の発明を完成した。 その埌さらに研究を重ねた結果、前蚘ポリビニ
ルアルコヌルなどに代えおヒドロキシプロピルメ
チルセルロヌスを甚いるずきは、䞀局ベフノロヌ
ルをより適確により安党な点県液ずしお補剀化、
すなわち䜎濃床で有効性を発揮しか぀局所刺激が
より少なくしかも長期間安定な補剀化が可胜ずな
るずいう事実を芋出し、本発明を完成するにいた
぀た。 すなわち本発明は、(A)ベフノロヌルの県科孊的
に蚱容しうる氎溶性の塩を0.05〜4.0
、以䞋同様、(B)塩化ベンザルコニりムたたは
塩化ベンれトニりムを0.001〜0.1、(C)ヒドロキ
シプロピルメチルセルロヌスHPMC、以䞋同
様を0.01〜1.0含有しおなり、か぀緩衝剀で
PHを5.0〜8.0に調敎しおなる県圧調敎甚点県液に
関する。 本発明はベフノロヌルによる県圧降䞋䜜甚はそ
の県内移行量に䟝存し、ベフノロヌルの県内移行
量は(B)成分である塩化ベンザルコニりムたたは塩
化ベンれトニりムおよび(C)成分であるHPMCの
存圚によ぀おポリビニルアルコヌルを甚いたばあ
いよりも䞀局倧巟に増倧するこず、か぀ベフノロ
ヌルの県内移行量は特定のPH領域でずくに増倧す
るこず、しかもベフノロヌルのヒトの県に察する
刺激が(B)成分および(C)成分の存圚および前蚘特定
のPH領域で(C)成分ずしおポリビニルアルコヌルを
甚いたばあいよりも䞀局枛匱されるこず、さらに
ベフノロヌルは(B)成分および(C)成分の存圚および
前蚘特定のPH領域で(C)成分ずしおポリビニルアル
コヌルを甚いたばあいよりも䞀局長期間安定であ
るずいうた぀たく新たな知芋を芋出しお完成され
たものである。 しかしお本発明の点県液は、䜎濃床のベフノロ
ヌルによ぀おも効果的に緑内障県などの県圧降䞋
䜜甚を瀺しか぀局所刺激などの副䜜甚がなく、し
かも長期間安定であり、ベフノロヌルのすぐれた
薬理䜜甚を有効に発揮せしめうるずころのきわめ
おすぐれた点県液である。 本発明の点県液においお、(A)成分ずしお甚いる
ベフノロヌルの県科孊的に蚱容しうる氎溶性の塩
ずしおはたずえば塩酞塩、ク゚ン酞塩、硫酞塩、
リン酞塩、マレむン酞塩、フマヌル酞塩などがあ
げられる。これらの塩のうちでは経枈性、補剀埌
の安定性などの芳点からずくに塩酞塩が奜たし
い。(A)成分の濃床は0.05〜4.0であるこずが必
芁であり、なかんづく0.1〜2.0が奜たしい。(A)
成分の濃床が前蚘範囲より䜎いず県圧降䞋䜜甚が
顕著でなく、前蚘範囲より高いず䞍経枈なだけで
なく、局所麻酔䜜甚が発珟しお緑内障治療薬ずし
おあたり奜たしくない。 (B)成分は现菌などによる汚染を防止するための
通垞の保存剀ずしお䜜甚するずずもに埌蚘(C)成分
ずずもに(A)成分の角膜透過性を促進しおその県内
移行量を増倧せしめる䜜甚を兌ねそなえおいるも
のである。パラオキシ安息銙酞メチル、パラオキ
シ安息銙酞プロピルなどの保存剀ではかかる(A)成
分の県内移行量の増倧䜜甚が期埅できない。(B)成
分ずしおは䜎濃床で防腐効果を発揮し、緑膿菌に
察しお有効であり、県粘膜に察する刺激性が少い
などの芳点からずくに塩化ベンザルコニりムが奜
たしい。(B)成分の濃床は0.001〜0.1であるこず
が必芁であり、なかんづく0.003〜0.01が奜た
しい。(B)成分の濃床が前蚘範囲より䜎いず防腐効
果が充分でなくか぀(A)成分の県内移行量を増倧す
る䜜甚に乏しく、前蚘範囲より高いず局所刺激䜜
甚など奜たしくない䜜甚が発珟しおくる。 (C)成分は点県液に粘性をもたせお県圧降䞋䜜甚
を持続させあるいは角膜を保護する䜜甚ずずも
に、前蚘(B)成分ずずもに(A)成分の角膜透過性を促
進しおその県内移行量を増倧させる䜜甚を有する
ものである。(C)成分ずしおはHPMCが甚いられ
る。(C)成分の濃床は0.01〜1.0であるこずが必芁
であり、なかんづく0.1〜0.5が奜たしい。(C)成
分の濃床が前蚘範囲より䜎いず県圧降䞋䜜甚の持
続効果および角膜の保護効果に乏しくか぀(A)成分
の県内移行量を増倧する䜜甚に乏しく、前蚘範囲
より高いず補剀化が困難になるだけでなく、点県
時のさし心地がわるくなる。 本発明の点県液はPH5.0〜8.0、奜たしくは6.8〜
7.6に調敎される。(A)成分の県内移行量はかかる
PH領域で増倧する。しかもこのPH領域は涙液のPH
ずほずんど䞀臎しおおり、前蚘(B)成分および(C)成
分の存圚ずこのPH領域ずが盞た぀お(A)成分の刺激
䜜甚が枛匱される。しかしおPHが前蚘範囲より倧
きいず(A)成分の溶解性が䜎䞋し、前蚘範囲より小
さいず(A)成分の県内移行量が䜎䞋する。PH調敎甚
の緩衝剀ずしおは県科孊的に蚱容しうるものであ
ればずくに制限されないが、たずえばリン酞二氎
玠カリりムずリン酞氎玠二ナトリりムの組合わせ
がずくに奜たしいものずしおあげられる。 本発明の点県液には前蚘成分以倖に塩化ナトリ
りム、塩化カリりム、ホり酞などの通垞の添加剀
を配合しおもよい。 本発明の点県液はたずえば高県圧緑内障患者に
〜滎皋床点県するず玄〜時間で正垞県圧
にもどる皋床にすぐれた県圧降䞋䜜甚を瀺す。 本発明の点県液の調補法はずくに制限されない
が、たずえば緩衝剀の氎溶液に(C)成分を添加溶解
し、぀いでこれに(A)成分ず(B)成分を添加溶解し、
えられた溶液に氎を加えお所望の濃床に調敎した
のち陀菌過するこずによ぀お調補される。媒䜓
の氎ずしおは通垞滅菌粟補氎が甚いられる。 ぀ぎに実斜䟋および比范䟋をあげお本発明の点
県液を説明する。 実斜䟋および比范䟋〜 第衚に瀺される凊方にしたが぀お点県液を調
敎した。(A)成分、(B)成分および(C)成分をPH5.0〜
8.0の緩衝液に溶解し、氎を加えお各点県液を調
補した。第衚においおBFEはベフノロヌルの
塩酞塩を意味する。
The present invention relates to a novel ophthalmic solution for adjusting intraocular pressure, particularly to an ophthalmic solution for regulating intraocular pressure that is effective in treating ocular hypertension or glaucoma. Pilocarpine eye drops have been widely used as an intraocular pressure regulator for ocular hypertension or glaucoma. However, pilocarpine eye drops not only lower intraocular pressure, but also act on the pupillary sphincter and ciliary body, and are known to have side effects such as a feeling of darkness due to miosis, accommodative disorders, and conjunctival hyperemia. Such side effects pose an extremely serious danger to those working in transportation and traffic-related fields in particular. Furthermore, in the case of elderly patients with cataracts, miosis will aggravate visual impairment. For these reasons, it is desired to develop an intraocular pressure regulator for ocular hypertension or glaucoma that can replace pilocarpine eye drops. Epinephrine ophthalmic solutions were born out of this need, but these ophthalmic solutions also have side effects such as conjunctival congestion, eyebrow pain, and allergic blepharoconjunctivitis, and can sometimes lead to increased intraocular pressure due to mydriasis. , is not used much. In addition, surface anesthetics, psychotropic agents, and other drugs have been clinically tried as drugs for lowering intraocular pressure in patients with glaucoma, but none of these have been put into practical use. Recently, β-receptor blockers have started to be seen as promising in this field, and 2-acetyl-7-(2-acetyl-7-
It has been found that benzofuran (hydroxy-3-isopropylaminopropoxy) (hereinafter abbreviated as befunolol) is also useful as an eye drop for the treatment of ocular hypertension or glaucoma. By the way, the basic properties that medicines should have include efficacy, safety, and stability. When looking at eye drops for the treatment of ocular hypertension or glaucoma, they have the effect of lowering intraocular pressure and have a moderate sustainability effect, and have no side effects, that is, they do not affect the pupillary accommodation mechanism and do not affect the refraction of the eye. It is required that the drug does not cause any harmful effects, has no irritating properties, and is stable as a formulation. Looking at the Befunolol ophthalmic solution from this perspective, its efficacy and safety have been demonstrated to a certain extent by Taikon et al. ("Ophthalmology Clinic Report")
(Refer to Vol. 73, No. 3, pp. 35-40 (1978)), but it still cannot be called a perfect eye drop. Therefore, the present inventors first discovered the fact that by mixing polyvinyl alcohol etc. with Befunolol eye drops, it is possible to formulate a more accurate and safer eye drop.
-52609 Publication) was completed. As a result of further research, we found that when hydroxypropyl methylcellulose was used in place of polyvinyl alcohol, we were able to formulate befunolol more accurately and safely as an eye drop.
That is, they discovered that it is possible to formulate a formulation that is effective at low concentrations, causes less local irritation, and is stable for a long period of time, leading to the completion of the present invention. That is, the present invention provides (A) an ophthalmologically acceptable water-soluble salt of befunolol in an amount of 0.05 to 4.0% (W/V
%, hereinafter the same), (B) 0.001 to 0.1% of benzalkonium chloride or benzethonium chloride, (C) 0.01 to 1.0% of hydroxypropyl methyl cellulose (HPMC, hereinafter the same), and with a buffering agent.
This invention relates to an eye drop for adjusting intraocular pressure, which has a pH adjusted to 5.0 to 8.0. The present invention shows that the intraocular hypotensive effect of befunolol depends on the amount of befunolol transferred into the eye, and that the amount of befunolol transferred into the eye depends on the presence of benzalkonium chloride or benzethonium chloride as component (B) and HPMC as component (C). Therefore, the increase is much greater than when polyvinyl alcohol is used, and the amount of befunolol transferred into the eye increases particularly in a specific pH range.Furthermore, the irritation of befunolol to the human eye is due to component (B). and that befunolol is further attenuated in the presence of component (C) and in the above specific PH range than when polyvinyl alcohol is used as component (C); This was completed based on the striking new finding that, in a specific pH range, this method is more stable for a longer period of time than when polyvinyl alcohol is used as component (C). Therefore, the eye drops of the present invention effectively lower the intraocular pressure in glaucoma eyes even with low concentrations of befunolol, have no side effects such as local irritation, and are stable for a long period of time. It is an extremely excellent eye drop that can effectively exert pharmacological effects. In the eye drops of the present invention, examples of ophthalmologically acceptable water-soluble salts of befunolol used as component (A) include hydrochloride, citrate, sulfate,
Examples include phosphates, maleates, and fumarates. Among these salts, hydrochloride is particularly preferred from the viewpoint of economical efficiency and stability after formulation. The concentration of component (A) needs to be 0.05 to 4.0%, and preferably 0.1 to 2.0%. (A)
If the concentration of the component is lower than the above range, the intraocular pressure lowering effect will not be significant, and if it is higher than the above range, it will not only be uneconomical but also develop local anesthetic effect, making it less desirable as a therapeutic agent for glaucoma. Component (B) acts as a normal preservative to prevent contamination by bacteria, etc., and together with component (C) described later, it promotes the corneal permeability of component (A) and increases the amount of it transferred into the eye. It is also equipped with the following functions. Preservatives such as methyl paraoxybenzoate and propyl paraoxybenzoate cannot be expected to increase the amount of component (A) transferred into the eye. As component (B), benzalkonium chloride is particularly preferred from the viewpoints of exhibiting a preservative effect at low concentrations, being effective against Pseudomonas aeruginosa, and having little irritation to the ocular mucosa. The concentration of component (B) needs to be 0.001 to 0.1%, and preferably 0.003 to 0.01%. If the concentration of component (B) is lower than the above range, the preservative effect will not be sufficient and the effect of increasing the amount of component (A) transferred into the eye will be poor, and if it is higher than the above range, undesirable effects such as local irritation will occur. It's coming. Component (C) adds viscosity to the eye drops to maintain the intraocular pressure lowering effect or protect the cornea, and together with component (B), promotes the corneal permeability of component (A) to increase the amount of its intraocular transfer. It has the effect of increasing the HPMC is used as the component (C). The concentration of component (C) needs to be 0.01 to 1.0, and preferably 0.1 to 0.5%. If the concentration of component (C) is lower than the above range, the sustained effect of lowering intraocular pressure and the protective effect on the cornea will be poor, and if the concentration of component (A) is lower than the above range, the effect of increasing the amount of intraocular transfer of component (A) will be poor. This not only makes it difficult to apply the eye drops, but also makes it uncomfortable to insert the eye drops. The ophthalmic solution of the present invention has a pH of 5.0 to 8.0, preferably 6.8 to 8.0.
Adjusted to 7.6. (A) The amount of ingredients transferred into the eye is
Increases in the PH region. Moreover, this PH range is the PH of tear fluid.
The presence of components (B) and (C) together with this PH range attenuates the stimulatory effect of component (A). However, if the pH is higher than the above range, the solubility of component (A) will decrease, and if it is lower than the above range, the amount of component (A) transferred into the eye will decrease. The buffering agent for pH adjustment is not particularly limited as long as it is ophthalmologically acceptable; for example, a combination of potassium dihydrogen phosphate and disodium hydrogen phosphate is particularly preferred. In addition to the above-mentioned components, the eye drops of the present invention may contain conventional additives such as sodium chloride, potassium chloride, and boric acid. When the eye drops of the present invention are injected into the eyes of a patient with high intraocular pressure glaucoma, for example, 1 to 2 drops exhibit an excellent effect of lowering intraocular pressure to the extent that the intraocular pressure returns to normal in about 3 to 4 hours. The method for preparing the eye drops of the present invention is not particularly limited, but for example, component (C) is added and dissolved in an aqueous solution of a buffer, then components (A) and (B) are added and dissolved therein,
It is prepared by adding water to the resulting solution to adjust it to the desired concentration, and then sterilizing and filtering it. Sterilized purified water is usually used as the water medium. Next, the ophthalmic solution of the present invention will be explained with reference to Examples and Comparative Examples. Example 1 and Comparative Examples 1 to 4 Eye drops were prepared according to the prescriptions shown in Table 1. (A) component, (B) component and (C) component at pH5.0~
Each eye drop was prepared by dissolving in 8.0 buffer and adding water. In Table 1, BFE means befunolol hydrochloride.

【衚】 実斜䟋の点県液は、リン酞二氎玠カリりム
無氎ずリン酞氎玠二ナトリりム12氎塩を
滅菌粟補氎に溶解した溶液80mlに塩化ナトリりム
を溶解し、これにHPMCを添加し、激しく撹拌
しお完党に溶解せしめ、぀いでBFEず10塩化
ベンザルコニりム溶液を添加し溶解せしめ、えら
れた溶液に滅菌粟補氎を加えお党量を100mlにし
たのち陀菌過するこずによ぀お調敎した。実斜
䟋の点県液は遮光容噚䞭に保存したばあいサン
ラむトボツクス40〜50℃、隔日6000ルツクス以
䞊䞭にカ月間攟眮しおも䜕ら倉化しなか぀
た。 比范䟋の点県液は、HPMCに代えおポリビ
ニルアルコヌルを甚いたほかは実斜䟋ず同様の
条件で調敎したずころ、実斜䟋ずた぀たく同様
の結果を瀺した。 比范䟋〜の点県液はリン酞二氎玠カリりム
無氎ずリン酞氎玠二ナトリりム12氎塩を
滅菌粟補氎に溶解した溶液80mlに塩化ナトリりム
を溶解し、぀いでBFEず10塩化ベンザルコニ
りム溶液比范䟋を添加するかあるいは
BFEずパラオキシ安息銙酞メチルおよびパラオ
キシ安息銙酞プロピルを添加比范䟋〜
し、玄60゜にお溶解せしめ、えられた溶液に滅菌
粟補氎を加えお党量を100mlにしたのち、陀菌
過するこずによ぀お調補した。 えられた点県液を぀ぎの詊隓に䟛した。 (1) BFEの県内移行量 各点県液を麻酔しない矜のりサギの目に
20Ό点県し、20分埌房氎をシリンゞで匕き出
し、房氎䞭のBFE濃床を枬定した。それぞれ
䞀矀矜、合蚈60矜のりサギを甚いお点県埌
時間、時間、時間および時間における房
氎䞭のBFE濃床を枬定した。結果を第図に
瀺す。第図における房氎䞭のBFE濃床は
矜のりサギの平均倀である。 (2) 県圧降䞋䜜甚 県圧蚈により各時間の県圧を枬定し、点県液
を点県する前の県圧ずの差〔県圧降䞋mm
Hg〕を求めた。結果を第図に瀺す。第図
における県圧降䞋mmHgは䞀矀矜のりサ
ギの平均倀である。 (3) 県に察する刺激䜜甚 幎什22〜39才の正垞な成人男子人の有志者
に各点県液を滎玄35Ό点県し、刺激の
皋床を芳察した。結果を第図に瀺す。第図
における刺激の皋床は぀ぎの基準によ぀た。 −た぀たく刺激を感じない。 わずかに刺激を感じる。 明確に刺激を感じる。 匷い刺激を感じる。 第〜図から明らかなごずく、BFEの県内
移行量および県圧降䞋䜜甚は塩化ベンザルコニり
ムおよびHPMCの存圚により増匷されるこず、
さらにヒトの県に察する刺激も塩化ベンザルコニ
りムおよびHPMCの存圚によ぀お枛匱されるこ
ずがわかる。 実斜䟋〜および比范䟋〜 リン酞二氎玠カリりム無氎ずリン酞氎玠二
ナトリりム12氎塩の䜿甚量を倉えお点県液の
PHを第衚に瀺すごずく倉曎したほかは実斜䟋
ず同様にしお点県液を調敎した。なおPH8.5の点
県液比范䟋は沈殿が生じ調敎が䞍可胜であ
぀た。 えられた各点県液に぀いお実斜䟋ず同様にし
お点県時間埌のBFEの県内移行量房氎䞭の
BFE濃床を調べた。結果を第衚に瀺す。
[Table] The eye drops of Example 1 were prepared by dissolving sodium chloride in 80 ml of a solution of potassium dihydrogen phosphate (anhydrous) and disodium hydrogen phosphate (12 hydrate) dissolved in sterile purified water, and adding HPMC to this solution. Add and stir vigorously to completely dissolve, then add and dissolve BFE and 10% benzalkonium chloride solution, add sterile purified water to the resulting solution to make a total volume of 100ml, and sterilize. Adjusted by. When the eye drop of Example 1 was stored in a light-shielding container, no change occurred even when it was left in a sunlight box (40-50°C, 6000 lux or more every other day) for one month. The eye drops of Comparative Example 1 were prepared under the same conditions as in Example 1 except that polyvinyl alcohol was used instead of HPMC, and the results were exactly the same as in Example 1. The eye drops of Comparative Examples 2 to 4 were prepared by dissolving sodium chloride in 80 ml of a solution of potassium dihydrogen phosphate (anhydrous) and disodium hydrogen phosphate (12 hydrate) dissolved in sterile purified water, and then adding BFE and 10% chloride. Add benzalkonium solution (Comparative Example 2) or
Addition of BFE and methyl paraoxybenzoate and propyl paraoxybenzoate (Comparative Examples 3 to 4)
The solution was dissolved at about 60°, sterilized purified water was added to the resulting solution to make a total volume of 100 ml, and the solution was sterilized and filtered. The obtained eye drops were subjected to the following test. (1) Amount of BFE transferred into the eye The eyes of three rabbits that were not anesthetized with each eye drop
A 20Ό drop was applied to the eye, and 20 minutes later, the aqueous humor was withdrawn with a syringe and the BFE concentration in the aqueous humor was measured. 1 after instillation using a total of 60 rabbits, 3 rabbits per group.
The BFE concentration in the aqueous humor was measured at 2 hours, 4 hours and 6 hours. The results are shown in Figure 1. The BFE concentration in the aqueous humor in Figure 1 is 3
This is the average value of rabbit feathers. (2) Intraocular pressure lowering effect Measure the intraocular pressure at each hour using a tonometer, and calculate the difference between the intraocular pressure before instilling the eye drops [intraocular pressure reduction (mm
Hg)] was calculated. The results are shown in Figure 2. The intraocular pressure drop (mmHg) in Figure 2 is the average value of three rabbits per group. (3) Eye irritation One drop (approximately 35 microns) of each eye drop was instilled into the eyes of six normal adult male volunteers aged 22 to 39 years old, and the degree of irritation was observed. The results are shown in Figure 3. The degree of stimulation in Figure 3 was based on the following criteria. -: I don't feel any stimulation. +: Slight irritation felt. : I feel clearly stimulated. : I feel a strong stimulation. As is clear from Figures 1 to 3, the amount of BFE transferred into the eye and the intraocular hypotensive effect are enhanced by the presence of benzalkonium chloride and HPMC;
Furthermore, it can be seen that irritation to human eyes is also attenuated by the presence of benzalkonium chloride and HPMC. Examples 2 to 4 and Comparative Examples 5 to 6 Eye drops were prepared by changing the amounts of potassium dihydrogen phosphate (anhydrous) and disodium hydrogen phosphate (decahydrate).
Example 1 except that the pH was changed as shown in Table 2.
Eye drops were prepared in the same manner as above. It should be noted that the eye drops with a pH of 8.5 (Comparative Example 6) caused precipitation and could not be adjusted. The amount of BFE transferred into the eye (in the aqueous humor) after 1 hour of instillation was carried out in the same manner as in Example 1 for each of the obtained eye drops.
BFE concentration) was investigated. The results are shown in Table 2.

【衚】 第衚から、PHが高くなるに぀れおBFEの県
内移行量が増倧し、PHが5.0〜8.0の範囲内の点県
液実斜䟋〜のばあいはBFEの県内移行
量が充分であるこずがわかる。PH5.0より䜎い点
県液比范䟋のばあいはBFEの県内移行量
が充分でない。なおPHが8.0より高くなるず前述
のごずく点県液の調補が䞍可胜である。 実斜䟋〜および比范䟋〜 塩化ベンザルコニりムの濃床を第衚に瀺すご
ずく倉曎したほかは実斜䟋ず同様にしお点県液
を調補した。 えられた各点県液に぀いお実斜䟋ず同様にし
お点県20分埌のBFEの県内移行量房氎䞭の
BFE濃床を調べた。結果を第衚に瀺す。
[Table] From Table 2, the amount of BFE transferred into the eye increases as the pH increases, and in the case of eye drops with a pH within the range of 5.0 to 8.0 (Examples 2 to 4), BFE transfer into the eye It can be seen that the amount is sufficient. In the case of an eye drop with a pH lower than 5.0 (Comparative Example 5), the amount of BFE transferred into the eye was insufficient. Note that if the pH is higher than 8.0, it is impossible to prepare eye drops as described above. Examples 5 to 9 and Comparative Examples 7 to 9 Eye drops were prepared in the same manner as in Example 1, except that the concentration of benzalkonium chloride was changed as shown in Table 3. The amount of BFE transferred into the eye (in the aqueous humor) after 20 minutes of instillation was carried out in the same manner as in Example 1 for each of the obtained eye drops.
BFE concentration) was investigated. The results are shown in Table 3.

【衚】 第衚から、塩化ベンザルコニりムの濃床が高
くなるに぀れおBFEの県内移行量が増倧し、塩
化ベンザルコニりムの濃床が0.001〜0.1の範囲
の点県液実斜䟋〜のばあいはBFEの県
内移行量が充分であるこずがわかる。塩化ベンザ
ルコニりムの濃床が0.001より䜎い点県液比
范䟋〜のばあいはBFEの県内移行量が充
分でなく、䞀方0.1より高い点県液比范䟋
のばあいはBFEの県内移行量がそれ以䞊増倧せ
ずか぀県粘膜に察する刺激が匷すぎるので奜たし
くない。 実斜䟋 10〜12 第衚に瀺される凊方にしたが぀お実斜䟋ず
同様にしお点県液を調補した。
[Table] Table 3 shows that as the concentration of benzalkonium chloride increases, the amount of BFE transferred into the eye increases. ) indicates that the amount of BFE transferred into the eye is sufficient. In the case of eye drops with a benzalkonium chloride concentration lower than 0.001% (Comparative Examples 7 to 8), the amount of BFE transferred into the eye is insufficient, while in the case of eye drops with a concentration of benzalkonium chloride higher than 0.1% (Comparative Example 9)
In this case, the amount of BFE transferred into the eye does not increase any further and the irritation to the ocular mucosa is too strong, which is not preferable. Examples 10-12 Eye drops were prepared in the same manner as in Example 1 according to the formulations shown in Table 4.

【衚】 えられた点県液はいずれもすぐれた県圧降䞋䜜
甚を瀺しか぀県に察する刺激も枛匱されおおり、
しかも安定性にすぐれたものであ぀た。
[Table] All of the obtained eye drops exhibited excellent intraocular hypotensive action and reduced eye irritation.
Moreover, it had excellent stability.

【図面の簡単な説明】[Brief explanation of drawings]

第〜図はそれぞれ実斜䟋および比范䟋
〜の点県液をりサギの県に点県したさいにおけ
る房氎䞭のBFE濃床の倉化および県圧の倉化を
瀺すグラフであり、第図は実斜䟋および比范
䟋〜の点県液をヒトの県に点県したさいにお
ける刺激頻床を瀺すグラフである。
Figures 1 and 2 are Example 1 and Comparative Example 1, respectively.
Fig. 3 is a graph showing changes in BFE concentration in the aqueous humor and changes in intraocular pressure when the eye drops of Example 1 and Comparative Examples 1 to 4 were applied to rabbit eyes. It is a graph showing the stimulation frequency when the eye is instilled.

Claims (1)

【特蚱請求の範囲】  (A)−アセチル−−−ヒドロキシ−
−む゜プロピルアミノプロポキシベンゟフラン
の県科孊的に蚱容しうる氎溶性の塩を0.05〜
4.0W、(B)塩化ベンザルコニりムたたは塩
化ベンれトニりムを0.001〜0.1W、(C)ヒド
ロキシプロピルメチルセルロヌスを0.01〜
1.0W含有しおなり、か぀緩衝剀でPHを5.0
〜8.0に調敎しおなる県圧調敎甚点県液。  (A)成分の濃床が0.1〜2.0Wである特蚱
請求の範囲第項蚘茉の点県液。  (B)成分の濃床が0.003〜0.01Wである
特蚱請求の範囲第項蚘茉の点県液。  (C)成分の濃床が0.1〜0.5Wである特蚱
請求の範囲第項蚘茉の点県液。  PHが6.8〜7.6である特蚱請求の範囲第項蚘
茉の点県液。  (A)成分が塩酞塩である特蚱請求の範囲第項
蚘茉の点県液。
[Claims] 1 (A) 2-acetyl-7-(2-hydroxy-3
- an ophthalmologically acceptable water-soluble salt of benzofuran (isopropylaminopropoxy) from 0.05 to
4.0W/V%, (B) benzalkonium chloride or benzethonium chloride from 0.001 to 0.1W/V%, (C) hydroxypropyl methylcellulose from 0.01 to
Contains 1.0W/V% and has a pH of 5.0 with a buffer.
Eye drops for adjusting intraocular pressure adjusted to ~8.0. 2. The eye drop according to claim 1, wherein the concentration of component (A) is 0.1 to 2.0 W/V%. 3. The eye drop according to claim 1, wherein the concentration of component (B) is 0.003 to 0.01 W/V%. 4. The eye drop according to claim 1, wherein the concentration of component (C) is 0.1 to 0.5 W/V%. 5. The eye drop according to claim 1, which has a pH of 6.8 to 7.6. 6. The eye drop according to claim 1, wherein component (A) is a hydrochloride.
JP9206780A 1979-09-06 1980-07-05 Eye drop for adjusting intraocular pressure Granted JPS5716817A (en)

Priority Applications (6)

Application Number Priority Date Filing Date Title
JP9206780A JPS5716817A (en) 1980-07-05 1980-07-05 Eye drop for adjusting intraocular pressure
CA000359015A CA1141663A (en) 1979-09-06 1980-08-26 Ophthalmic solution for intraocular pressure adjustment
DE8080105202T DE3064137D1 (en) 1979-09-06 1980-09-02 Ophthalmic solution for intraocular pressure adjustment
EP80105202A EP0025202B1 (en) 1979-09-06 1980-09-02 Ophthalmic solution for intraocular pressure adjustment
US06/183,756 US4382953A (en) 1979-09-06 1980-09-03 Ophthalmic solution for intraocular pressure reduction
ES494808A ES8107021A1 (en) 1979-09-06 1980-09-05 Ophthalmic solution for intraocular pressure adjustment.

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
JP9206780A JPS5716817A (en) 1980-07-05 1980-07-05 Eye drop for adjusting intraocular pressure

Publications (2)

Publication Number Publication Date
JPS5716817A JPS5716817A (en) 1982-01-28
JPS6410497B2 true JPS6410497B2 (en) 1989-02-22

Family

ID=14044117

Family Applications (1)

Application Number Title Priority Date Filing Date
JP9206780A Granted JPS5716817A (en) 1979-09-06 1980-07-05 Eye drop for adjusting intraocular pressure

Country Status (1)

Country Link
JP (1) JPS5716817A (en)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0673542B2 (en) * 1991-01-18 1994-09-21 有限䌚瀟アキダマ Deodorant aqueous solution composition
JP2005008596A (en) * 2003-06-20 2005-01-13 Kobayashi Pharmaceut Co Ltd Ophthalmological composition
JP4969052B2 (en) * 2005-03-31 2012-07-04 小林補薬株匏䌚瀟 Ophthalmic composition
EP2398443A2 (en) * 2009-02-20 2011-12-28 Micro Labs Limited Storage stable prostaglandin product
JP5627235B2 (en) * 2009-12-28 2014-11-19 小林補薬株匏䌚瀟 Ophthalmic composition

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5639013A (en) * 1979-09-06 1981-04-14 Kaken Pharmaceut Co Ltd Ophthalmic solution for regulating intraocular tension

Also Published As

Publication number Publication date
JPS5716817A (en) 1982-01-28

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