WO2004069822A1 - Composition for inhibiting steroid side effect - Google Patents

Composition for inhibiting steroid side effect Download PDF

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Publication number
WO2004069822A1
WO2004069822A1 PCT/JP2004/001173 JP2004001173W WO2004069822A1 WO 2004069822 A1 WO2004069822 A1 WO 2004069822A1 JP 2004001173 W JP2004001173 W JP 2004001173W WO 2004069822 A1 WO2004069822 A1 WO 2004069822A1
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Prior art keywords
intraocular pressure
steroid
composition
vitamin
suppressing
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PCT/JP2004/001173
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French (fr)
Japanese (ja)
Inventor
Kazuyuki Sasaki
Mitsuaki Kuwano
Masanobu Nagata
Fumitaka Tasaka
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Santen Pharmaceutical Co., Ltd.
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Publication of WO2004069822A1 publication Critical patent/WO2004069822A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/70—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with two hydrocarbon radicals attached in position 2 and elements other than carbon and hydrogen in position 6
    • C07D311/72—3,4-Dihydro derivatives having in position 2 at least one methyl radical and in position 6 one oxygen atom, e.g. tocopherols

Definitions

  • the present invention relates to a steroid-inhibiting intraocular pressure rise-inhibiting composition characterized by containing pitamine E, specifically, by mixing a steroid compound or a salt or ester thereof with vitamin E,
  • the present invention relates to a composition for suppressing steroid-induced increase in intraocular pressure.
  • Steroid compounds are widely used as therapeutic agents for various inflammatory diseases.
  • Steroid compounds used for ophthalmic applications include, for example, betamethasone, dexamethasone, prednisolone, methyl prednisolone, and fluorometron.
  • betamethasone in the case of continuous administration ⁇ in steroid-sensitive patients, local or systemic administration of steroid compounds has the side effect of increasing intraocular pressure induced by steroids. Steroid compounds must be administered under control. If the side effects are severe, it may be necessary to discontinue administration of steroid compounds.
  • Vitamin E is a pitamine that is abundant in embryos and soybeans, and includes ⁇ -, ⁇ -, ⁇ -, and ⁇ -tocopherol, which are known to improve infertility and growth disorders.
  • the present invention is a composition for suppressing steroid-induced intraocular pressure elevation, which comprises vitamin E. More specifically, the present invention is a composition for suppressing steroid-induced increase in intraocular pressure, which comprises a steroid compound or a salt or ester thereof and vitamin E.
  • vitamin E in the present invention examples include ⁇ -, ⁇ -, ⁇ -, ⁇ -tocopherol and their esters.
  • the blending amount of vitamin ⁇ is not particularly limited, but is 0.01 to 10% (/ ⁇ ), more preferably 0.0 ;! to 5.0% (wZv). If the amount of vitamin E is less than 0.01% (w / v), the effect of suppressing intraocular pressure rise is not sufficient, and if it exceeds 10% (wZV), a drug containing pitamine E Is difficult to prepare.
  • the type of the steroid compound is not particularly limited. The most common are betamethasone, prednisolone, triamcinolone or dexamethasone.
  • the salts of the steroid compounds of the present invention are There is no particular limitation as long as it is a pharmaceutically acceptable salt, and examples thereof include a sodium salt and a potassium salt.
  • ester of the steroid compound of the present invention is also particularly preferable if it is a pharmaceutically acceptable ester.
  • examples thereof include acetate, phosphate, (methsulfo) benzoate, maleate, formate, valerate and propionate.
  • composition of the present invention has an excellent inhibitory effect on steroid-induced increase in intraocular pressure, as is clear from the results of an intraocular pressure increase suppression test using a heron and a cat in the pharmacological test described below. However, it can be seen that an effect of suppressing an increase in intraocular pressure that occurs when various steroid compounds are administered is exhibited.
  • the composition of the present invention can be administered orally or parenterally.
  • the dosage forms include tablets, capsules, granules, powders, ointments, inhalants, eye drops, eye ointments, and injections. And the like, and particularly preferred are eye drops or injections. These can be formulated using commonly used techniques.
  • eye drops are prepared by appropriately mixing additives such as isotonicity agents, buffers, pH regulators, suspending agents, solubilizers, thickeners, stabilizers, and preservatives. can do.
  • a stable ophthalmic solution can be obtained by adding a thickener, a dispersant, a suspending agent, a solubilizing agent, and the like, and suspending or dissolving the steroid compound.
  • the tonicity agent include glycerin, propylene glycol, sodium chloride, potassium chloride, sorbitol, mannitol and the like.
  • buffer examples include phosphoric acid, phosphate, citric acid, acetic acid, ⁇ -aminocaproic acid, trometamol, and the like.
  • pH regulator examples include hydrochloric acid, citric acid, phosphoric acid, acetic acid, sodium hydroxide, potassium hydroxide, boric acid, borax, sodium carbonate, sodium hydrogen carbonate and the like.
  • suspending agent and the solubilizing agent examples include polysorbate 80, polyoxetylene hardened castor oil 60, macrogol 400 and the like.
  • thickener and dispersant examples include cellulosic polymers such as hydroxypropylmethylcellulose and hydroxypropylcellulose, and polypinyl alcohol and polypinylbilidone, and examples of the stabilizer include edetic acid and edetate. Acid sodium and the like can be mentioned.
  • preservatives examples include general-purpose sorbic acid, potassium sorbate, benzalkonium chloride, benzethonium chloride, methyl paraoxybenzoate, propyl paraoxybenzoate, chlorobutanol, and the like. It can also be used.
  • the pH of the eye drop of the present invention is desirably set to 4.0 to 8.5, and the osmotic pressure ratio is desirably set to around 1.0.
  • Injectables can be prepared by adding additives such as an osmotic pressure adjusting agent such as sodium chloride and a buffering agent such as sodium phosphate.
  • the method of subconjunctival administration may be the usual subconjunctival injection, and the procedure is relatively simple and the burden on the patient is small.
  • the Tenon's capsule near the conjunctiva may be injected. It is desirable that the pH of the injection is also set to 4.0 to 8.5, and that the osmotic pressure ratio is set to around 1.0.
  • the present invention also relates to a method for treating a disease that causes an increase in intraocular pressure, comprising administering to a patient the above-mentioned composition for suppressing intraocular pressure elevation, which is therapeutically effective.
  • the concentration of the steroid compound in the form of eye drops or injection in the present invention is 0.001 to 5% (w / V), preferably 0.01 to 2% (w / v).
  • the concentration of vitamin E is between 0.01 and 10% (w / v), preferably between 0.1 and 5% (wZV).
  • composition having the above concentration into the eye drop (once or several times a day) or subconjunctivally.
  • Figure 1 is a graph showing changes in intraocular pressure when betamethasone and vitamin E were combined and administered under the conjunctiva of a heron.
  • FIG. 2 is a graph showing changes in intraocular pressure when a cat was administered with a combination of betamethasone phosphate and vitamin E. BEST MODE FOR CARRYING OUT THE INVENTION
  • the composition of the present invention was applied to Japanese colored herons (strain: Dutch, gender: male) and cats (strain: Eur, gender: male). Each of the products was subjected to subconjunctival injection or ophthalmic administration to test the effect of suppressing intraocular pressure elevation.
  • BM methazone
  • VEA d- ⁇ -tocopherol acetate
  • BM 0.1 lg was added to this emulsion, and the mixture was dispersed using a mortar to obtain a suspension.
  • BM (0.1 lg) was added to a phosphate buffer (10 ml) and dispersed using a mortar to obtain a suspension.
  • the inhibitory effect of 1 mg / eye of BM (containing 2.5% VEA) on the increase in intraocular pressure was examined.
  • BMlmg ye alone the effect of 100 D was also examined.
  • the control was administered only with the base (phosphate buffer).
  • Colored herons (strain: Dutch, gender: male, 4 animals per group) were used as experimental animals. ⁇ 1% BM (containing 2.5% VEA), 1% BM and the base were injected into the both eyes of the heron eyeball conjunctiva three times, once a week at 100 L / eye each. The measurement of intraocular pressure was performed over 5 weeks using an applanation tonometer, and the difference from that immediately before administration was determined, and a comparison was made between the combination treatment group combining BM and VEA and the BM single treatment group .
  • Fig. 1 shows the results of an intraocular pressure rise suppression test using a heron.
  • the intraocular pressure change indicates a change value (average value) from the initial intraocular pressure.
  • the number of cases is 8 eyes each.
  • FIG. 1 when BM and VEA are administered together in the conjunctiva of a egret, an excellent inhibitory effect on steroid-induced increase in intraocular pressure is achieved.
  • BP Metasonadium phosphate
  • VEA Metasonadium phosphate
  • the 23 ⁇ 4BP solution was used as a control solution as it was.
  • Intraocular pressure was performed over 22 days using an applanation tonometer. The intraocular pressure difference between the instilled eye and the untreated eye was indicated by the difference between that immediately before administration and the combination of BP and VEA. A comparison was made between the combination treatment group and the BP alone treatment group.
  • Figure 2 shows the results of an intraocular pressure rise suppression test using cats.
  • the change in intraocular pressure indicates a change value (average value) from the initial intraocular pressure.
  • the number of cases is 3 eyes each.
  • BP alone showed an intraocular pressure-increasing effect
  • BM and VEA combined with ophthalmic administration to cats were superior against steroid-induced intraocular pressure increase. It has an effective suppression effect.
  • the present invention enables the development of a drug capable of suppressing the side effect of steroid-induced increase in intraocular pressure when a steroid compound is administered in the field of ophthalmic drugs.

Abstract

It is intended to inhibit a steroid-induced increase in eye pressure associating the administration of a steroid compound. An ophthalmic composition characterized by containing a steroid compound together with vitamin E exerts an excellent effect of inhibiting a steroid-induced increase in eye pressure, when dropped into eyes or subconjunctivally administered.

Description

明 細 書 ステロイ ド副作用抑制組成物 技術分野  Description Steroid side effect suppression composition Technical field
本発明は、 ピタミン Eを含有することを特徴とするステロイ ド誘発性の眼圧上 昇抑制組成物に関し、 具体的にはステロイ ド化合物またはその塩若しくはエステ ルとビタミン Eを配合することにより、 ステロイ ド誘発性の眼圧上昇を抑制する 組成物に関する。 背景技術  The present invention relates to a steroid-inhibiting intraocular pressure rise-inhibiting composition characterized by containing pitamine E, specifically, by mixing a steroid compound or a salt or ester thereof with vitamin E, The present invention relates to a composition for suppressing steroid-induced increase in intraocular pressure. Background art
眼科分野において、 ステロイ ド化合物は、 各種の炎症性疾患の治療剤と して広く用いられている。 眼科用途に用いられているステロイ ド化合物と しては、 例えばべタメ夕ゾン、 デキサメタゾン、 プレ ドニゾロン、 メチル プレ ドニゾロン、 フルォロメ トロンなどが挙げられる。 しかし、 継続投与 を行った場合ゃステロイ ド感受性の患者の場合には、 ステロイ ド化合物を 局所あるいは全身投与すればステロイ ド誘発性の眼圧上昇という副作用を 伴うので、 眼科医は注意深く この副作用をコン ト ロールしながらステロイ ド化合物を投与しなければならない。 また、 副作用が重篤な場合には、 や むを得ずステロイ ド化合物の投与を中止しなければならないこともある。 一方、 ビタミン Eは、胚芽や大豆などに多く含まれるピタミンであって、 α—、 β―、 γ―、 δ— トコフエロールがあり、 不妊症や成長障害などを改善すること で知られている。  In the field of ophthalmology, steroid compounds are widely used as therapeutic agents for various inflammatory diseases. Steroid compounds used for ophthalmic applications include, for example, betamethasone, dexamethasone, prednisolone, methyl prednisolone, and fluorometron. However, in the case of continuous administration ゃ in steroid-sensitive patients, local or systemic administration of steroid compounds has the side effect of increasing intraocular pressure induced by steroids. Steroid compounds must be administered under control. If the side effects are severe, it may be necessary to discontinue administration of steroid compounds. Vitamin E, on the other hand, is a pitamine that is abundant in embryos and soybeans, and includes α-, β-, γ-, and δ-tocopherol, which are known to improve infertility and growth disorders.
ビタミン Εを眼科用途に適用するものとしては、 「あたらしい眼科」 1 1 ( 1 ) : 7 9〜 8 3頁 （ 1 9 9 4年） にはメチルプレゾニゾロンにビタミン Εを in vitro で作用させると、摘出水晶体の白内障化を抑制することが報告されている。また、 Ophthalmic Res. , 31 (6), 440 - 445 (1999) には緑内障濾過手術後にビタミン Ε酢 酸エステルを結膜下に注射すると、 術後の一過性の眼圧上昇を抑制することが開 示されている。 As for the application of vitamin に for ophthalmic use, “New Ophthalmology” 11 (1): pp. 79-83 (1994) shows that vitamin に acts on methylprezonizone in vitro. It is reported that cataracts of the extracted lens are suppressed. Ophthalmic Res., 31 (6), 440-445 (1999) also reported that vitamin Ε vinegar after glaucoma filtration surgery. It has been shown that injection of acid esters subconjunctivally inhibits postoperative transient intraocular pressure rise.
しかしながら、 上記いずれの文献にも、 ステロイ ド化合物とビタミン Eを同時 に投与することによってステロイ ド誘発性の眼圧上昇を抑制できることは、 全く 示唆されていない。 発明の開示  However, none of the above documents suggest that simultaneous administration of a steroid compound and vitamin E can suppress steroid-induced increase in intraocular pressure. Disclosure of the invention
眼科薬の領域において、 ステロイ ド化合物を投与する場合にステロイ ド 誘発性の眼圧上昇という副作用を抑制できる薬剤の開発が望まれている。 本発明者らは、 ビタミン Eに着目 して鋭意研究を重ねた結果、 ステロイ ド化合物とビタミ ン Eを同時に投与することによ りステロイ ド誘発性の眼 圧上昇を効果的に抑制できることを見出し、 本発明に至った。  In the field of ophthalmic drugs, there is a demand for the development of a drug that can suppress the side effect of steroid-induced increase in intraocular pressure when a steroid compound is administered. The present inventors have conducted intensive studies focusing on vitamin E and found that simultaneous administration of a steroid compound and vitamin E can effectively suppress steroid-induced increase in intraocular pressure. The present invention has been achieved.
本発明は、 ビタミン Eを含有することを特徴とするステロイ ド誘発性の眼圧上 昇抑制組成物である。 より詳細には、 ステロイ ド化合物またはその塩若しくはェ ステルとビタミン Eを配合することを特徴とする、 ステロイ ド誘発性の眼圧上昇 を抑制する組成物である。  The present invention is a composition for suppressing steroid-induced intraocular pressure elevation, which comprises vitamin E. More specifically, the present invention is a composition for suppressing steroid-induced increase in intraocular pressure, which comprises a steroid compound or a salt or ester thereof and vitamin E.
本発明におけるビタミン Eとしては、 例えば α —、 β ―、 ァ 一、 δ — ト コフエロールおょぴそれらのエステルが挙げられる。  Examples of the vitamin E in the present invention include α-, β-, α-, δ-tocopherol and their esters.
ビタミン Εの配合量は特に制限されないが、 0 . 0 1〜 1 0 % ( / ν ) であ り、 より好ましくは 0 . ；!〜 5 . 0 % ( wZ v ) である。 ビタミン Eの配合量が 0 . 0 1 % (w/ v ) 未満では眼圧上昇を抑制する効果が充分でなく、 また、 1 0 % ( wZ V )を超える場合にはピタミン Eを配合した薬剤の調製が困難になる。 本発明においてはステロイ ド化合物の種類に特に制限はないが、 例えばべタメ 夕ゾン、 デキサメタゾン、 プレドニゾロン、 メチルプレドニゾロン、 フルォロメ トロン、 トリアムシノロン、 ハイ ド口コルチゾン、 ベクロメタゾン、 プロゲステ ロンなどが挙げられ、 より適切なものはべタメ夕ゾン、 プレドニゾロン、 トリア ムシノロン若しくはデキサメタゾンである。 本発明のステロイ ド化合物の塩は医 薬として許容される塩類であれば特に制限はなく、 例えばナトリウム塩、 力リウ ム塩などが挙げられ、 また、 本発明のステロイ ド化合物のエステルも、 医薬とし て許容されるエステルであれば特に制限はなく、 例えば酢酸エステル、 リン酸ェ ステル、 （メタスルホ） 安息香酸エステル、 マレイン酸エステル、 蟻酸エステル、 吉草酸エステル、 プロピオン酸エステルなどが挙げられる。 The blending amount of vitamin が is not particularly limited, but is 0.01 to 10% (/ ν), more preferably 0.0 ;! to 5.0% (wZv). If the amount of vitamin E is less than 0.01% (w / v), the effect of suppressing intraocular pressure rise is not sufficient, and if it exceeds 10% (wZV), a drug containing pitamine E Is difficult to prepare. In the present invention, the type of the steroid compound is not particularly limited. The most common are betamethasone, prednisolone, triamcinolone or dexamethasone. The salts of the steroid compounds of the present invention are There is no particular limitation as long as it is a pharmaceutically acceptable salt, and examples thereof include a sodium salt and a potassium salt. In addition, the ester of the steroid compound of the present invention is also particularly preferable if it is a pharmaceutically acceptable ester. There is no limitation, and examples thereof include acetate, phosphate, (methsulfo) benzoate, maleate, formate, valerate and propionate.
本発明の組成物は、 後述の薬理試験におけるゥサギおよびネコを用いた 眼圧上昇抑制試験の結果から明らかなように、 ステロイ ド誘発性の眼圧上 昇に対して優れた抑制作用を有するので、 種々のステロイ ド化合物を投与 する場合に生じる眼圧上昇を抑制する効果を発揮することがわかる。  Since the composition of the present invention has an excellent inhibitory effect on steroid-induced increase in intraocular pressure, as is clear from the results of an intraocular pressure increase suppression test using a heron and a cat in the pharmacological test described below. However, it can be seen that an effect of suppressing an increase in intraocular pressure that occurs when various steroid compounds are administered is exhibited.
本発明の組成物は、 経口でも、 非経口でも投与することができ、 その投与剤型 としては、 錠剤、 カプセル剤、 顆粒剤、 散剤、 軟膏剤、 吸入剤、 点眼剤、 眼軟膏、 注射剤等が挙げられるが、 特に点眼剤または注射剤が好ましい。 これらは汎用さ れている技術を用いて製剤化することができる。 例えば、 点眼剤は、 添加物として、 等張化剤、 緩衝剤、 p H調節剤、 懸濁化剤 、 可溶化剤、 增粘剤、 安定化剤、 保存剤等を適宜配合して、 調製することができ る。 また、 増粘剤、 分散剤、 懸濁化剤、 可溶化剤などを添加し、 ステロイ ド化合 物を懸濁あるいは溶解させることによって、 安定な点眼液を得ることができる。 等張化剤としては、 例えばグリセリン、 プロピレングリコール、 塩化ナトリウ ム、 塩化カリウム、 ソルビトール、 マンニトール等を挙げることができる。  The composition of the present invention can be administered orally or parenterally. The dosage forms include tablets, capsules, granules, powders, ointments, inhalants, eye drops, eye ointments, and injections. And the like, and particularly preferred are eye drops or injections. These can be formulated using commonly used techniques. For example, eye drops are prepared by appropriately mixing additives such as isotonicity agents, buffers, pH regulators, suspending agents, solubilizers, thickeners, stabilizers, and preservatives. can do. In addition, a stable ophthalmic solution can be obtained by adding a thickener, a dispersant, a suspending agent, a solubilizing agent, and the like, and suspending or dissolving the steroid compound. Examples of the tonicity agent include glycerin, propylene glycol, sodium chloride, potassium chloride, sorbitol, mannitol and the like.
緩衝剤としては例えば、 リン酸、 リン酸塩、 クェン酸、 酢酸、 ε -アミノカプロ ン酸、 トロメタモール等を挙げることができる。  Examples of the buffer include phosphoric acid, phosphate, citric acid, acetic acid, ε-aminocaproic acid, trometamol, and the like.
p H調節剤としては、 例えば塩酸、 クェン酸、 リン酸、 酢酸、 水酸化ナトリウ ム、 水酸化カリウム、 ホウ酸、 ホウ砂、 炭酸ナトリウム、 炭酸水素ナトリウム等 を挙げることができる。  Examples of the pH regulator include hydrochloric acid, citric acid, phosphoric acid, acetic acid, sodium hydroxide, potassium hydroxide, boric acid, borax, sodium carbonate, sodium hydrogen carbonate and the like.
懸濁化剤、 可溶化剤としては、 例えばポリソルべ一ト 8 0、 ポリォキシェチレ ン硬化ヒマシ油 6 0、 マクロゴール 4 0 0等を挙げることができる。 増粘剤、 分散剤としては、 例えばヒドロキシプロピルメチルセルロース、 ヒド ロキシプロピルセルロースなどのセルロース系高分子、 ポリピニルアルコール、 ポリピニルビ口リ ドン等を、 また、 安定化剤としては、 例えばェデト酸、 ェデト 酸ナトリゥム等を挙げることができる。 Examples of the suspending agent and the solubilizing agent include polysorbate 80, polyoxetylene hardened castor oil 60, macrogol 400 and the like. Examples of the thickener and dispersant include cellulosic polymers such as hydroxypropylmethylcellulose and hydroxypropylcellulose, and polypinyl alcohol and polypinylbilidone, and examples of the stabilizer include edetic acid and edetate. Acid sodium and the like can be mentioned.
保存剤 （防腐剤） としては、 汎用のソルピン酸、 ソルビン酸カリウム、 塩化べ ンザルコニゥム、 塩化べンゼトニゥム、 パラォキシ安息香酸メチル、 パラォキシ 安息香酸プロピル、 クロロブ夕ノール等が挙げられ、 これらの保存剤を組み合わ せて使用することもできる。  Examples of preservatives (preservatives) include general-purpose sorbic acid, potassium sorbate, benzalkonium chloride, benzethonium chloride, methyl paraoxybenzoate, propyl paraoxybenzoate, chlorobutanol, and the like. It can also be used.
本発明の点眼剤の P Hは 4 . 0 ~ 8 . 5に設定することが望ましく、 また、 浸 透圧比を 1 . 0付近に設定することが望ましい。  The pH of the eye drop of the present invention is desirably set to 4.0 to 8.5, and the osmotic pressure ratio is desirably set to around 1.0.
また、 注射剤は、 例えば塩化ナトリウムなどの浸透圧調整剤、 リン酸ナトリウ ムなどの緩衝剤等の添加剤を加えて、 調製することができる。 結膜下への投与方 法は、 通常行なわれている結膜下注射を用いればよく、 手技は比較的簡便で、 か つ、患者への負担も少ない。なお、結膜近傍にあるテノン嚢に注射をしてもよい。 注射剤の p Hも 4 . 0 ~ 8 . 5に設定することが望ましく、 また、 浸透圧比を 1 . 0付近に設定することが望ましい。  Injectables can be prepared by adding additives such as an osmotic pressure adjusting agent such as sodium chloride and a buffering agent such as sodium phosphate. The method of subconjunctival administration may be the usual subconjunctival injection, and the procedure is relatively simple and the burden on the patient is small. The Tenon's capsule near the conjunctiva may be injected. It is desirable that the pH of the injection is also set to 4.0 to 8.5, and that the osmotic pressure ratio is set to around 1.0.
本発明は、 上記眼圧上昇抑制組成物を患者に治療に有効な量投与することから なる、 眼圧上昇をきたす疾患の治療方法にも関する。  The present invention also relates to a method for treating a disease that causes an increase in intraocular pressure, comprising administering to a patient the above-mentioned composition for suppressing intraocular pressure elevation, which is therapeutically effective.
本発明におけるステロイ ド化合物の点眼剤や注射剤としての濃度は、 0 . 0 0 1 ~ 5 % ( w / V ) , 好ましくは 0 . 0 1 ~ 2 % ( w / v ) であり、 また、 ビタミ ン Eの濃度は、 0 . 0 1〜： 1 0 % (w / v ) , 好ましくは 0 . 1〜 5 % (wZ V ) である。  The concentration of the steroid compound in the form of eye drops or injection in the present invention is 0.001 to 5% (w / V), preferably 0.01 to 2% (w / v). The concentration of vitamin E is between 0.01 and 10% (w / v), preferably between 0.1 and 5% (wZV).
本発明の眼圧上昇抑制組成物は、 上記濃度のものを点眼（ 1 日 1回または数回） または結膜下に注射することが好ましい。  It is preferable to inject the composition having the above concentration into the eye drop (once or several times a day) or subconjunctivally.
ゥサギを用いた眼圧上昇抑制試験 （結膜下投与） およびネコを用いた眼圧上昇 抑制試験 （点眼投与） の項で詳述するが、 ステロイ ド化合物とビタミン Eを配合 した眼圧上昇抑制組成物を眼に投与すれば、 ステロイ ド化合物の投与に伴う眼圧 上昇に対して優れた抑制効果を発揮する。 したがって、 本発明のビタミン Eを含 有することを特徴とする眼科用組成物は、 ステロイ ド誘発性の眼圧上昇を抑制す ることができる。 図面の簡単な説明 す る Details in the IOP suppression test using a heron (subconjunctival administration) and the IOP suppression test using cats (ophthalmic administration) contain a steroid compound and vitamin E. When the composition for suppressing an increase in intraocular pressure is administered to the eye, the composition exerts an excellent inhibitory effect on the increase in intraocular pressure accompanying the administration of a steroid compound. Therefore, the ophthalmic composition characterized by containing the vitamin E of the present invention can suppress steroid-induced increase in intraocular pressure. BRIEF DESCRIPTION OF THE FIGURES
図 1 は、 ベタメタゾンとビタミ ン Eを組み合わせてゥサギの結膜下に投 与した場合の眼圧変化を示すグラフである。  Figure 1 is a graph showing changes in intraocular pressure when betamethasone and vitamin E were combined and administered under the conjunctiva of a heron.
図 2は、 リ ン酸ベタメタゾンとビタミン Eを組み合わせてネコに点眼投 与した場合の眼圧変化を示すグラフである。 発明を実施するための最良の形態  FIG. 2 is a graph showing changes in intraocular pressure when a cat was administered with a combination of betamethasone phosphate and vitamin E. BEST MODE FOR CARRYING OUT THE INVENTION
以下に製剤例および薬理試験の結果を示すが、 これらの実施例は、 本発明をよ りよく理解するためのものであり、 本発明の範囲を限定するものではない。  The formulation examples and the results of the pharmacological tests are shown below, but these examples are for better understanding of the present invention and do not limit the scope of the present invention.
[薬理試験]  [Pharmacological test]
ビタミ ン Eのステロイ ド誘発性の眼圧上昇に対する抑制効果を調べるた め、 日本有色ゥサギ （系統： Du t ch, 性別 ：雄性） およびネコ （系統： Eur,性別 ： 雄性） に本発明の組成物をそれぞれ、 結膜下注射あるいは点眼投与して眼圧上昇 抑制効果試験を実施した。  To examine the inhibitory effect of vitamin E on the steroid-induced increase in intraocular pressure, the composition of the present invention was applied to Japanese colored herons (strain: Dutch, gender: male) and cats (strain: Eur, gender: male). Each of the products was subjected to subconjunctival injection or ophthalmic administration to test the effect of suppressing intraocular pressure elevation.
1 . ゥサギを用いた眼圧上昇抑制試験 1. Intraocular pressure increase suppression test using Egret
(被験化合物含有液の調製）  (Preparation of test compound-containing solution)
ステロイ ド化合物としてはべ夕メタゾン （以下、 B Mとする）、 ビタミン Eとし ては酢酸 d— α — トコフエロール （以下、 V E Aとする） を用いた。 エタノール に V E A (0. 25g)とポリソルべ一ト 8 0 (0. 125g)を溶解させ、エタノールを蒸発除 去した後、 60でに加温したリン酸緩衝液（10ml)を加え、 室温下で分散 '攪拌し、 乳 濁液を調製した。 ついで、 この乳濁液に B M (0. l g)を加え、 乳鉢を用いて分散さ せ、 懸濁液を得た。 (比較対照液の調製） As a steroid compound, methazone (hereinafter referred to as BM) was used, and as vitamin E, d-α-tocopherol acetate (hereinafter, referred to as VEA) was used. Dissolve VEA (0.25 g) and polysorbate 80 (0.125 g) in ethanol, evaporate and remove ethanol, add phosphate buffer (10 ml) heated at 60, add room temperature And stirred to prepare an emulsion. Next, BM (0.1 lg) was added to this emulsion, and the mixture was dispersed using a mortar to obtain a suspension. (Preparation of comparative control solution)
リン酸緩衝液（lOml)に、 BM(0. lg)を加え、 乳鉢を用いて分散させ、 懸濁液を 得た。  BM (0.1 lg) was added to a phosphate buffer (10 ml) and dispersed using a mortar to obtain a suspension.
(投与方法および測定方法）  (Administration method and measurement method)
BM1 mg/eye ( 2.5%VEA含有） の眼圧上昇抑制効果を検討した。 比較対照 として、 BMlmg ye単独投与 （100 D による効果も検討した。 コントロー ルには、 基剤 （リン酸緩衝液） のみを投与した。  The inhibitory effect of 1 mg / eye of BM (containing 2.5% VEA) on the increase in intraocular pressure was examined. As a control, the effect of BMlmg ye alone (the effect of 100 D was also examined. The control was administered only with the base (phosphate buffer).
実験動物として、 有色ゥサギ （系統： Dutch、 性別 ：雄性、 一群 4匹） を使用 した。 ゥサギ眼球結膜下に 1 % BM (2.5%VEA含有）、 1 %BMおよび基剤を それぞれ 100 L/eye で週 1回、 計 3回、 両眼に注射した。 眼圧の測定は、 圧平 式眼圧計を用いて 5週間に渡って行い、 投与直前時のものとの差を求め、 BM と V E Aを併用した配合剤投与群と B M単独投与群で比較した。  Colored herons (strain: Dutch, gender: male, 4 animals per group) were used as experimental animals.ゥ 1% BM (containing 2.5% VEA), 1% BM and the base were injected into the both eyes of the heron eyeball conjunctiva three times, once a week at 100 L / eye each. The measurement of intraocular pressure was performed over 5 weeks using an applanation tonometer, and the difference from that immediately before administration was determined, and a comparison was made between the combination treatment group combining BM and VEA and the BM single treatment group .
(結果および考察）  (Results and Discussion)
ゥサギを用いた眼圧上昇抑制試験の結果を図 1に示す。 眼圧変化は、 初期眼圧 からの変化値 （平均値） を示す。 なお、 例数は各 8眼である。 図 1から明らかな ように、 BMと VE Aを併用してゥサギの結膜下に投与すれば、 ステロイ ド誘発 性の眼圧上昇に対して優れた抑制効果を奏する。  Fig. 1 shows the results of an intraocular pressure rise suppression test using a heron. The intraocular pressure change indicates a change value (average value) from the initial intraocular pressure. The number of cases is 8 eyes each. As is evident from FIG. 1, when BM and VEA are administered together in the conjunctiva of a egret, an excellent inhibitory effect on steroid-induced increase in intraocular pressure is achieved.
2. ネコを用いた眼圧上昇抑制試験 2. Intraocular pressure increase suppression test using cats
(被験化合物含有液の調製）  (Preparation of test compound-containing solution)
ステロイ ド化合物としてはリン酸べ夕メタゾンナトリゥム（以下、 B Pとする）、 ビタミン Eとしては V E Aを用いた。 エタノールに V E A (0.5g)とポリソルベー ト 80 (0.25g)を溶解させ、 エタノールを蒸発除去後、 60 に加温した 2%B P溶 液（10ml)を加え、 室温下で分散 '攪拌し、 乳濁液を得た。  Metasonadium phosphate (hereinafter referred to as BP) was used as a steroid compound, and VEA was used as vitamin E. Dissolve VEA (0.5 g) and polysorbate 80 (0.25 g) in ethanol, remove the ethanol by evaporation, add 2% BP solution (10 ml) heated to 60, disperse at room temperature, stir, A suspension was obtained.
(比較対照液の調製）  (Preparation of comparative control solution)
2¾B P溶液をそのまま比較対照液として用いた。  The 2¾BP solution was used as a control solution as it was.
(投与方法および測定方法）  (Administration method and measurement method)
2 % B P (5.0%VE A含有）の眼圧上昇抑制効果を検討した。比較対照として、 2 % B P単独投与による効果も検討した。 対側眼は点眼未処置とした。 実験動物 として、 ネコ （系統： Eur、 性別 ：雄性、 一群 3 匹） を使用した。 点眼はネコ片 眼に 2% B P (5.0% V E A含有） あるいは 2 % B Pを 1回 1 0 L、 1 日 2回、 2 2 日間行った。 The effect of 2% BP (containing 5.0% VE A) on suppressing intraocular pressure rise was examined. As a control, The effect of 2% BP alone was also examined. The contralateral eye was untreated. Cats (strain: Eur, gender: male, 3 animals per group) were used as experimental animals. Instillation was performed on one cat with 2% BP (containing 5.0% VEA) or 2% BP once 10 L twice daily for 22 days.
眼圧の測定は、 圧平式眼圧計を用いて 2 2 日間に渡って行い、 点眼眼と未処置 眼との眼圧差を投与直前時のものとの差で示し、 B Pと V E Aを併用した配合 剤投与群と B P単独投与群で比較した。  Measurement of intraocular pressure was performed over 22 days using an applanation tonometer.The intraocular pressure difference between the instilled eye and the untreated eye was indicated by the difference between that immediately before administration and the combination of BP and VEA. A comparison was made between the combination treatment group and the BP alone treatment group.
(結果および考察）  (Results and Discussion)
ネコを用いた眼圧上昇抑制試験の結果を図 2に示す。 眼圧変化は、 初期眼圧か らの変化値 （平均値） を示す。 なお、 例数は各 3眼である。 図 2から明らかなよ うに、 B P単独投与では、 眼圧上昇作用を示すのに対し、 B Mと VE Aを併用し てネコに点眼投与すれば、 ステロイ ド誘発性の眼圧上昇に対して優れた抑制効果 を奏する。  Figure 2 shows the results of an intraocular pressure rise suppression test using cats. The change in intraocular pressure indicates a change value (average value) from the initial intraocular pressure. The number of cases is 3 eyes each. As is evident from Fig. 2, BP alone showed an intraocular pressure-increasing effect, while BM and VEA combined with ophthalmic administration to cats were superior against steroid-induced intraocular pressure increase. It has an effective suppression effect.
[製剤例]  [Formulation example]
1. 点眼剤 1. Eye drops
本発明のステロイ ド化合物とビタミン Eを組み合わせた点眼剤の一般的な製剤 例を以下に示す。  Examples of general formulations of eye drops obtained by combining the steroid compound of the present invention with vitamin E are shown below.
処方 1 ( 1 0 0 m L中） Prescription 1 (in 100 mL)
リン酸べタメ夕ゾンナトリウム 0. l g 酢酸 d— 一トコフエ口一ル 1. 0 g 濃グリセリン 0. 5 g ポリソルべ一ト 80 0. 5 g  Betame dilute sodium phosphate 0.1 g l-acetic acid d-per tocophore 1.0 g concentrated glycerin 0.5 g polysorbate 80 0.5 g
塩化ナトリウム 適量  Sodium chloride
リン酸二水素ナトリウム二水和物 適量  Sodium dihydrogen phosphate dihydrate qs
1 N水酸化ナトリウム 適量  1 N sodium hydroxide
塩酸 適量 滅菌精製水 適 処方 2 ( 1 0 0 m L中） Hydrochloric acid Suitable for sterile purified water Formulation 2 (in 100 mL)
リン酸べタメタゾンナトリウム 2 g 酢酸 d— α— トコフエロール 5 g 濃グリセリン 0. 5 ポリソルべ一ト 8 0 2. 5 g 塩化ナトリウム 適量  Betamethasone sodium phosphate 2 g Acetic acid d-α-Tocopherol 5 g Concentrated glycerin 0.5 Polysorbate 8 0 2.5 g Sodium chloride qs
リン酸二水素ナトリウム二水和物 適量  Sodium dihydrogen phosphate dihydrate qs
1 N水酸化ナトリウム 適量  1 N sodium hydroxide
塩酸 適量  Hydrochloric acid
滅菌精製水 適量  Appropriate amount of sterilized purified water
2. 注射剤 2. Injection
本発明のステロイ ド化合物とビタミン Eを組み合わせた注射剤の一般的な製剤 例を以下に示す。  Examples of general preparations of injections comprising the steroid compound of the present invention and vitamin E in combination are shown below.
処方 1 ( 1 0 0 m L中） Prescription 1 (in 100 mL)
リン酸べタメタゾンナトリウム l g 酢酸 d— a— トコフエロール 2. 5 g ポリソルべ一ト 8 0 1. 2 5 g 生理食塩水 適量 産業上の刺用可能 ft  Betamethasone sodium phosphate l g Acetic acid d—a—Tocopherol 2.5 g Polysorbate 8 0 1.2 5 g Physiological saline qs Industrial piercing possible ft
本発明は、 眼科薬の領域において、 ステロイ ド化合物を投与する場合 にステロイ ド誘発性の眼圧上昇という副作用を抑制できる薬剤の開発を可 能にするものである。  INDUSTRIAL APPLICABILITY The present invention enables the development of a drug capable of suppressing the side effect of steroid-induced increase in intraocular pressure when a steroid compound is administered in the field of ophthalmic drugs.

Claims

請求の範囲 The scope of the claims
1 . ビタミン Eを含有することを特徴とするステロイ ド誘発性の眼圧上昇 抑制組成物。 1. A composition for suppressing steroid-induced increase in intraocular pressure, comprising vitamin E.
2 . ステロイ ド化合物またはその塩若しくはそのエステルとビタミン Eを 配合することを特徴とするステロイ ド誘発性の眼圧上昇抑制組成物。  2. A composition for inhibiting steroid-induced increase in intraocular pressure, comprising a steroid compound or a salt or ester thereof and vitamin E.
3 . ステロイ ド化合物が、 ベタメタゾン、 プレドニゾロン、 トリアムシノ ロンまたはデキサメタゾンである請求項 2記載の眼圧上昇抑制組成物。  3. The composition according to claim 2, wherein the steroid compound is betamethasone, prednisolone, triamcinolone or dexamethasone.
4 . ビタミン Eの配合量が 0 . 0 1 ~ 1 0 % ( w / V ) である請求項 2記 載の眼圧上昇抑制組成物。  4. The composition for suppressing intraocular pressure elevation according to claim 2, wherein the amount of vitamin E is 0.01 to 10% (w / V).
5 . 眼圧上昇抑制組成物の剤型が、 点眼剤または注射剤である請求項 2記 載の眼圧上昇抑制組成物。  5. The composition for suppressing intraocular pressure elevation according to claim 2, wherein the dosage form of the composition for suppressing intraocular pressure elevation is an eye drop or an injection.
6 . 請求項 1から 5のいずれかに記載の眼圧上昇抑制組成物を患者に治療 に有効な量投与することからなる、ステロイ ド誘発性の眼圧上昇を抑制する方法。  6. A method for suppressing steroid-induced intraocular pressure increase, comprising administering to a patient a therapeutically effective amount of the composition for suppressing intraocular pressure increase according to any one of claims 1 to 5.
7 . 眼圧上昇抑制剤の製造のための、 請求項 1から 5のいずれかに記載の 眼圧上昇抑制組成物の使用。 7. Use of the intraocular pressure rise-suppressing composition according to any one of claims 1 to 5 for the manufacture of an intraocular pressure rise inhibitor.
^圧変化（mmHg) ^ Pressure change (mmHg)
Figure imgf000011_0001
Figure imgf000011_0001
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WO2018230713A1 (en) 2017-06-16 2018-12-20 学校法人同志社 Compounds having caspase inhibitory activity, pharmaceutical agent containing said compounds and for treating or preventing corneal endothelial symptoms, disorders, or diseases, and application of said pharmaceutical agent
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Publication number Priority date Publication date Assignee Title
WO2018230713A1 (en) 2017-06-16 2018-12-20 学校法人同志社 Compounds having caspase inhibitory activity, pharmaceutical agent containing said compounds and for treating or preventing corneal endothelial symptoms, disorders, or diseases, and application of said pharmaceutical agent
US11433090B2 (en) 2017-06-16 2022-09-06 The Doshisha mTOR-inhibitor-containing medicine for treating or preventing ophthalmic symptoms, disorders, or diseases, and application thereof

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