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WO2004069822A1 - Composition pour inhiber un effet secondaire de steroides - Google Patents

Composition pour inhiber un effet secondaire de steroides 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
Authority
WO
WIPO (PCT)
Prior art keywords
intraocular pressure
steroid
composition
vitamin
suppressing
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.)
Ceased
Application number
PCT/JP2004/001173
Other languages
English (en)
Japanese (ja)
Inventor
Kazuyuki Sasaki
Mitsuaki Kuwano
Masanobu Nagata
Fumitaka Tasaka
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.)
Santen Pharmaceutical Co Ltd
Original Assignee
Santen 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 Santen Pharmaceutical Co Ltd filed Critical Santen Pharmaceutical Co Ltd
Publication of WO2004069822A1 publication Critical patent/WO2004069822A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Ophthalmology & Optometry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne l'inhibition d'une augmentation de la pression oculaire induite des stéroïdes, associée à l'administration d'un composé stéroïdique. L'invention concerne une composition ophtalmique caractérisée en ce qu'elle contient un composé stéroïdique, ainsi que de la vitamine E. Cette composition présente un excellent effet d'inhibition de l'augmentation de la pression oculaire induite par des stéroïdes, lorsqu'elle est instillée dans les yeux ou de manière sous-conjonctivale.
PCT/JP2004/001173 2003-02-05 2004-02-05 Composition pour inhiber un effet secondaire de steroides Ceased WO2004069822A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2003028159 2003-02-05
JP2003-028159 2003-02-05

Publications (1)

Publication Number Publication Date
WO2004069822A1 true WO2004069822A1 (fr) 2004-08-19

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ID=32844193

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2004/001173 Ceased WO2004069822A1 (fr) 2003-02-05 2004-02-05 Composition pour inhiber un effet secondaire de steroides

Country Status (1)

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WO (1) WO2004069822A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018230713A1 (fr) 2017-06-16 2018-12-20 学校法人同志社 Composés ayant une activité inhibitrice de caspase, agent pharmaceutique les contenant pour le traitement ou la prévention des symptômes, troubles ou maladies de l'endothélium cornéen, et application dudit agent pharmaceutique
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

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002047183A (ja) * 2000-06-16 2002-02-12 Matthias Rath 人体の機関の平滑筋細胞の収縮によって生じる健康状態の予防および治療用組成物に生物化学物質を用いる方法

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002047183A (ja) * 2000-06-16 2002-02-12 Matthias Rath 人体の機関の平滑筋細胞の収縮によって生じる健康状態の予防および治療用組成物に生物化学物質を用いる方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
EVANS S.C.: "Ophthalmic Nutrition and Prevention of Eye Disorder and Blindness", NUTRITION AND METABOLISM, vol. 21 (SUPPL.1), 1977, pages 268 - 272, XP002979729 *
TRIPATHI R.C. ET AL: "Corticosteroids and Glaucoma Risk", DRUGS AND AGING, vol. 15, no. 6, 1999, pages 439 - 450, XP002979730 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018230713A1 (fr) 2017-06-16 2018-12-20 学校法人同志社 Composés ayant une activité inhibitrice de caspase, agent pharmaceutique les contenant pour le traitement ou la prévention des symptômes, troubles ou maladies de l'endothélium cornéen, et application dudit agent pharmaceutique
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
US12343356B2 (en) 2017-06-16 2025-07-01 The Doshisha mTOR-inhibitor-containing medicine for treating or preventing ophthalmic symptoms, disorders, or diseases, and application thereof

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