WO2001066561A1 - Medicaments preventifs ou therapeutiques contre des maladies des yeux - Google Patents

Medicaments preventifs ou therapeutiques contre des maladies des yeux Download PDF

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Publication number
WO2001066561A1
WO2001066561A1 PCT/JP2001/001756 JP0101756W WO0166561A1 WO 2001066561 A1 WO2001066561 A1 WO 2001066561A1 JP 0101756 W JP0101756 W JP 0101756W WO 0166561 A1 WO0166561 A1 WO 0166561A1
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WO
WIPO (PCT)
Prior art keywords
group
intraocular pressure
ophthalmic solution
prescription
day
Prior art date
Application number
PCT/JP2001/001756
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English (en)
Japanese (ja)
Inventor
Koichi Ito
Atsushi Hattori
Original Assignee
Kissei Pharmaceutical Co., Ltd.
Nihon Tenganyaku 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 Kissei Pharmaceutical Co., Ltd., Nihon Tenganyaku Co., Ltd. filed Critical Kissei Pharmaceutical Co., Ltd.
Priority to AU2001241045A priority Critical patent/AU2001241045A1/en
Publication of WO2001066561A1 publication Critical patent/WO2001066561A1/fr

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Classifications

    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • 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
    • A61P27/06—Antiglaucoma agents or miotics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane

Definitions

  • the present invention relates to a prophylactic / therapeutic agent for eye diseases c
  • the present invention provides a formula
  • KSR-592 17 ⁇ -methyl methyl rubonate
  • the present invention relates to an agent for preventing and treating a disease.
  • the steroid compound represented by the formula (I), which is contained as an active ingredient in the prophylactic / therapeutic agent for ophthalmic diseases of the present invention, is represented by the general formula:
  • R ' is a free hydroxyl group or a hydroxyl group esterified with a carboxylic acid having up to 7 carbon atoms
  • R ⁇ is a methyl or methylene group in ⁇ - or 3-configuration
  • R ′ and may be taken together to represent a 16,17-dihydroxyacetonide group
  • X is hydrogen or chlorine atom
  • ⁇ is chlorine or fluorine atom
  • steroid compounds including the steroid compound represented by the above general formula (II), exhibit anti-inflammatory activity in rat foreign body granuloma test, and are used as anti-inflammatory drugs, especially in dermatology. It only states that it can be done, but does not show any specific data showing the effects and effects, and does not describe any application to eye diseases. There is no report or suggestion that KSR-592 represented by the above formula (I) of the present invention has an intraocular pressure increase suppressing effect or an intraocular pressure decreasing effect.
  • steroid compounds have an intraocular pressure-increasing effect, and there is a concern that side effects such as steroid glaucoma may occur due to the intraocular pressure-increasing effect. Therefore, steroidal anti-inflammatory drugs cannot always be applied to ocular diseases.
  • CH-, COCHg As a steroid compound having a strong anti-inflammatory effect and a reduced intraocular pressure increasing effect, CH-, COCHg
  • Fluorometron represented by is known, but shows a tendency to increase intraocular pressure after long-term administration.
  • steroid compounds generally have a strong intraocular pressure-increasing effect, and the occurrence of side effects such as steroid glaucoma, which exhibits symptoms of ocular hypertension due to this intraocular pressure-increasing effect, is considered to be a therapeutic problem when applied as a therapeutic agent for ocular diseases. ing.
  • steroid compounds have strong systemic side effects due to metabolic abnormalities, and are expressed even when administered locally such as eye drops, and long-term administration is often restricted.
  • the problem to be solved by the present invention is a safe steroid drug which has a strong anti-inflammatory action and an inhibitory action on intraocular pressure rise, does not cause an increase in intraocular pressure even in long-term use, and furthermore has a low occurrence of systemic side effects.
  • a prophylactic / therapeutic agent for eye diseases To develop a prophylactic / therapeutic agent for eye diseases.
  • the present inventors have developed a safe steroid drug for preventing or treating ocular diseases, which has a strong anti-inflammatory effect and an inhibitory effect on increase of intraocular pressure, does not cause an increase in intraocular pressure even in long-term use, and has few systemic side effects.
  • KSR-592 represented by the above formula (I) has a strong anti-inflammatory effect in ophthalmic applications, and does not cause an increase in intraocular pressure even after prolonged use.
  • the present inventors have found that the present invention has an effective action and effect, and have accomplished the present invention.
  • KSR-592 represented by the above formula (I) shows a strong anti-inflammatory effect, and It has an inhibitory effect on intraocular pressure increase or a decrease in intraocular pressure, does not cause an increase in intraocular pressure even when used for a long period of time, lowers intraocular pressure at a relatively high dose, and further reduces the weight loss specific to steroid compounds.
  • the KSR-592 was included as an active ingredient. As a result, it has been found that it is possible to develop a safe and preventive therapeutic agent for eye diseases that can be used for a long time without causing side effects such as steroid glaucoma exhibiting ocular hypertension.
  • the present inventors produced 0.025%, 0.05%, and 0.1% ophthalmic solutions of the KSR-592, using saline as a control, and 0.1% phosphoric acid of the existing drug.
  • dexamethasone ophthalmic solution as a comparator, Japanese white male male egret was instilled for 4 weeks, and intraocular pressure was measured to confirm changes in intraocular pressure.
  • Drug group remained at the initial value level until the first week of instillation, but after 10 days, it clearly showed higher intraocular pressure than the initial value, indicating a significant increase in intraocular pressure, including during the drug holiday
  • the KSR-592 group showed a tendency to decrease intraocular pressure, although not significantly, in the group administered 0.025% ophthalmic solution, and furthermore, 0.05% and 0.1% ophthalmic solution administered The group showed a significant intraocular pressure lowering effect.
  • KSR-592 ophthalmic solution of another existing drug 0.1% betamethasone sodium phosphate, were used as comparators for 4 consecutive weeks in the same manner as above. The test was performed, and the tonometry was performed twice a day at 10:00 (one hour after the first instillation) and 16:00 (one hour before the third instillation).
  • the 0.1% betamethasone sodium phosphate ophthalmic solution (comparative drug 1) administration group and the 0.1 ° / 0 fluorometron instillation were used in the 0.1% ophthalmic solution administration group of 1:31 to 592.
  • Liquid (comparative drug 2) significantly heavier than the group to which KSR-592 was administered, and KSR-592 had clearly weaker systemic side effects due to metabolic abnormalities compared to betamethasone sodium phosphate and fluorometholone, and fewer side effects even after long-term administration was confirmed.
  • KSR-592 of the present invention represented by the above formula (I) has a strong anti-inflammatory effect and an inhibitory effect on intraocular pressure rise or a lowering effect on intraocular pressure, and also has a systemic effect due to abnormal metabolism. It has very specific side effects compared to conventional steroid compounds, with weak side effects and few side effects even after long-term administration.
  • the ophthalmic solution containing the KSR-592 represented by the above formula (I) as an active ingredient of the present invention not only does not cause an increase in intraocular pressure even in long-term use, but also has an intraocular pressure lowering effect at a high dose.
  • it has low systemic side effects due to metabolic abnormalities, and is useful not only as a therapeutic agent for inflammatory, especially prolonged eye diseases that require long-term treatment, but also as a preventive therapeutic agent for ocular diseases with high intraocular pressure It is expected to have excellent characteristics as compared with conventional therapeutic agents for ophthalmic diseases.
  • KSR-592 represented by the formula (I) of the present invention is a known compound, and can be easily produced by a known method, for example, a method described in JP-A-52-102264.
  • KSR-592 represented by the above formula (I) of the present invention has strong anti-inflammatory action and intraocular pressure. It has an inhibitory effect on elevation, does not exhibit intraocular pressure increasing effect even after long-term use, and has weak systemic side effects. Therefore, by containing KSR-592 as an active ingredient, it is possible to produce a therapeutic agent for inflammatory ocular diseases of the external and anterior ocular regions, which is free from side effects such as steroid glaucoma, is safe and can be used for a long time. Can do things.
  • Inflammatory ocular diseases of the extraocular and anterior eye areas include blepharitis, conjunctivitis, keratitis, scleritis, episcleritis, pudoumanitis, ulceris, iridocyclitis, postoperative inflammation, etc. I can do it.
  • the KSR-592 of the present invention represented by the above formula (I) not only does not show an intraocular pressure increasing effect in long-term use, but also has a significant intraocular pressure lowering effect in relatively high-concentration eye drops. Demonstrate. Therefore, a prophylactic or therapeutic agent for ocular hypertension such as ocular hypertension or glaucoma can be produced by adding a relatively high concentration of KSR-592 as an active ingredient.
  • KSR-592 represented by the above formula (I) of the present invention is used for actual treatment, it is most commonly administered topically as an eye drop, but it can also be administered as other dosage forms. is there.
  • Eye drops and other pharmaceutical compositions can be manufactured according to the usual pharmaceutical procedures.
  • the ophthalmic solution is prepared by adding KSR-592 represented by the above formula (I) of the present invention to sterile purified water, and adding an appropriate solubilizing agent, suspending agent and the like as necessary. It can be prepared by dissolving or suspending, adding a preservative, an isotonic agent, pH adjustment, etc., if necessary, and removing dust and bacteria.
  • the dose of the active ingredient is appropriately determined depending on the age and weight of the patient, the type of disease to be applied, the degree of the disease, and the like.
  • an ophthalmic solution having a concentration of about 0.01 to 2%, preferably about 0.05 to 0.1% is instilled one to several times a day.
  • Suitable amount 10 OmL 100 mL of 0% suspension ophthalmic solution of KSR-592 is prepared according to a conventional method.
  • Prescription example 4 100 mL of 0% suspension ophthalmic solution of KSR-592 is prepared according to a conventional method.
  • Group B Prescription example 1 ophthalmic solution (Prescription 1) administration group
  • Group C Prescription example 2 ophthalmic solution (Prescription 2) administration group
  • Group D Prescription example 3 ophthalmic solution (Prescription 3) administration group
  • Group E Comparative drug (0.1% dexamethasone sodium phosphate ophthalmic solution) administration group
  • the administration of ophthalmic solution includes control solution (saline), test solution (Formulation 1, Formulation 2, Formulation 3) and comparison drug
  • the solution was instilled 25 ⁇ L at a time, three times a day (9:00, 13:00 and 17:00), and administered continuously for 4 weeks.
  • withdrawal at 2-day intervals (after discontinuation of drug administration) Measured once a day at 10:00 (1 hour after the first instillation) once a day on each measurement day until the first week, before starting the instillation
  • the measured value was used as the initial value, and the intraocular pressure value on each measurement day was compared.
  • the measurement method was as follows: Ophthalmic surface anesthetic (0.4% Oxippro-force in ophthalmic solution, manufactured by Nippon Ophthalmic Research Institute Co., Ltd.) diluted to an appropriate concentration with physiological saline was applied to each eye drop by drop. The measurement was performed using an ALCON APP LANAT I ON PNEUMATONOGRAPH tonometer (manufactured by Japan Alcon Corporation). In addition, body weight changes were measured daily until the end of the study.
  • the results of intraocular pressure fluctuation measurement showed that in group B (prescription 1 administration group), the initial value level from the start of instillation or, although not significant, a tendency to decrease intraocular pressure. . Both group (prescription 2 administration group) and group D (prescription 3 administration group) showed significant tendency to decrease intraocular pressure.
  • group E comparativative drug administration group
  • the initial value level remained almost the same until 1 week after instillation, but after day 10 after instillation, the intraocular pressure value was higher than the initial value, and Significant increases in intraocular pressure were confirmed on days 9, 22, 25, and 28 and on each measurement day during the drug holiday.
  • group B prescription 1 administration group
  • group C prescription 2 administration group
  • group D Formulation 3 administration group
  • group E comparative drug administration group
  • group E comparative drug administration group
  • betamethasone sodium phosphate ophthalmic solution (Verbezolone solution, manufactured by Nippon Ophthalmic Research Institute, Inc.) using the ophthalmic solutions of Formulation Example 3 (Formulation 3) and Formulation Example 4 (Formulation 4)
  • a comparative drug was used to conduct a continuous administration test for 4 weeks in the same manner as in Example 1 to measure changes in intraocular pressure and body weight In the test, 20 Japanese white male male herons were used, and 4 groups of 5 males And subjected to the tests of the following groups.
  • Group B Prescription example 3 ophthalmic solution (Prescription 3) administration group
  • Group D Comparison drug (0.1% betamethasone sodium phosphate ophthalmic solution) administration group Ophthalmic solution was administered in the control solution (physiological saline), the test solution (Formulation 3, Formulation 4), and the comparison drug in all cases. The solution was instilled 50 ⁇ L / time three times a day (9:00, 13:00 and 17:00) and continuously administered for 4 weeks. Intraocular pressure measurement is performed before and Drug suspension after start (after discontinuation of medication) Measured daily, twice a day at 10:00 (1 hour after the first instillation) and 16:00 (1 hour before the third instillation) until the first week, before starting the instillation The measured value was used as the initial value, and the intraocular pressure value on each measurement day was compared.
  • the measurement method was the same as in Example 1, except that an ophthalmic surface anesthetic (0.4% oxybuprocaine hydrochloride ophthalmic solution, manufactured by Nippon Ophthalmic Research Laboratories) diluted to an appropriate concentration with physiological saline was used in both eyes. After instilling one drop at a time, the measurement was carried out using an ALCON APPLANAT I ON P NEUMATONOGR A PH tonometer (manufactured by Japan Alcon Corporation). Further, the body weight fluctuation was measured once a day until the end of the test as in Example 1.
  • group B group B (prescription 3 administration group) showed a significant decrease in intraocular pressure in all measurements during the instillation period
  • group C preference 4 administration group also started on all measurement days.
  • the days on which the intraocular pressure decreased from the values and did not show a significant decrease were only days 1, 7, and 8 of the start of instillation.
  • group D comparativative drug administration group
  • the intraocular pressure tended to decrease from the initial value until the 9th day from the start of instillation, but increased from the 10th day on the measurement day including the withdrawal period
  • significant intraocular pressure increases were observed on days 14, 15, 19 to 23, and 26 and withdrawals 1, 2, 4, and 5 days.
  • the B group prescription 3 administration group
  • the C group prescription 4 administration group
  • group D comparativative drug administration group
  • group D showed the same level of strength or a decrease from the initial value until the 13th day from the start of instillation, but showed a tendency to increase from the second week onward.
  • Day 21 showed a significant increase in intraocular pressure.
  • Table 3 shows only the initial values, the measurement results every week after instillation, and the measurement results during the first week of withdrawal.
  • group B (prescription 3 administration group) showed a clear increase trend from the initial value, but body weight gain was slightly suppressed compared to group A (control solution administration group).
  • group C (prescription 4 administration group) little change was observed from the initial value, and it is considered that suppression of body weight increase has occurred.
  • group D comparative drug administration group.
  • Table 4 only the initial values, values after instillation and weekly after withdrawal are extracted and shown.
  • Formulation Example 3 Using the ophthalmic solution of Formulation Example 3 (Formulation 3), 0.1% betamethasone sodium phosphate ophthalmic solution (Berbezolone solution, manufactured by Nippon Ophthalmic Research Institute Co., Ltd.) and 0.1% fluorometron ophthalmic solution (Fluomesolone 0.1% ophthalmic solution, manufactured by Nippon Ophthalmic Research Laboratories, Inc.) was used as a comparative drug, and a continuous administration test for 9 weeks was performed to measure changes in intraocular pressure and body weight. For the test, 16 Japanese white male male egrets were used, divided into 4 groups of 4 each, and subjected to the tests of the following groups.
  • Group B Prescription example 3 ophthalmic solution (Prescription 3) administration group
  • Group C Comparative drug 1 (0.1% betamethasone sodium phosphate ophthalmic solution) administration group
  • the ophthalmic solution should be administered as a control solution (physiological saline), test solution (prescription 3), and comparative drugs 1 and 2 100 L each at a time, 4 times a day (9:00, 11:30 , 14: 00 and 16: 30), and administered continuously for 9 weeks.
  • Intraocular pressure is measured before and at the start of instillation, 9 weeks after the start of instillation, every day except for holidays (39 measurement days), once a day, 10:00 (1 hour after the first instillation) and before instillation. The intraocular pressure value on each measurement day was compared with the initial value.
  • the measurement method was the same as in Examples 1 and 2, except that an ophthalmic surface anesthetic (0.4% oxybupro hydrochloride in ophthalmic solution, manufactured by Nippon Ophthalmic Laboratory Co., Ltd.) diluted to an appropriate concentration with physiological saline was used. After instilling one drop at a time into the eyes, the measurement was performed using an ALC ON APPLANAT I ON PNEUMATONOGRAPH tonometer (manufactured by Alcon Corporation of Japan). Furthermore, body weight fluctuation was measured once a day until the end of the test, as in Examples 1 and 2.
  • group B (prescription 3 administration group) showed a significant decrease in intraocular pressure on most of the measurement days during the instillation period from day 4 after the start of instillation, and compared with group A (control solution administration group).
  • group C comparative drug 1 administration group
  • group D comparative drug 2 administration group
  • Table 5 shows only the measurement results for the first week, every week after instillation (however, for week 6, day 45). did.
  • Group B Prescription example 3 ophthalmic solution (Prescription 3) administration group
  • Group A (control group) had no eye drops.
  • Groups B and C applied 5 L each of test solution (formulation 3) and comparative drug to both eyes.
  • 15 minutes after instillation of test drug 1% carrageenan ( 0.05 ml was injected under the conjunctiva of the upper eyelid to cause edema.
  • rats were sacrificed by cervical dislocation in order to quantitatively determine the degree of inflammation that occurred, and the method of Maistre 11 o et al. (J. Pharm. Sci. 62, 1455) was used.
  • the scalp was peeled toward the eyelid, the skin and the inflamed area (edema area) were separated along the eyelid area, and the weight of the edema area of the eyelid conjunctivitis caused by force lagenin was precisely determined.
  • the weight was read to the nearest 0.1 mg and the measured value was rounded off to the nearest digit.
  • group A untreated control group
  • group B prescription 3 administration group
  • group C comparative drug administration group
  • the steroid compound represented by the formula (I) has a strong anti-inflammatory effect, an inhibitory effect on intraocular pressure increase or an intraocular pressure lowering effect, and a small weight loss characteristic of the steroid compound.
  • the present invention does not cause side effects such as steroid glaucoma, which exhibits ocular hypertension, and can be used for a long period of time.
  • An agent for preventing or treating ocular diseases such as ocular hypertension or glaucoma can be provided.

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  • Health & Medical Sciences (AREA)
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  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des médicaments préventifs ou thérapeutiques contre des maladies des yeux, notamment des maladies oculaires inflammatoires, l'hypertension oculaire et le glaucome. Ces médicaments contiennent un ingrédient actif, à savoir un composé stéroïdique (I) présentant un puissant effet anti-inflammatoire et un effet permettant soit d'inhiber l'augmentation de la tension oculaire soit de la réduire sans pour autant provoquer une augmentation de ladite tension même après une administration prolongée.
PCT/JP2001/001756 2000-03-09 2001-03-07 Medicaments preventifs ou therapeutiques contre des maladies des yeux WO2001066561A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001241045A AU2001241045A1 (en) 2000-03-09 2001-03-07 Preventive or therapeutic drugs for eye diseases

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2000-65604 2000-03-09
JP2000065604 2000-03-09

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WO2001066561A1 true WO2001066561A1 (fr) 2001-09-13

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996022764A1 (fr) * 1995-01-24 1996-08-01 Novartis Ag Liposomes contenant un corticosteroide
WO1997042214A1 (fr) * 1996-05-09 1997-11-13 Soft Drugs, Inc. Derives de l'androstene
EP0868919A2 (fr) * 1997-03-14 1998-10-07 Senju Pharmaceutical Co., Ltd. Suspension aqueuse de loteprednol etabonate

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996022764A1 (fr) * 1995-01-24 1996-08-01 Novartis Ag Liposomes contenant un corticosteroide
WO1997042214A1 (fr) * 1996-05-09 1997-11-13 Soft Drugs, Inc. Derives de l'androstene
EP0868919A2 (fr) * 1997-03-14 1998-10-07 Senju Pharmaceutical Co., Ltd. Suspension aqueuse de loteprednol etabonate

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BARTLETT J.D. ET AL.: "Intraocular pressure response to...steroid responders", J. OCUL. PHARMACOL., vol. 9, no. 2, 1993, pages 157 - 165, XP002941487 *

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