WO2014163142A1 - Composition ophtalmique - Google Patents

Composition ophtalmique Download PDF

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Publication number
WO2014163142A1
WO2014163142A1 PCT/JP2014/059838 JP2014059838W WO2014163142A1 WO 2014163142 A1 WO2014163142 A1 WO 2014163142A1 JP 2014059838 W JP2014059838 W JP 2014059838W WO 2014163142 A1 WO2014163142 A1 WO 2014163142A1
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WO
WIPO (PCT)
Prior art keywords
ophthalmic composition
bisacodyl
instillation
present
eye
Prior art date
Application number
PCT/JP2014/059838
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English (en)
Japanese (ja)
Inventor
裕一 大橋
白石　敦
小林　剛
Original Assignee
国立大学法人愛媛大学
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 国立大学法人愛媛大学 filed Critical 国立大学法人愛媛大学
Priority to JP2015510127A priority Critical patent/JPWO2014163142A1/ja
Publication of WO2014163142A1 publication Critical patent/WO2014163142A1/fr

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    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/04—Artificial tears; Irrigation solutions

Definitions

  • the present invention relates to an ophthalmic composition
  • an ophthalmic composition comprising as an active ingredient a compound having a water regulating action in the digestive tract. More particularly, it relates to a pharmaceutical composition effective for the treatment of dry eye.
  • the state where the health of the surface of the eye, cornea, or conjunctiva is impaired due to the decrease or change in tears is called dry eye.
  • the lack of tears due to decreased secretion of tears, dryness of the eyes due to excessive evaporation of tears, and poor tear stability cause rough surfaces of the cornea and conjunctiva, resulting in symptoms such as eye discomfort and fatigue.
  • diquafosol sodium acts on the P2Y2 receptor on the conjunctival epithelium and the conjunctival goblet cell membrane to increase the intracellular calcium ion concentration, thereby promoting water and mucin secretion and making the ocular surface environment more normal. It is thought to be close to the condition and to improve dry eye symptoms and keratoconjunctival epithelial disorder.
  • bisacodyl is included in constipation drugs for over-the-counter medicines to improve unpleasant symptoms such as constipation and associated head weight, abdominal fullness, loss of appetite (decreased appetite), and abnormal intestinal fermentation. .
  • bisacodyl acts directly on the intestinal mucosa to stimulate the defecation reflex and promote defecation.
  • picosulfate sodium is known as a component that is combined with a constipation drug to have a laxative action by enhancing the peristaltic movement of the large intestine and suppressing water absorption.
  • Various dosage forms containing these as active ingredients have been developed for the purpose of acting on the digestive tract (for example, Patent Documents 1 and 2).
  • bisacodyl As the action of bisacodyl, by reducing the expression level of AQP3 in the colonic mucosal epithelial cells, it is suggested that water movement from the intestinal tract side to the vascular side may be suppressed, and that it may show a swallowing action, as this mechanism, bisacodyl is first increased secretion of COX2 and PGE 2 from the large intestine of macrophages, then it has been reported that PGE 2 has reduced the expression of AQP3 colon mucosal epithelial cells (non-Patent Document 1 ).
  • the present inventors have intensively studied methods for treating dry eye for many years. Since the conjunctiva of the eye secretes and absorbs water in the same way as the digestive tract, we examined the administration of a drug that has the effect of suppressing water absorption in the digestive tract as an instillation. As a result, when a dry eye model mouse was instilled with an aqueous solution of bisacodyl or picosulfate sodium, which is a component of constipation drugs that are generally marketed, it has the effect of significantly increasing tear volume 3 hours after the end of the period. The present invention has been completed.
  • the present invention provides the following.
  • An ophthalmic composition comprising, as an active ingredient, a compound having a moisture regulating action in the gastrointestinal tract.
  • the ophthalmic composition according to [1] for treating a disease or condition associated with tear volume.
  • the ophthalmic composition according to [2], wherein the disease or condition related to tear volume is dry eye.
  • the compound according to any one of [1] to [4], wherein the compound having a water regulating action in the gastrointestinal tract is any one selected from bisacodyl, picosulfate and a pharmaceutically acceptable salt thereof.
  • Ophthalmic composition [6] The ophthalmic composition according to any one of [1] to [5], containing 0.05 to 3% of an active ingredient.
  • the term “ophthalmic composition” means a pharmaceutical composition in a form suitable for application to the eye, unless otherwise specified.
  • the ophthalmic composition is adjusted in pH and / or osmotic pressure as appropriate for application to the eye as needed, may be adjusted in viscosity, and may be sterile.
  • Ophthalmic compositions include eye drops, eye perfusates, eye ointments, eye viscosities, contact lens mounting fluids and contact lens care agents.
  • the present invention provides an ophthalmic composition
  • a compound having a water regulating action in the digestive tract Particularly preferred examples of the active ingredient of the ophthalmic composition of the present invention are bisacodyl, picosulfate and pharmaceutically acceptable salts thereof.
  • an increase in PGE 2 in the conjunctiva was observed in both normal mice and dry eye model mice by bisacodyl instillation (see the Examples section of the present specification). This is similar to the effect of bisacodyl reported on the colonic mucosa.
  • Bisacodyl (chemical name: 4,4 '-(Pyridin-2-ylmethylene) bis (phenylacetate) has the following structure.
  • Picosulfate (chemical name 4,4 '-(pyridin-2-ylmethylene) bis (phenylsulfate)) is a commercially available drug and is contained as sodium picosulfate of the following formula.
  • the picosulfate salt used in the ophthalmic composition of the present invention is not particularly limited as long as it is pharmaceutically acceptable.
  • alkali metal salts for example, sodium salts and potassium salts
  • alkaline earth metal salts for example, magnesium salt, calcium salt
  • ammonium salt mono-, di- or tri-lower (alkyl or hydroxyalkyl) ammonium salt (eg ethanolammonium salt, diethanolammonium salt, triethanolammonium salt, tromethamine salt)
  • hydrochloride Hydrobromide, hydroiodide, nitrate, phosphate, sulfate, formate, acetate, citrate, oxalate, fumarate, maleate, succinate, malic acid Salt, tartrate, aspartate, trichloroacetate, trifluoroacetate, methanesulfonate Benzenesulfonate, p- toluenesulfonate, may be mentioned mesity
  • the compound of the present invention or a salt thereof when referring to the compound of the present invention or a salt thereof, it may be an anhydride or a solvate, and the solvate includes a hydrate, a methanol solvate, an ethanol solvate, a propanol solvate, and 2-propanol. Japanese products are included.
  • the active ingredient may be one or a plurality of combinations.
  • the content of the active ingredient (as a total amount when a plurality of active ingredients are used) is 0.0001 to 5%, preferably 0.001 to 3%, more preferably 0.05 to 3%, and particularly preferably about 0.1 to 1%.
  • the dose of the ophthalmic composition of the present invention can be appropriately designed by those skilled in the art.
  • it can be applied every several hours or once to several times a day.
  • administration period of the ophthalmic composition of the present invention can be appropriately designed by those skilled in the art.
  • administration 1 to several times a day, several days to several weeks, for example 3 can be used continuously for 7 days or 14 days.
  • the ophthalmic composition of the present invention can be used to treat diseases or conditions related to tear volume.
  • treatment includes prevention and treatment unless otherwise specified. Prevention includes reducing the risk of onset.
  • the ophthalmic composition of the present invention is particularly suitable for use for the treatment of dry eye. Dry eye is generally a chronic disease of tears and keratoconjunctival epithelium due to various factors, and is accompanied by eye discomfort and abnormal visual function, and is also used in this sense in the present invention.
  • the ophthalmic composition of the present invention can be suitably used for any of them.
  • the ophthalmic composition of the present invention can be used in severe dry eyes such as Sjogren's syndrome even with dry eyes with reduced tear secretion (normally irritating secretion is normal). Yes, even if the lacrimal stimulatory secretion is also reduced.
  • transpiration-type dry eyes because of staring at a PC monitor, etc., blinking is reduced, oil is not properly supplied due to aging, etc., and moisture cannot be kept on the eye surface.
  • the ophthalmic composition of the present invention is also useful for corneal epithelial disorders related to dry eye.
  • the active ingredient of the ophthalmic composition of the present invention can increase the amount of tears in the target eye.
  • an increase in tear volume can be observed after instillation, minutes to hours, for example, 3 hours.
  • Prior art eye drops for the treatment of dry eye were not sufficient for long-lasting and severe cases, but the ophthalmic composition of the present invention provided long-lasting and / or severe cases. I can expect.
  • Whether or not it is dry eye and whether or not the amount of tears is increased by applying the ophthalmic composition of the present invention can be confirmed by a known inspection method.
  • known inspection methods include screening with a slit lamp, staining inspection, Schirmer test (using filter paper or phenol red thread), BUT measurement (measurement of tear film breakage time), clearance test, and the like.
  • ophthalmic composition of the present invention various pharmaceutically acceptable additives can be blended as long as the effects of the present invention are not impaired.
  • An isotonic agent can be blended in the ophthalmic composition of the present invention.
  • isotonic agents that can be used in the present invention include inorganic salts such as sodium chloride and potassium chloride. Inorganic salts are used depending on what is used, but are usually used in an amount of about 0.001 to 5%, preferably about 0.001 to 1%, more preferably about 0.005 to 0.5%.
  • the ophthalmic composition of the present invention is used by adjusting to an osmotic pressure within a range acceptable for a living body, if necessary.
  • the osmotic pressure is about 100 to 1200 mOsm, preferably about 100 to 600 mOsm, particularly preferably about 150 to 400 mOsm, and the osmotic pressure ratio with respect to physiological saline is usually 0.4 to 4.1, preferably 0.3 to 2.1, particularly preferably 0.5 to 1.4. Degree.
  • an additive (buffer) for pH adjustment can be blended.
  • the buffer that can be used in the present invention include borate buffer, phosphate buffer, carbonate buffer, citrate buffer, acetate buffer, HEPES buffer, and MOPS buffer. More specific examples include: boric acid, sodium borate, potassium tetraborate, potassium metaborate, etc., phosphoric acid, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, carbonic acid, sodium hydrogen carbonate, carbonic acid Examples thereof include compounds such as sodium, citric acid, sodium citrate, potassium citrate, acetic acid, sodium acetate, HEPES, and MOPS, and combinations of two or more compounds selected from these groups.
  • the ophthalmic composition of the present invention is used after adjusting to a pH within a range applicable to a living body, if necessary.
  • the pH is, for example, pH 4.0 to 9.0, preferably 5.0 to 8.5, more preferably 5.5 to 8.5.
  • the ophthalmic composition of the present invention can be set to an appropriate viscosity to obtain a desired effect.
  • the viscosity of the ophthalmic composition affects the comfort (use feeling) and drug retention capacity when applied to the ocular mucosa, so an appropriate viscosity is designed and the designed viscosity is maintained stably over the long term. It is good to be done.
  • the appropriate viscosity is, for example, a viscosity at 20 ° C.
  • the viscosity can be adjusted using the buffer, the pH adjuster, the thickener (for example, methylcellulose, hydroxypropylmethylcellulose) and the like.
  • solubilizers for example, triethanolamine, diethanolamine
  • stabilizers for example, anhydrous sodium sulfite
  • suspending agents for example, sodium carboxymethylcellulose, polysorbate 80
  • Surfactants, preservatives (for example, parabens), bactericides or antibacterial agents, fragrances or refreshing agents, and various additives such as sugars can be mentioned.
  • the ophthalmic composition of the present invention can be formulated by combining other active ingredients.
  • active ingredients that can be used in the present invention include a decongestant component, an eye muscle modulator component, an anti-inflammatory component or an astringent component, an antihistamine component or an antiallergy that are commonly used in ophthalmic compositions.
  • Medicinal components, vitamins, amino acids, local anesthetic components, steroid components and the like can be mentioned.
  • the ophthalmic composition of the present invention can be produced by a known method.
  • a filtration sterilization process, an aseptic filling process into a container, and the like can be added.
  • ophthalmic composition of the present invention When the ophthalmic composition of the present invention is used as an ophthalmic solution, if appropriate, components other than the active ingredient can have a configuration similar to that of an existing ophthalmic solution. Some examples are given below.
  • Example 1 (pH 5.0) Boric acid 20.0 Methyl paraoxybenzoate 0.26 Propyl paraoxybenzoate 0.14 Sterile purified water ad 1000.0
  • Example 4 (Viscous eye drops) Methylcellulose (4000CPS) 0.3 Sodium chloride 0.9 Benzethonium chloride 0.02 Sterile purified water ad 100.0
  • Example 5 In the case of eye drop oil.
  • the active ingredient can be dissolved or suspended in the oil.
  • Aluminum monostearate 2g Refined vegetable oil ad 100g
  • a dosage form in use for example, a solution and a set of an active ingredient stored in a container separate from the solution.
  • mice Bisacodyl eye drop experiment
  • C57BL / 6 12-week-old mice were tested in 5 mice (10 eyes) each.
  • the dry eye model mice were anesthetized by intraperitoneal injection of 0.2% 4% trichloroacetaldehyde female C57BL / 6 mice at 8 weeks of age. It was created by excising the lacrimal gland from the lacrimal gland opening in the vicinity of the opening. In this experiment, subjects 4 weeks after the lacrimal gland resection were used.
  • Bisacodyl (Sigma-Aldrich Co. LLC) was dissolved in dimethyl sulfoxide (DMSO) to prepare a 10% (w / v) solution. 20% of Bisacodyl DMSO solution (10%) was added to 980 ⁇ l of physiological saline to prepare 0.2% bisacodyl ophthalmic solution (containing 2% DMSO). A solution obtained by adding 20 ⁇ l of DMSO to 980 ⁇ l of physiological saline was used as a placebo ophthalmic solution (2% DMSO).
  • DMSO dimethyl sulfoxide
  • a 0.2% bisacodyl solution (containing 2% DMSO) or a placebo (2% DMSO) was prepared, and each eye drop was instilled 3 times at 25 ⁇ L, 5 minute intervals. On the first day, a placebo was applied, and on the second day, 0.2% bisacodyl ophthalmic solution was administered. Prior to instillation, 1 hour after instillation, 2 hours, 3 hours and 6 hours later, the amount of tears was measured with a phenol red thread (Zonequick (registered trademark) Showa Yakuhin Kako Co., Ltd., measurement time 30 seconds).
  • Real-time PCR was performed using cDNA as a template, and AQP1, AQP3, IL-1 ⁇ , IL-6, and TNF ⁇ mRNA were quantified.
  • StepOnePlus TM Real-Time PCR System (Life Technologies Corporation) and TaqMan (registered trademark) gene expression assay (Life Technologies Corporation) were used.
  • the IDs of TaqMan® gene expression assays used for the analysis are Mm00431834 # m1 (Aqp1), Mm01208559 # m1 (AQP3), Mm00434228 # m1 (IL-1 ⁇ ), Mm00446190 # m1 (IL-6), Mm00443260 # g1 (TNF ⁇ ).
  • Picosulfate instillation experiment was conducted using normal mice. C57BL / 6 12-week-old mice, 11 (22 eyes) were used as subjects.
  • 0.75% picosulfate sodium (Laxoberon) was prepared, and 25 ⁇ L per eye was instilled 3 times at 5-minute intervals. Prior to instillation, 1 hour after instillation, 2 hours, 3 hours, and 4 hours later, the amount of tears was measured with a phenol red thread (Zonequick (registered trademark) Showa Yakuhin Kako Co., Ltd., measurement time 30 seconds).
  • Real-time PCR was performed using cDNA as a template, and Ptgs1 (Cyclooxygenase-1, COX-1) and Ptgs2 (Cyclooxygenase-2, COX-2) mRNAs were quantified.
  • Ptgs1 Cyclooxygenase-1, COX-1
  • Ptgs2 Cyclooxygenase-2, COX-2
  • mRNA quantification by Real-time PCR StepOnePlus TM Real-Time PCR System (Life Technologies Corporation) and TaqMan (registered trademark) gene expression assay (Life Technologies Corporation) were used.
  • the IDs of the TaqMan® gene expression assay used for the analysis are Mm00477214 # m1 (Ptgs1) and Mm00478374 # m1 (Ptgs2).
  • FIG. 1 An example of corneal fluorescein staining of a dry eye model eye is shown in FIG.
  • a stained site showing corneal epithelial disorder was found in a wide range of the cornea.
  • the staining range was reduced and corneal epithelial disorder was reduced.

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

Abstract

La présente invention vise à fournir une composition ophtalmique qui laisse envisager un effet longue durée et un effet thérapeutique dans des cas sérieux et est efficace dans le traitement de la sécheresse oculaire. La présente invention concerne par conséquent une composition ophtalmique qui comprend en tant qu'ingrédient actif un composé ayant un effet d'ajustement d'humidité dans un tractus digestif. Un exemple préférable du composé ayant un effet d'ajustement d'humidité dans un tractus digestif sont un élément sélectionné dans le groupe constitué d'un bisacodyle, d'un picosulfate et de leurs sels pharmaceutiquement acceptables. L'ingrédient actif de la composition ophtalmique selon la présente invention peut augmenter la quantité de larmes dans un œil à traiter. Quand du bisacodyle ou du picosulfate est utilisé en tant qu'ingrédient actif de la composition ophtalmique selon la présente invention, une augmentation de la quantité de larmes peut être observée de plusieurs minutes à plusieurs heures, par exemple 3 heures, après instillation.
PCT/JP2014/059838 2013-04-03 2014-04-03 Composition ophtalmique WO2014163142A1 (fr)

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JP2015510127A JPWO2014163142A1 (ja) 2013-04-03 2014-04-03 眼科用組成物

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JP2013077862 2013-04-03
JP2013-077862 2013-04-03

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017043612A1 (fr) * 2015-09-10 2017-03-16 株式会社Ｌｔｔバイオファーマ Agent pour le traitement de l'oeil sec

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002003377A (ja) * 2000-06-20 2002-01-09 Taisho Pharmaceut Co Ltd ピコスルファートナトリウム配合緩下剤
JP2005538110A (ja) * 2002-07-29 2005-12-15 ニトロメッド インコーポレーティッド シクロオキシゲナーゼ−２選択的阻害剤、組成物、および使用方法
JP2012224619A (ja) * 2011-04-07 2012-11-15 Taisho Pharmaceutical Co Ltd ジオクチルソジウムスルホサクシネート配合固形製剤

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002003377A (ja) * 2000-06-20 2002-01-09 Taisho Pharmaceut Co Ltd ピコスルファートナトリウム配合緩下剤
JP2005538110A (ja) * 2002-07-29 2005-12-15 ニトロメッド インコーポレーティッド シクロオキシゲナーゼ−２選択的阻害剤、組成物、および使用方法
JP2012224619A (ja) * 2011-04-07 2012-11-15 Taisho Pharmaceutical Co Ltd ジオクチルソジウムスルホサクシネート配合固形製剤

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
N.IKARASHI ET AL.: "The laxative effect of bisacodyl is attributable to decreased aquaporin-3 expression in the colon induced by increased PGE2 secretion from macrophages.", AMERICAN JOURNAL OF PHYSIOLOGY - GASTROINTESTINAL AND LIVER PHYSIOLOGY, vol. 301, 2011, pages G887 - G895 *
TAKESHI KOBAYASHI ET AL.: "Dry Eye Model Mouse no Ketsumakunonai Ruieki Choryuryo ni Oyobosu Bisacodyl Tengan no Eikyo", JAPAN CORNEA SOCIETY SOKAI .KERATOPLASTY SOCIETY OF JAPAN PROGRAM .SHOROKUSHU, 31 January 2014 (2014-01-31), pages 79, 027 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017043612A1 (fr) * 2015-09-10 2017-03-16 株式会社Ｌｔｔバイオファーマ Agent pour le traitement de l'oeil sec

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