WO2016047647A1 - 角膜厚調節剤 - Google Patents
角膜厚調節剤 Download PDFInfo
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- WO2016047647A1 WO2016047647A1 PCT/JP2015/076835 JP2015076835W WO2016047647A1 WO 2016047647 A1 WO2016047647 A1 WO 2016047647A1 JP 2015076835 W JP2015076835 W JP 2015076835W WO 2016047647 A1 WO2016047647 A1 WO 2016047647A1
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- corneal
- corneal thickness
- cornea
- thickness
- compound
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Classifications
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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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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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
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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
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- 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
Definitions
- the present invention relates to a corneal thickness regulator. More specifically, the present invention relates to a cornea comprising 1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof or a solvate thereof as an active ingredient. It relates to a thickness regulator.
- the cornea is an important tissue that constitutes the eyeball wall together with the sclera, and at the same time, is an entrance for taking an image of the outside world as a transparent tissue into the eye.
- the cornea is avascular and transparent, and has a smooth spherical surface on both sides.
- the outer surface of the cornea is covered with a tear film and the inner side is in contact with the anterior chamber filled with aqueous humor.
- the thickness of the cornea is about 500 ⁇ m at the center, and is composed of five layers of corneal epithelium, Bowman membrane, parenchyma, Descemet membrane, and endothelium from the outside.
- the corneal epithelial layer is about 10% of the total thickness of the cornea and is formed of corneal epithelial cells. When the corneal epithelium is damaged, the surrounding epithelial cells move and proliferate to repair the damaged part.
- the corneal stroma accounts for about 90% of the total thickness of the cornea.
- the main component of the corneal stroma is collagen, but it also contains mucopolysaccharide. This mucopolysaccharide is water-absorbing and always absorbs moisture and swells (swells). However, the water content of the corneal stroma is always kept constant by the pump function and the barrier function of the corneal endothelium.
- the corneal endothelium is made up of corneal endothelial cells, and human corneal endothelial cells do not divide and therefore do not regenerate once they fall off.
- human corneal endothelial cells When human corneal endothelial cells are damaged and dropped and lost, they cannot be repaired by proliferation, and the surrounding endothelial cells migrate and stretch to form new cell adhesions to make up for the defect. .
- the adhesion of human corneal endothelial cells is an important function for repairing damaged sites.
- the damage becomes enormous, repair with a limited number of cells becomes impossible, and a defective site is formed in the corneal endothelium. When a defect site is formed in the corneal endothelium, irreversible serious dysfunction is caused.
- corneal endothelial cells when the density of corneal endothelial cells is about 500 cells / mm 2 or less, it becomes impossible to repair the defective part of the corneal endothelium, edema occurs in the cornea (bullous keratopathy), and irreversible turbidity It becomes.
- the density of normal corneal endothelial cells is about 2500 to 3000 cells / mm 2 .
- the corneal endothelial cells have a pump function that discharges water from the corneal stroma to absorb and swell water to the anterior chamber, and a barrier function that controls movement of water from the anterior chamber to the corneal stroma.
- the corneal stroma When these functions of corneal endothelial cells are reduced, the corneal stroma will contain excess water, which not only increases the thickness of the cornea, but also causes edema (bullous keratopathy), irreversible turbidity, and visual acuity It will fall extremely. Since the swelling of the cornea increases the thickness of the cornea and causes the occurrence of edema, it is necessary to thin the cornea and prevent the cornea from swelling.
- Corneal endothelium dysfunction is said to account for about 60% of all corneal dysfunction. Bullous cornea with irreversible corneal edema when the corneal endothelium is deficient due to physical disorder or progressive corneal endothelial dystrophy (typically Fuchs corneal dystrophy) becomes bullous keratopathy. If visual loss is significant, corneal transplantation is required. Human corneal endothelial cells do not divide in vivo, but in vitro culture has been studied (see Non-Patent Documents 1 and 2). This is because human corneal endothelial cells cultured and proliferated in vitro can be transplanted into the cornea for treatment.
- Non-Patent Documents 1 and 2 This is because human corneal endothelial cells cultured and proliferated in vitro can be transplanted into the cornea for treatment.
- corneal endothelial cells Because of this, it promotes adhesion of corneal endothelial cells, repairs damaged areas of corneal endothelium, and maintains and restores corneal endothelium function, as well as human corneal endothelial cells.
- a culture solution for cultivating corneal cells a preservation solution for preserving corneal endothelial cells and corneal endothelial tissues until transplantation, and a drug for regulating corneal thickness is desired.
- Rho-associated coiled-coil containing protein kinase: ROCK
- ROCK coiled-coil containing protein kinase
- Rho kinase is a serine threonine kinase with a molecular weight of about 160 kDa, and its gene is widely conserved from lower animals such as nematodes and Drosophila to humans.
- Rho kinase is involved not only in the contraction of smooth muscle cells, but also in physiological functions such as cell morphology control, migration, and gene expression control.
- Rho kinase inhibitors are being developed as therapeutic agents for cardiovascular diseases and the like. It is being advanced. In recent years, it has also been developed as a locally administered drug for eye diseases such as the treatment of glaucoma.
- (+)-trans-4- (1-aminoethyl) -1- (4-pyridylaminocarbonyl) cyclohexane (hereinafter referred to as Y-27632), which is one of Rho kinase inhibitors, is also used. It is reported that rabbit corneal endothelial cells can be cultured in the presence of (see Non-Patent Documents 3 and 4), and monkey corneal endothelial cells can also be cultured in the same manner (see Patent Document 1).
- Patent Document 1 reports that 1- (5-isoquinolinesulfonyl) -1,4-homopiperazine (hereinafter referred to as fasudil) also promotes adhesion of rabbit corneal endothelial cells.
- fasudil 1- (5-isoquinolinesulfonyl) -1,4-homopiperazine
- Y (Refer to Patent Document 2 and Non-Patent Document 7).
- the 50% inhibitory concentrations (IC 50 ) of Y-39983 and Y-27632 for Rho kinase are 0.0036 ⁇ M and 0.11 ⁇ M, respectively, and there is a difference of about 30 times. Is considered to have resulted in a difference in activity against corneal endothelial cells.
- Y-27632 and Y-39983 used in these documents are both N-pyridylamide compounds, but fasudil is a 1-sulfone-1,4-homopiperazine compound.
- 1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine (hereinafter sometimes referred to as compound A) is similar to 1-sulfone-1,4-homo, similar to fasudil. It is a piperazine-based compound, has selectivity as compared with fasudil, has been described to have stronger Rho kinase inhibitory activity than fasudil, and is reported to be useful for the prevention and treatment of asthma (Patent Document 3). Compound 6). Patent Document 3 states that the 50% inhibitory concentration (IC 50 ) for Rho kinase of Compound A and Fasudil is 0.2 ⁇ M and 1.5 ⁇ M, respectively.
- the 50% inhibitory concentration (IC 50 ) for Rho kinase of Compound A is considered to be stronger than Fasudil but weaker or comparable to Y-27632.
- IC 50 50% inhibitory concentration
- it is useful for the prevention and treatment of glaucoma by combining Compound A and a carbonic anhydrase inhibitor (see Patent Document 4), and the prevention and treatment of fundus disease for Compound A.
- the effect of Compound A on the corneal thickness has not been reported.
- the present invention provides a corneal thickness regulator for maintaining and recovering corneal thickness, and means for maintaining and recovering corneal thickness using the same, for example, means for thinning the cornea.
- Compound A 1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine (hereinafter referred to as Compound A). It has been found that the corneal thickness can be kept thin, and the salt or solvate thereof is a safer and more effective drug for corneal tissue. It was also found that it can be administered by eye drops and can be formulated with less burden on the patient.
- the present invention relates to a corneal thickness regulator comprising 1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof or a solvate thereof.
- the present invention also relates to a corneal thinning agent comprising 1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof or a solvate thereof.
- the present invention relates to a preventive agent for corneal edema comprising 1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof or a solvate thereof.
- a corneal thickness regulator comprising 1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof or a solvate thereof.
- (2) 1- (4-Fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine is represented by (S)-( ⁇ )-1- (4-fluoro-5-isoquinolinesulfonyl) -2
- the corneal thickness regulator according to (1) which is methyl-1,4-homopiperazine (hereinafter sometimes referred to as compound B).
- the present invention provides a corneal thickness adjusting agent for preventing and / or treating a corneal disorder causing corneal thickness modulation.
- the corneal thickness regulator of the present invention can prevent and / or treat various corneal endothelial disorders such as corneal endothelial diseases such as bullous keratopathy and corneal endotheliitis, and corneal endothelial abnormalities due to corneal transplantation and the like.
- the corneal thickness regulator of the present invention is effective even at a low concentration of the active ingredient, can maintain the corneal thickness thin, and can be used as a safe and highly effective pharmaceutical composition with few side effects. .
- the corneal thickness regulator of the present invention can be provided as an eye drop with less burden on the patient.
- FIG. 1 is a box-and-whisker diagram showing changes in the thickness of the cornea when Compound B is administered to human eye drops.
- Compound A in the present invention has one asymmetric carbon atom, and (R) isomer and (S) isomer exist.
- (R) isomer, the (S) isomer, or a mixture thereof can be used.
- As an active ingredient of a medicine (R) -form or (S) -form high-purity optically active form is preferable.
- the (S) isomer is preferred from the viewpoint of activity.
- the (S) form is simply referred to as Compound B.
- 1- (4-Fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine which is an active ingredient of the present invention, is a cerebrovascular therapeutic agent, asthma therapeutic agent, substance P antagonistic action, leukotriene D 4 antagonistic It is known as a compound having an action and a Rho kinase inhibitory action (see Patent Document 3), and can be produced by a known method, for example, a method described in International Patent Publication No. 99/20620 pamphlet.
- Examples of the salt of Compound A include salts of inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, hydrofluoric acid and hydrobromic acid, or acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid, methane
- Examples include salts with organic acids such as sulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid and camphorsulfonic acid, and hydrochloride is particularly preferable.
- Compound A or a salt thereof can exist not only as an unsolvated form but also as a hydrate or a solvate. Hydrates are preferred, but in the present invention, all crystal forms and hydrates or solvates are included.
- the “corneal thickness adjusting agent” adjusts the thickness of the cornea to maintain the normal function of the cornea.
- the thickness of the cornea mainly depends on the function of the corneal endothelium, and the “corneal thickness regulator” of the present invention is capable of functioning when the corneal endothelium has a functional disorder such as an increase or decrease in corneal endothelial function. It is considered that the thickness of the cornea can be adjusted by adjusting to a more normal state. That is, the corneal endothelium has important functions for maintaining visual acuity such as a pump function and a barrier function, and when these functions are enhanced, it is suppressed and these functions are reduced. It is considered that the corneal thickness becomes more normal by promoting this.
- the function of the corneal endothelium can be adjusted to reduce the thickness of the cornea (thinning).
- a corneal thinning agent, a preventive / therapeutic agent for corneal edema, and / or a prophylactic / therapeutic agent for corneal endothelial dysfunction can be administered to reduce the thickness of the cornea (thinning).
- the “corneal thickness regulator” of the present invention is formulated into a dosage form suitable for topical ocular administration by a conventional formulation technique widely used in the art.
- a liquid agent such as an injection solution in the anterior chamber, an eye perfusate, or an eye drop is preferable, but it is not limited thereto.
- Preferable preparations include an anterior chamber injection solution and ocular perfusate which are preferable dosage forms from the viewpoint of therapeutic effect, but they impose a heavy burden on patients and include eye drops for ease of administration.
- the eye drop of the present invention contains Compound A, preferably Compound B or a salt thereof or a solvate thereof, which is an active ingredient of the present invention, and a carrier acceptable for eye drops.
- the desired components described above are dissolved or suspended in an aqueous solvent such as sterilized purified water or physiological saline, or a non-aqueous solvent such as vegetable oil such as cottonseed oil, soybean oil, sesame oil, or peanut oil.
- an ointment base can be included in addition to the various components described above.
- the ointment base is not particularly limited, but is an oily base such as petroleum jelly, liquid paraffin, or polyethylene; an emulsion base obtained by emulsifying a cocoon oil phase and an aqueous phase with a surfactant, etc .; hydroxypropylmethylcellulose, carboxymethylcellulose A water-soluble base composed of polyethylene glycol or the like is preferred.
- the dosage is the patient's body weight, age, sex, symptom, dosage form and administration frequency. Usually, it is 0.025 to 10000 ⁇ g, preferably 0.025 to 2000 ⁇ g, more preferably 0.1 to 2000 ⁇ g, more preferably 0.025 per day as Compound A, preferably Compound B, for adults. The range is up to 200 ⁇ g and 0.025 to 100 ⁇ g.
- the active ingredient can be used at a concentration of about 0.0001 to 5 w / v%, preferably about 0.01 to 4 w / v%.
- the number of administrations is not particularly limited, but it is preferable to administer once or several times. In the case of liquid eye drops, one to several drops may be instilled at a time.
- Examples of the administration target of the “corneal thickness regulator” of the present invention include mammals (eg, human, mouse, rat, hamster, rabbit, cat, dog, cow, horse, sheep, monkey, etc.).
- mammals eg, human, mouse, rat, hamster, rabbit, cat, dog, cow, horse, sheep, monkey, etc.
- Preferred mammals include primates such as humans and monkeys. Particularly preferred is human.
- FIG. 1 shows the result for the right eye
- FIG. 1 shows the result for the left eye
- the vertical axis represents the change value ( ⁇ m) from week 0, and the horizontal axis represents the administration week.
- the 9 o'clock measurement was shown as (0) and the 11 o'clock measurement as (2).
- the corneal thickness before the start of administration was 531.6 ⁇ 28.0 ⁇ m for the right eye and 530.9 ⁇ 27.9 ⁇ m for the left eye (both mean values ⁇ standard deviation).
- the cornea thickness decreases during the administration period of Compound B of the present invention. Even if administration is continued, the thickness of the cornea is maintained at a substantially constant value. Further, after 28 weeks and 52 weeks, the cornea thickness tended to return to the value before the start of administration of Compound B (0 week) before instillation (0), but 2 hours after instillation (2) The cornea thickness was decreased.
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Abstract
Description
角膜の厚さは中央部で約500μmであり、外側から角膜上皮、ボーマン膜(Bowman membrane)、実質、デスメ膜(Descemet membrane)、及び内皮の5層からなっている。角膜上皮層は角膜全体の厚さの約10%であり、角膜上皮細胞で形成されている。角膜上皮に損傷が生じた場合には、周辺の上皮細胞が移動し、増殖して損傷部分を修復する。角膜実質は角膜全体の厚さの約90%を占めている。角膜実質の主成分はコラーゲンであるが、他にムコ多糖を含んでいる。このムコ多糖は吸水性で、常に水分を吸収してふくれよう(膨潤)としている。しかし、角膜内皮のポンプ機能及びバリア機能により、角膜実質の含水率は常に一定に保たれている。
角膜内皮細胞は、水を吸収して膨潤しようとする角膜実質から水を前房に排出するポンプ機能、及び前房から角膜実質への水の移動を制御するバリア機能を有している。角膜内皮細胞のこれらの機能が低下すると、角膜実質が過剰の水分を含むことになり、角膜の厚みが増すだけでなく、浮腫が生じ(水疱性角膜症)、不可逆性の混濁となり、視力が極度に低下することになる。角膜の膨潤は角膜の厚さを増加させ、浮腫の発生を惹起させるに至ることから、角膜を菲薄化し角膜の膨潤を防止する必要がある。
ヒトの角膜内皮細胞は生体内では細胞分裂しないが、インビトロ(In vitro)での培養が検討されてきている(非特許文献1及び2参照)。インビトロ(In vitro)で培養して増殖させたヒトの角膜内皮細胞を角膜に移植して治療することが可能となるからである。
このようなことから、角膜内皮細胞の接着性を促進させ、また、角膜内皮の損傷部位を修復するためや、角膜内皮の機能の維持や回復のための薬剤だけでなく、ヒトの角膜内皮細胞を培養増殖させるための培養液や、移植までの角膜内皮細胞や角膜内皮組織を保存するための保存液、更には角膜厚を調節する薬剤などの開発が望まれている。
また、近年では、緑内障の治療などの眼疾患のための局所投与薬としても開発されてきている。さらに、角膜内皮細胞の培養についても、Rhoキナーゼ阻害剤の1種である(+)-トランス-4-(1-アミノエチル)-1-(4-ピリジルアミノカルボニル)シクロヘキサン(以下、Y-27632という)の存在下でウサギの角膜内皮細胞を培養できることが報告され(非特許文献3及び4参照)、サルの角膜内皮細胞も同様に培養できることが報告されている(特許文献1参照)。特許文献1では、1-(5-イソキノリンスルホニル)-1,4-ホモピペラジン(以下、ファスジルという)でもウサギの角膜内皮細胞の接着性を促進することが報告されている。そして、ウサギの角膜内皮損傷についてのY-27632による処置(非特許文献5参照)や、ヒトのフックス角膜内皮変性症におけるY-27632による治療(非特許文献6参照)が報告されてきている。また、ウサギの角膜内皮損傷についての(R)-(+)-N-(1H-ピロロ[2,3-b]ピリジン-4-イル)-4-(1-アミノエチル)ベンズアミド(以下、Y-39983という)による処置(特許文献2及び非特許文献7参照)も報告されている。非特許文献7によれば、Y-39983とY-27632のRhoキナーゼに対する50%阻止濃度(IC50)は、それぞれ0.0036μMと0.11μMであり、約30倍の相違があり、この違いが角膜内皮細胞に対する活性の相違となったのではないかとされている。
これらの文献で使用されているY-27632とY-39983は、いずれもN-ピリジルアミド系の化合物であるが、ファスジルは1-スルホン-1,4-ホモピペラジン系の化合物である。
化合物Aを用いた眼疾患については、化合物Aと炭酸脱水酵素阻害剤とを組み合わせることにより緑内障の予防・治療に有用であること(特許文献4参照)や、化合物Aが眼底疾患の予防・治療に有用であること(特許文献5参照)が報告されているが、化合物Aによる角膜厚に対する作用は報告されていない。
また、本発明は、1-(4-フルオロ-5-イソキノリンスルホニル)-2-メチル-1,4-ホモピペラジン若しくはその塩又はそれらの溶媒和物を含有してなる角膜菲薄化剤に関する。
さらに、本発明は、1-(4-フルオロ-5-イソキノリンスルホニル)-2-メチル-1,4-ホモピペラジン若しくはその塩又はそれらの溶媒和物を含有してなる角膜浮腫の予防剤に関する。
(1)1-(4-フルオロ-5-イソキノリンスルホニル)-2-メチル-1,4-ホモピペラジン若しくはその塩又はそれらの溶媒和物を含有してなる角膜厚調節剤。
(2)1-(4-フルオロ-5-イソキノリンスルホニル)-2-メチル-1,4-ホモピペラジンが、(S)-(-)-1-(4-フルオロ-5-イソキノリンスルホニル)-2-メチル-1,4-ホモピペラジン(以下、化合物Bと表記することがある。)である、前記(1)に記載の角膜厚調節剤。
(3)角膜厚調節剤が、角膜菲薄化剤である、前記(1)又は(2)に記載の角膜厚調節剤。
(4)角膜厚調節剤が、角膜浮腫の予防及び/又は治療剤である、前記(1)又は(2)に記載の角膜厚調節剤。
(5)角膜厚調節剤が、角膜内皮障害の予防及び/又は治療剤である、前記(1)又は(2)に記載の角膜厚調節剤。
(6)角膜内皮障害が、水疱性角膜症又は角膜内皮炎などの角膜内皮疾患である、前記(5)に記載の角膜厚調節剤。
(7)角膜厚調節剤が、液剤である、前記(1)から(6)のいずれか1項に記載の角膜厚調節剤。
(8)角膜厚調節剤が、点眼剤である、前記(1)から(7)のいずれか1項に記載の角膜厚調節剤。
(9)角膜が、霊長類の角膜である、前記(1)から(8)のいずれか1項に記載の角膜厚調節剤。
(10)角膜が、ヒトの角膜である、前記(1)から(9)のいずれか1項に記載の角膜厚調節剤。
(11)1-(4-フルオロ-5-イソキノリンスルホニル)-2-メチル-1,4-ホモピペラジン若しくはその塩又はそれらの溶媒和物、及び製薬上許容される担体を混合する工程を含有してなる、前記(1)から(10)のいずれか1項に記載の角膜厚調節剤の製剤を製造する方法。
また、本発明の角膜厚調節剤は、患者の負担が少ない点眼剤として提供することができる。
本発明における化合物Aは、1個の不斉炭素原子を有しており、(R)体と(S)体が存在している。本発明においては、(R)体若しくは(S)体、又はこれらの混合物のいずれかを用いることができる。医薬の有効成分としては、(R)体又は(S)体の高純度の光学活性体が好ましい。(R)体と(S)体の中では活性の点から、(S)体が好ましい。本明細書においては、(S)体を単に化合物Bと表記する。
化合物A又はその塩は、未溶媒和型のみならず水和物又は溶媒和物としても存在することができる。水和物が好ましいが、本発明においては、全ての結晶型及び水和若しくは溶媒和物を含むものである。
本発明の「角膜厚調節剤」を投与することにより、角膜内皮の機能を調整して、角膜の厚さを薄くする(菲薄化)ことができるので、本発明の「角膜厚調節剤」は、角膜菲薄化剤、角膜浮腫の予防・治療剤、及び/又は角膜内皮障害の予防・治療剤としても使用することができる。
本発明の点眼薬は、本発明の有効成分である化合物A、好ましくは化合物B若しくはその塩又はそれらの溶媒和物、及び点眼薬に許容される担体を含有するものである。
点眼剤として使用する場合には、有効成分を約0.0001~5w/v%、好ましくは約0.01~4w/v%の濃度で使用することができる。
眼科疾患を有する対象における化合物Bの長期投与試験において、角膜に対する影響を調べた(27-34例)。すなわち、化合物B0.4%点眼液の1日2回投与、52週点眼群において、投与開始前(0週)、投与2週後、投与4週後、以降は4週毎に、角膜厚をパキメーターにて測定した。測定は5回行い、5回の平均値を採用した。測定日は9時に点眼し、11時に測定した。なお、28週後、52週後、フォローアップ(最終投与日から7-28日後)時は、9時(28週後、52週後においては点眼前)と11時の2回測定した。
Claims (6)
- 1-(4-フルオロ-5-イソキノリンスルホニル)-2-メチル-1,4-ホモピペラジン若しくはその塩又はそれらの溶媒和物を含有してなる角膜厚調節剤。
- 1-(4-フルオロ-5-イソキノリンスルホニル)-2-メチル-1,4-ホモピペラジンが、(S)-(-)-1-(4-フルオロ-5-イソキノリンスルホニル)-2-メチル-1,4-ホモピペラジンである、請求項1に記載の角膜厚調節剤。
- 角膜厚調節剤が、角膜菲薄化剤である、請求項1又は2に記載の角膜厚調節剤。
- 角膜厚調節剤が、角膜浮腫の予防及び/又は治療剤である、請求項1又は2に記載の角膜厚調節剤。
- 角膜厚調節剤が、液剤である、請求項1から4のいずれか1項に記載の角膜厚調節剤。
- 角膜が、霊長類の角膜である、請求項1から5のいずれか1項に記載の角膜厚調節剤。
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KR1020177008808A KR102432692B1 (ko) | 2014-09-24 | 2015-09-24 | 각막 두께 조절제 |
EP15844777.1A EP3199155B1 (en) | 2014-09-24 | 2015-09-24 | Corneal thickness modulating agent |
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Cited By (3)
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US10537579B2 (en) | 2017-05-12 | 2020-01-21 | Juntendo Educational Foundation | Rejection reaction suppressant |
JP2020200296A (ja) * | 2019-06-13 | 2020-12-17 | 久貴 藤本 | 角膜内皮障害の予防及び/又は治療のための薬剤 |
EP3930844A4 (en) * | 2019-02-28 | 2022-12-07 | Kowa Company, Ltd. | EXTRACELLULAR MATRIX MODULANT |
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CN105050600B (zh) * | 2013-04-24 | 2018-09-28 | 国立大学法人九州大学 | 眼底疾病治疗剂 |
DK3199161T3 (da) * | 2014-09-25 | 2022-01-03 | Kowa Co | Farmaceutisk præparat |
CN107164328A (zh) * | 2017-06-30 | 2017-09-15 | 太仓卡斯特姆新材料有限公司 | 一种高稳定性mcf‑7乳腺癌细胞的复苏方法 |
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
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US10537579B2 (en) | 2017-05-12 | 2020-01-21 | Juntendo Educational Foundation | Rejection reaction suppressant |
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JP2020200296A (ja) * | 2019-06-13 | 2020-12-17 | 久貴 藤本 | 角膜内皮障害の予防及び/又は治療のための薬剤 |
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KR20170058385A (ko) | 2017-05-26 |
EP3199155A1 (en) | 2017-08-02 |
JPWO2016047647A1 (ja) | 2017-07-06 |
US20170290840A1 (en) | 2017-10-12 |
US10034885B2 (en) | 2018-07-31 |
EP3199155A4 (en) | 2018-06-20 |
JP6598381B2 (ja) | 2019-10-30 |
EP3199155B1 (en) | 2021-06-16 |
CN106604730A (zh) | 2017-04-26 |
CN106604730B (zh) | 2019-12-20 |
KR102432692B1 (ko) | 2022-08-12 |
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