WO2010117077A1 - Therapeutic agent for chorioretinal diseases comprising sirolimus derivative as active ingredient - Google Patents

Therapeutic agent for chorioretinal diseases comprising sirolimus derivative as active ingredient Download PDF

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WO2010117077A1
WO2010117077A1 PCT/JP2010/056498 JP2010056498W WO2010117077A1 WO 2010117077 A1 WO2010117077 A1 WO 2010117077A1 JP 2010056498 W JP2010056498 W JP 2010056498W WO 2010117077 A1 WO2010117077 A1 WO 2010117077A1
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therapeutic agent
compound
administration
retinal
agent
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PCT/JP2010/056498
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Japanese (ja)
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淑起 大橋
康司 大橋
正明 景山
健一 遠藤
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参天製薬株式会社
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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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems

Definitions

  • the present invention relates to a therapeutic agent for a choroidal disease containing a sirolimus derivative as an active ingredient.
  • Age-related macular degeneration is a disease characterized by damage to the retinal tissue of the macular region with age, causing visual impairment, and one of the causes of visual impairment in the elderly that can lead to blindness It is.
  • wet age-related macular degeneration is a disease in which neovascular vessels derived from the choroid develop under the retina of the macular region, causing bleeding and cell exudation.
  • Pegaptanib sodium has been developed as a new treatment for wet age-related macular degeneration.
  • Pegaptanib sodium is a new type of therapeutic agent that is administered directly into the vitreous, and its designated usage is to be administered intravitreally once every 6 weeks.
  • Patent Document 1 describes that sirolimus is used for retinal diseases such as age-related macular degeneration.
  • both temsirolimus and everolimus are derivatives of sirolimus and are known to have immunosuppressive action, tumor therapeutic action, and the like.
  • DDS drug delivery system
  • the present inventors focused on sirolimus derivatives that have been reported to have a therapeutic effect on age-related macular degeneration.
  • the present invention includes age-related macular degeneration, polypoidal choroidal vasculopathy, retinal hemangiomatosis, diabetic retinopathy, diabetic macular edema, retinal vein, which contains a sirolimus derivative (hereinafter also referred to as the present compound) as an active ingredient.
  • the present invention relates to a therapeutic agent for choroidal diseases such as obstruction, retinal artery occlusion or retinopathy of prematurity.
  • the salt is not particularly limited as long as it is a pharmaceutically acceptable salt.
  • the quaternary ammonium salt of is illustrated.
  • this compound may take the form of the hydrate or the solvate.
  • the sirolimus derivative in the present compound preferably refers to a derivative obtained by chemically converting the hydroxyl group at position 42 of sirolimus.
  • Preferred examples of the present compound include temsirolimus, everolimus, zotarolimus or deforolimus.
  • More preferable examples of the present compound include temsirolimus represented by the following formula (1) and everolimus represented by the following formula (2).
  • the reticulochoroidal disease refers to a disease in the retina or choroid, such as age-related macular degeneration (drusen formation in early age-related macular degeneration, atrophic age-related macular degeneration, exudative age-related macular degeneration), polyp Choroidal angiopathy, retinal hemangiomatous proliferation, diabetic retinopathy (simple diabetic retinopathy, preproliferative diabetic retinopathy, proliferative diabetic retinopathy), diabetic macular edema, proliferative vitreoretinopathy, retinal vein occlusion, retinal artery occlusion And retinopathy of prematurity, preferably age-related macular degeneration, polypoidal choroidal vasculopathy, retinal hemangiomatosis, diabetic retinopathy, diabetic macular edema, and the like.
  • age-related macular degeneration drusen formation in early age-related macular degeneration, atroph
  • This compound can be formulated by using a technique commonly used as a single preparation or a combination preparation by adding a pharmaceutically acceptable additive as necessary.
  • this compound When this compound is used for the treatment of the aforementioned eye diseases, it can be administered to patients orally or parenterally.
  • oral administration topical administration to the eye (eye drops, conjunctiva)
  • Intracapsular administration Intravitreal administration, subconjunctival administration, subtenon administration, etc.), intravenous administration, transdermal administration, and the like.
  • an eye drop or an eye ointment is used, or an injection, particularly a subconjunctival agent, a tenon sac administration agent or an intravitreal administration agent. Used.
  • a preparation containing the present compound as an active ingredient is formulated into a dosage form suitable for administration, together with a pharmaceutically acceptable additive, if necessary.
  • dosage forms suitable for oral administration include tablets, capsules, granules, powders, etc.
  • dosage forms suitable for parenteral administration include injections, eye drops, eye ointments, and patches.
  • Agents, gels, and intercalating agents can be prepared using ordinary techniques widely used in the field.
  • an intraocular implant can be used. DDS preparations such as pharmaceutical preparations and microspheres may be used.
  • tablets are made of excipients such as lactose, glucose, D-mannitol, anhydrous calcium hydrogen phosphate, starch, sucrose; carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, crospovidone, starch, partially pregelatinized starch ,
  • Disintegrating agents such as low-substituted hydroxypropylcellulose; binders such as hydroxypropylcellulose, ethylcellulose, gum arabic, starch, partially pregelatinized starch, polyvinylpyrrolidone, polyvinyl alcohol; magnesium stearate, calcium stearate, talc, hydrous silicon dioxide ,
  • Lubricants such as hydrogenated oils; refined sucrose, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, ethylcellulose, polyvinyl chloride Coating agents such as Rupiroridon; citric acid, aspartame, using ascorbic acid, appropriately selected and the like flavoring agent such as menthol
  • the injection is selected from an isotonic agent such as sodium chloride; a buffering agent such as sodium phosphate; a surfactant such as polyoxyethylene sorbitan monooleate; a thickener such as methylcellulose as necessary. Can be prepared.
  • an isotonic agent such as sodium chloride
  • a buffering agent such as sodium phosphate
  • a surfactant such as polyoxyethylene sorbitan monooleate
  • a thickener such as methylcellulose as necessary.
  • Eye drops include isotonic agents such as sodium chloride and concentrated glycerin; buffering agents such as sodium phosphate and sodium acetate; surface activity such as polyoxyethylene sorbitan monooleate, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil Agents; Stabilizers such as sodium citrate and sodium edetate; can be selected and used as needed from preservatives such as benzalkonium chloride and paraben, and pH is acceptable for ophthalmic preparations Although it may be within the range, it is usually preferably within the range of 4-8.
  • the eye ointment can be prepared using a commonly used base such as white petrolatum or liquid paraffin.
  • the intercalating agent is prepared by pulverizing and mixing a biodegradable polymer, for example, a biodegradable polymer such as hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxyvinyl polymer, and polyacrylic acid, together with the compound, and compressing the powder. If necessary, an excipient, a binder, a stabilizer, and a pH adjuster can be used.
  • a biodegradable polymer for example, a biodegradable polymer such as hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxyvinyl polymer, and polyacrylic acid
  • Preparations for intraocular implants can be prepared using biodegradable polymers, for example, biodegradable polymers such as polylactic acid, polyglycolic acid, lactic acid / glycolic acid copolymer, and hydroxypropylcellulose.
  • biodegradable polymers such as polylactic acid, polyglycolic acid, lactic acid / glycolic acid copolymer, and hydroxypropylcellulose.
  • the dosage of the present compound can be appropriately changed according to the dosage form, the severity of symptoms of the patient to be administered, age, body weight, eye volume, doctor's judgment and the like.
  • 0.1 ⁇ g to 2000 ⁇ g can be administered per dose.
  • a preferable dose in this case can be calculated based on a vitreous volume ratio between a human and the disease model animal based on a dose effective in a pharmacological test described below. Since the substance administered into the vitreous is first dispersed in the vitreous body, the tissue concentration in the vicinity of the affected part of the substance can be obtained approximately by dividing the dose by the vitreous volume. The vitreous volume can be approximated by the eyeball volume.
  • the volume of human vitreous body is about 4.5 mL, and the vitreous volume of rat is about 50 ⁇ L (Oyster® C; The Human Eye, w 1999, Berkwitz BA et al .; Invest. ⁇ Ophthalmol. Vis. Sci. Vol. 39 391 pages, 1998). That is, the estimated clinical dose for humans can be converted by multiplying the dose in rats by about 90 times. In humans, the average vitreous volume may differ from the aforementioned volume value depending on race, age, sex, etc., and in rats, the strain, age, sex, etc. Can be confirmed by conducting clinical trials. Based on such a concept, the preferred dosage for intraocular administration, particularly intravitreal administration, of the present compound is 90 ⁇ g to 900 ⁇ g per dose, and more preferably 90 ⁇ g to 500 ⁇ g per dose.
  • 0.0001 to 2000 mg can be administered at a time.
  • An active ingredient having a concentration of 1% (w / v) can be administered.
  • a patch containing 0.0001 to 2000 mg can be applied to an adult.
  • 0.0001 to 2000 mg is included for an adult.
  • An intraocular implant formulation can be implanted in the eye.
  • the interval between administrations of the compound can be at least 12 weeks.
  • temsirolimus hereinafter also referred to as “compound A”
  • everolimus hereinafter also referred to as “compound B”
  • compound A temsirolimus
  • compound B everolimus
  • angiogenesis Surprisingly, in a pharmacological study in which the evaluation of the therapeutic effect is continued for a long time after a single administration, this compound such as Compound A can significantly maintain the choroidal neovascularization inhibitory effect even 12 weeks after the treatment. Indicated.
  • the present compound typified by Compound A and the like is a therapeutic agent for age-related macular degeneration, particularly reticulochoroidal diseases associated with angiogenesis such as exudative age-related macular degeneration, polypoidal choroidal vasculopathy, retinal hemangiomatous proliferation, etc. It is useful as a therapeutic agent for these diseases, where the therapeutic effect is sustained for a long time by a single administration.
  • Rats were anesthetized by intramuscular administration of 1 ml / kg of a mixed solution (7: 1) of 5% (W / V) ketamine hydrochloride injection and 2% xylazine hydrochloride injection, and 0.5% (W / V) Tropicamide-0.5% phenylephrine hydrochloride ophthalmic solution was instilled to make mydriasis, and then photocoagulated with a krypton laser photocoagulator.
  • Photocoagulation was carried out at 8 locations per eye, avoiding thick retinal blood vessels in the posterior region of the fundus, focusing on the deep retina (coagulation conditions: spot size 100 ⁇ m, output 100 Wm, coagulation time 0.1 seconds). . After photocoagulation, fundus photography was performed to confirm the laser irradiation site.
  • Temsirolimus (hereinafter also referred to as “Compound A”) or everolimus (hereinafter also referred to as “Compound B”) was added to a 0.4% Polysorbate 80 (W / V) /2.6% Glycerin (W / V) solution in an amount of 0.
  • the suspension was suspended to 2 mg / ml or 2 mg / ml, and intravitreally administered once on the photocoagulation treatment day at a dose of 1 ⁇ g / eye or 10 ⁇ g / eye, respectively.
  • the symbol attached with one asterisk indicates that the significance level is 5% or less as a result of the above statistical analysis
  • the symbol attached with two asterisks indicates that the significance level is 1% or less.
  • the number of cases in each administration group is 7-8.
  • [Pharmacological test 2] (Study of the persistence of angiogenesis inhibitory effect in krypton laser-induced rat choroidal neovascularization model) Similar to Pharmacological Test 1, krypton laser-induced rat choroidal neovascularization model animals were prepared, and the persistence of the angiogenesis inhibitory action of Compound A in krypton laser-induced rat choroidal neovascularization model animals was examined. Compound A was used as a test drug. Compound A was suspended at 0.4 mg / ml as in Example 1 and administered intravitreally at a dose of 2 ⁇ g / eye once on the photocoagulation surgery day.
  • FIG. 2 shows the change over time of the choroidal neovascularization inhibitory effect of Compound A in terms of inhibition rate. Symbols with two asterisks indicate a significance level of 1% or less as a result of the statistical analysis described above.
  • the number of cases in each administration group is 8.
  • Inhibition rate (%) (A 0 ⁇ A X ) / A 0 ⁇ 100
  • a 0 incidence rate of choroidal neovascularization in base administration group
  • a X incidence rate of choroidal neovascularization in drug administration group (result)
  • intravitreal administration of Compound A continuously inhibited choroidal neovascularization until 12 weeks after the photocoagulation treatment.
  • the inhibitory effect of Compound A on choroidal neovascularization was statistically significant throughout the administration period. From this, it was shown that the choroidal neovascularization inhibitory action of Compound A lasts for at least 12 weeks.
  • the present compound has a strong choroidal neovascularization inhibitory effect, and an unexpected effect of exhibiting excellent durability has been obtained.
  • the present compound typified by Compound A can be suitably used as a therapeutic agent for choroidal diseases associated with angiogenesis whose therapeutic effect lasts for a long time, particularly as a therapeutic agent whose effect lasts for at least 12 weeks.
  • formulation example The pharmaceutical agent of the present invention will be described more specifically with formulation examples, but the present invention is not limited to these formulation examples.
  • Formulation Example 1 Eyedrops 100mg Compound A 10mg Sodium chloride 900mg Polysorbate 80 Appropriate amount Disodium hydrogen phosphate Appropriate amount Sodium dihydrogen phosphate Appropriate amount Sterilized purified water Appropriate amount Add Compound A and the above-mentioned components to sterile purified water, and mix them well to prepare an ophthalmic solution. By changing the amount of compound A added, the concentration of 0.05% (w / v), 0.1% (w / v), 0.5% (w / v), 1% (w / v) Eye drops can be prepared.
  • Formulation Example 2 Eyedrops 10mg Compound B 10mg Sodium chloride 900mg Polysorbate 80 Appropriate amount Disodium hydrogen phosphate Appropriate amount Sodium dihydrogen phosphate Appropriate amount Sterilized purified water Appropriate amount Compound B and the other components are added to sterile purified water, and these are mixed well to prepare an ophthalmic solution. By changing the amount of compound B added, the concentrations of 0.05% (w / v), 0.1% (w / v), 0.5% (w / v), 1% (w / v) Eye drops can be prepared.
  • Formulation Example 2 Eye Ointment 100g Compound B 0.3g Liquid paraffin 10.0g White petrolatum appropriate amount An ointment is prepared by adding compound B to uniformly melted white petrolatum and liquid paraffin, mixing them well, and then gradually cooling. By changing the amount of compound B added, the concentration of 0.05% (w / v), 0.1% (w / v), 0.5% (w / v), 1% (w / w) An eye ointment can be prepared.
  • Formulation Example 3 Compound A 1 mg in 100 mg tablet Lactose 66.4mg Corn starch 20mg Carboxymethylcellulose calcium 6mg Hydroxypropylcellulose 6mg Magnesium stearate 0.6mg Compound A and lactose are mixed in a blender, carboxymethylcellulose calcium and hydroxypropylcellulose are added to the mixture and granulated. The resulting granules are dried and sized, and magnesium stearate is added to the sized granules. Mix and compress with a tableting machine. Moreover, the tablet whose content in 100 mg is 0.1 mg, 10 mg, and 50 mg can be prepared by changing the addition amount of the compound A.
  • Formulation Example 4 Injection 10 or intravitreal administration compound 10 ml of Compound A 10 mg Sodium chloride 90mg Polysorbate 80 Appropriate amount Sterilized purified water Appropriate amount Compound A and the above-mentioned other components are added to sterile purified water and mixed well to dissolve or suspend to prepare an injection. By changing the amount of compound A added, an injection with a content of 2 mg, 10 mg, 50 mg, and 200 mg in 10 ml can be prepared. The injection prepared as described above can be administered as an injection for intraocular administration, for example, an intravitreal administration.
  • Formulation Example 5 Injection or intravitreal administration compound 10 ml of Compound B 10 mg Glycerol 260mg Polysorbate 80 Appropriate amount Sterilized purified water Appropriate amount Compound B and the other components mentioned above are added to sterile purified water, mixed well and dissolved or suspended to prepare an injection. By changing the amount of Compound B added, injections with a content of 2 mg, 10 mg, 50 mg, and 200 mg in 10 ml can be prepared. The injection prepared as described above can be administered as an injection for intraocular administration, for example, an intravitreal administration.
  • FIG. 2 is a graph showing the relationship between the dose of Compound A and Compound B and the incidence of choroidal neovascularization. It is a graph which shows the relationship between time and choroidal neovascularization incidence.

Abstract

Disclosed is a novel prophylactic or therapeutic agent for chorioretinal diseases. Temsirolimus, everolimus and the like, which are sirolimus derivatives, exhibit an excellent anti-angiogenic activity in a retina and a choroid, and are therefore useful as therapeutic agents for chorioretinal diseases such as age-related macular degeneration.

Description

シロリムス誘導体を有効成分として含有する網脈絡膜疾患の治療剤Retinal choroidal disease therapeutic agent containing sirolimus derivative as an active ingredient
　本発明は、シロリムス誘導体を有効成分として含有する網脈絡膜疾患の治療剤に関する。 The present invention relates to a therapeutic agent for a choroidal disease containing a sirolimus derivative as an active ingredient.
　加齢黄斑変性は、加齢に伴い黄斑部の網膜組織に障害が生じ、視力障害を来たすことを特徴とする疾患であり、失明にいたることもある、高齢者の視力障害の原因の一つである。中でも、滲出型加齢黄斑変性は、黄斑部の網膜下に脈絡膜由来の新生血管が発育し、出血や細胞の滲出を来す疾患である。 Age-related macular degeneration is a disease characterized by damage to the retinal tissue of the macular region with age, causing visual impairment, and one of the causes of visual impairment in the elderly that can lead to blindness It is. In particular, wet age-related macular degeneration is a disease in which neovascular vessels derived from the choroid develop under the retina of the macular region, causing bleeding and cell exudation.
　滲出型加齢黄斑変性の治療法についてさまざまな検討が行われており、新生血管が中心窩に達していない比較的早期の場合にはレーザー光を照射して新生血管を凝固させる光凝固術によって治療が選択されることもある。新生血管が中心窩に達している場合には、光線感受性の薬剤を投与しておき、弱いレーザー光を照射して薬剤を励起させ治療に用いる、いわゆる光力学的療法(PDT)が行われるが、PDTの効果は視力の低下を抑制するに留まり、完治が期待できるような臨床上有効な治療法は未だ見出されていない。 Various studies have been conducted on the treatment of wet age-related macular degeneration. In the relatively early stage when the new blood vessels do not reach the fovea, photocoagulation is performed by irradiating a laser beam to coagulate the new blood vessels. Treatment may be selected. When the new blood vessels reach the fovea, so-called photodynamic therapy (PDT) is performed, in which a photosensitive drug is administered and the drug is excited by irradiation with a weak laser beam to be used for treatment. However, the effect of PDT is only to suppress the decrease in visual acuity, and no clinically effective treatment that can be expected to be completely cured has yet been found.
　近年、新たな滲出型加齢黄斑変性の治療剤として、ペガプタニブナトリウムが開発された。ペガプタニブナトリウムは硝子体内に直接投与する新しいタイプの治療剤であり、その指定用法は、6週間に1回硝子体内に投与することとされている。 Recently, pegaptanib sodium has been developed as a new treatment for wet age-related macular degeneration. Pegaptanib sodium is a new type of therapeutic agent that is administered directly into the vitreous, and its designated usage is to be administered intravitreally once every 6 weeks.
　シロリムスは加齢黄斑変性などの網膜疾患に用いられることが、特許文献１に記載されている。一方、テムシロリムスおよびエベロリムスはいずれもシロリムスの誘導体であり、免疫抑制作用、腫瘍の治療作用などを具備することが知られている。
米国特許出願公開第2005/0187111号明細書 Patent Document 1 describes that sirolimus is used for retinal diseases such as age-related macular degeneration. On the other hand, both temsirolimus and everolimus are derivatives of sirolimus and are known to have immunosuppressive action, tumor therapeutic action, and the like.
US Patent Application Publication No. 2005/0187111
　加齢黄斑変性のような網脈絡膜疾患を治療するには、有効成分を眼球の最奥部に存在する患部に到達させる必要がある。有効成分の患部への送達にはドラッグデリバリーシステム(以下、DDSともいう)など投与方法の改良が検討されることが多い。しかしながら、DDSを用いて患部へ有効成分を送達するには解決しなければならない種々の困難がある。このため、患部近傍に薬剤を直接注入することができる硝子体内投与は、患者への肉体的負担及び精神的負担が大きいという問題点があるにも拘わらず、なお有望な投与方法の１つと考えられる。 In order to treat retina choroidal diseases such as age-related macular degeneration, it is necessary to allow the active ingredient to reach the affected area in the innermost part of the eyeball. In order to deliver an active ingredient to an affected area, improvement of administration methods such as a drug delivery system (hereinafter also referred to as DDS) is often considered. However, there are various difficulties that must be solved to deliver active ingredients to the affected area using DDS. For this reason, intravitreal administration in which a drug can be directly injected into the vicinity of the affected area is still one of the promising administration methods despite the problems that the physical burden and the mental burden on the patient are large. It is done.
　薬剤の硝子体内投与によって加齢黄斑変性などの網脈絡膜疾患の治療を行うにあたり、患者への肉体的および精神的な負担を減少させるため、薬剤の硝子体内投与の頻度を減らすこと、すなわち、治療効果の持続期間が長い化合物を見出すことは、きわめて重要な課題である。 Reducing the frequency of intravitreal drug administration, in order to reduce the physical and mental burden on patients in treating choroidal diseases such as age-related macular degeneration by intravitreal drug administration Finding compounds with a long duration of effect is a very important task.
　本発明者等は、加齢黄斑変性への治療効果が報告されているシロリムスの誘導体に着目した。 The present inventors focused on sirolimus derivatives that have been reported to have a therapeutic effect on age-related macular degeneration.
　すなわち、本発明は、シロリムス誘導体（以下、本化合物とも言う）を有効成分として含有する、加齢黄斑変性、ポリープ状脈絡膜血管症、網膜血管腫状増殖、糖尿病網膜症、糖尿病黄斑浮腫、網膜静脈閉塞症、網膜動脈閉塞症または未熟児網膜症等の網脈絡膜疾患の治療剤に関する。 That is, the present invention includes age-related macular degeneration, polypoidal choroidal vasculopathy, retinal hemangiomatosis, diabetic retinopathy, diabetic macular edema, retinal vein, which contains a sirolimus derivative (hereinafter also referred to as the present compound) as an active ingredient. The present invention relates to a therapeutic agent for choroidal diseases such as obstruction, retinal artery occlusion or retinopathy of prematurity.
　本明細書において塩とは、医薬として許容される塩であれば特に制限はないが、例えばナトリウム、カリウム等のアルカリ金属元素との塩、又は、塩化物イオン、臭化物イオン、ヨウ化物イオン等との四級アンモニウム塩が例示される。 In the present specification, the salt is not particularly limited as long as it is a pharmaceutically acceptable salt. For example, a salt with an alkali metal element such as sodium or potassium, or a chloride ion, a bromide ion, an iodide ion, or the like. The quaternary ammonium salt of is illustrated.
　本化合物に幾何異性体又は光学異性体が存在する場合は、それらの異性体も本発明の範囲に含まれる。また、本化合物は水和物又は溶媒和物の形態をとっていてもよい。 When a geometric isomer or optical isomer is present in the present compound, these isomers are also included in the scope of the present invention. Moreover, this compound may take the form of the hydrate or the solvate.
　本化合物におけるシロリムス誘導体とは、好ましくは、シロリムスの42位の水酸基が化学的に変換された誘導体を言う。 The sirolimus derivative in the present compound preferably refers to a derivative obtained by chemically converting the hydroxyl group at position 42 of sirolimus.
　本化合物における好ましい例として、テムシロリムス、エベロリムス、ゾタロリムス又はデフォロリムスが挙げられる。 Preferred examples of the present compound include temsirolimus, everolimus, zotarolimus or deforolimus.
　本化合物におけるより好ましい例として、下記式（１）で示されるテムシロリムス、下記式（２）で示されるエベロリムスが挙げられる。
Figure JPOXMLDOC01-appb-C000001
Figure JPOXMLDOC01-appb-C000002
 More preferable examples of the present compound include temsirolimus represented by the following formula (1) and everolimus represented by the following formula (2).
Figure JPOXMLDOC01-appb-C000001
Figure JPOXMLDOC01-appb-C000002
　本発明において網脈絡膜疾患とは、網膜又は脈絡膜における疾患をいい、例えば、加齢黄斑変性（初期加齢黄斑変性におけるドルーゼン形成、萎縮型加齢黄斑変性、滲出型加齢黄斑変性）、ポリープ状脈絡膜血管症、網膜血管腫状増殖、糖尿病網膜症（単純糖尿病網膜症、増殖前糖尿病網膜症、増殖糖尿病網膜症）、糖尿病黄斑浮腫、増殖性硝子体網膜症、網膜静脈閉塞症、網膜動脈閉塞症、未熟児網膜症、といった網脈絡膜疾患が挙げられ、好ましくは、加齢黄斑変性、ポリープ状脈絡膜血管症、網膜血管腫状増殖、糖尿病網膜症、糖尿病黄斑浮腫といった網脈絡膜疾患が挙げられる。 In the present invention, the reticulochoroidal disease refers to a disease in the retina or choroid, such as age-related macular degeneration (drusen formation in early age-related macular degeneration, atrophic age-related macular degeneration, exudative age-related macular degeneration), polyp Choroidal angiopathy, retinal hemangiomatous proliferation, diabetic retinopathy (simple diabetic retinopathy, preproliferative diabetic retinopathy, proliferative diabetic retinopathy), diabetic macular edema, proliferative vitreoretinopathy, retinal vein occlusion, retinal artery occlusion And retinopathy of prematurity, preferably age-related macular degeneration, polypoidal choroidal vasculopathy, retinal hemangiomatosis, diabetic retinopathy, diabetic macular edema, and the like.
　本化合物は、必要に応じて、医薬として許容される添加剤を加え、単独製剤又は配合製剤として汎用されている技術を用いて製剤化することができる。 This compound can be formulated by using a technique commonly used as a single preparation or a combination preparation by adding a pharmaceutically acceptable additive as necessary.
　本化合物は、前述の眼疾患の治療に使用する場合、患者に対して経口的又は非経口的に投与することができ、投与形態としては、経口投与、眼への局所投与（点眼投与、結膜嚢内投与、硝子体内投与、結膜下投与、テノン嚢下投与等）、静脈内投与、経皮投与等が挙げられる。本化合物を眼に局所投与する際に用いられる好ましい剤型としては、点眼剤若しくは眼軟膏剤が用いられ、又は、注射剤、特に、結膜下投与剤、テノン嚢投与剤又は硝子体内投与剤が用いられる。本化合物を有効成分として含有する製剤は、必要に応じて、製薬学的に許容され得る添加剤と共に、投与に適した剤型に製剤化される。経口投与に適した剤型としては、例えば、錠剤、カプセル剤、顆粒剤、散剤等が挙げられ、非経口投与に適した剤型としては、例えば、注射剤、点眼剤、眼軟膏、貼布剤、ゲル、挿入剤等が挙げられる。これらは当該分野で汎用されている通常の技術を用いて調製することができる。また、本化合物は優れた治療効果の持続作用を具備するため、通常ＤＤＳ化された製剤とする必要はないが、さらに本発明の治療効果の持続作用をより有効に生かすために、眼内インプラント用製剤やマイクロスフェアー等のＤＤＳ化された製剤としてもよい。 When this compound is used for the treatment of the aforementioned eye diseases, it can be administered to patients orally or parenterally. As the dosage form, oral administration, topical administration to the eye (eye drops, conjunctiva) Intracapsular administration, intravitreal administration, subconjunctival administration, subtenon administration, etc.), intravenous administration, transdermal administration, and the like. As a preferable dosage form used when this compound is locally administered to the eye, an eye drop or an eye ointment is used, or an injection, particularly a subconjunctival agent, a tenon sac administration agent or an intravitreal administration agent. Used. A preparation containing the present compound as an active ingredient is formulated into a dosage form suitable for administration, together with a pharmaceutically acceptable additive, if necessary. Examples of dosage forms suitable for oral administration include tablets, capsules, granules, powders, etc. Examples of dosage forms suitable for parenteral administration include injections, eye drops, eye ointments, and patches. Agents, gels, and intercalating agents. These can be prepared using ordinary techniques widely used in the field. In addition, since the present compound has a long-lasting therapeutic effect, it is not usually necessary to prepare a DDS-formulated preparation. However, in order to more effectively utilize the long-lasting therapeutic effect of the present invention, an intraocular implant can be used. DDS preparations such as pharmaceutical preparations and microspheres may be used.
　例えば、錠剤は、乳糖、ブドウ糖、Ｄ－マンニトール、無水リン酸水素カルシウム、デンプン、ショ糖等の賦形剤；カルボキシメチルセルロース、カルボキシメチルセルロースカルシウム、クロスカルメロースナトリウム、クロスポピドン、デンプン、部分アルファー化デンプン、低置換度ヒドロキシプロピルセルロース等の崩壊剤；ヒドロキシプロピルセルロース、エチルセルロース、アラビアゴム、デンプン、部分アルファー化デンプン、ポリビニルピロリドン、ポリビニルアルコール等の結合剤；ステアリン酸マグネシウム、ステアリン酸カルシウム、タルク、含水二酸化ケイ素、硬化油等の滑沢剤；精製白糖、ヒドロキシプロピルメチルセルロース、ヒドロキシプロピルセルロース、メチルセルロース、エチルセルロース、ポリビニルピロリドン等のコーティング剤；クエン酸、アスパルテーム、アスコルビン酸、メントール等の矯味剤などを適宜選択して用い、調製することができる。 For example, tablets are made of excipients such as lactose, glucose, D-mannitol, anhydrous calcium hydrogen phosphate, starch, sucrose; carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, crospovidone, starch, partially pregelatinized starch , Disintegrating agents such as low-substituted hydroxypropylcellulose; binders such as hydroxypropylcellulose, ethylcellulose, gum arabic, starch, partially pregelatinized starch, polyvinylpyrrolidone, polyvinyl alcohol; magnesium stearate, calcium stearate, talc, hydrous silicon dioxide , Lubricants such as hydrogenated oils; refined sucrose, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, ethylcellulose, polyvinyl chloride Coating agents such as Rupiroridon; citric acid, aspartame, using ascorbic acid, appropriately selected and the like flavoring agent such as menthol, can be prepared.
　注射剤は、塩化ナトリウム等の等張化剤；リン酸ナトリウム等の緩衝化剤；ポリオキシエチレンソルビタンモノオレート等の界面活性剤；メチルセルロース等の増粘剤等を必要に応じて選択して用い、調製することができる。 The injection is selected from an isotonic agent such as sodium chloride; a buffering agent such as sodium phosphate; a surfactant such as polyoxyethylene sorbitan monooleate; a thickener such as methylcellulose as necessary. Can be prepared.
　点眼剤は、塩化ナトリウム、濃グリセリンなどの等張化剤；リン酸ナトリウム、酢酸ナトリウムなどの緩衝化剤；ポリオキシエチレンソルビタンモノオレート、ステアリン酸ポリオキシル４０、ポリオキシエチレン硬化ヒマシ油等の界面活性剤；クエン酸ナトリウム、エデト酸ナトリウム等の安定化剤；塩化ベンザルコニウム、パラベン等の防腐剤等から必要に応じて選択して用い、調製することができ、ｐＨは眼科製剤に許容される範囲内にあればよいが、通常４～８の範囲内が好ましい。また、眼軟膏は、白色ワセリン、流動パラフィン等の汎用される基剤を用い、調製することができる。 Eye drops include isotonic agents such as sodium chloride and concentrated glycerin; buffering agents such as sodium phosphate and sodium acetate; surface activity such as polyoxyethylene sorbitan monooleate, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil Agents; Stabilizers such as sodium citrate and sodium edetate; can be selected and used as needed from preservatives such as benzalkonium chloride and paraben, and pH is acceptable for ophthalmic preparations Although it may be within the range, it is usually preferably within the range of 4-8. The eye ointment can be prepared using a commonly used base such as white petrolatum or liquid paraffin.
　挿入剤は、生体分解性ポリマー、例えばヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、カルボキシビニルポリマー、ポリアクリル酸等の生体分解性ポリマーを本化合物とともに粉砕混合し、この粉末を圧縮成型することにより、調製することができ、必要に応じて、賦形剤、結合剤、安定化剤、ｐＨ調整剤を用いることができる。 The intercalating agent is prepared by pulverizing and mixing a biodegradable polymer, for example, a biodegradable polymer such as hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxyvinyl polymer, and polyacrylic acid, together with the compound, and compressing the powder. If necessary, an excipient, a binder, a stabilizer, and a pH adjuster can be used.
　眼内インプラント用製剤は、生体分解性ポリマー、例えばポリ乳酸、ポリグリコール酸、乳酸・グリコール酸共重合体、ヒドロキシプロピルセルロース等の生体分解性ポリマーを用い、調製することができる。 Preparations for intraocular implants can be prepared using biodegradable polymers, for example, biodegradable polymers such as polylactic acid, polyglycolic acid, lactic acid / glycolic acid copolymer, and hydroxypropylcellulose.
　本化合物の投与量は、剤型、投与すべき患者の症状の軽重、年令、体重、眼球容積、医師の判断等に応じて適宜変えるこができる。 The dosage of the present compound can be appropriately changed according to the dosage form, the severity of symptoms of the patient to be administered, age, body weight, eye volume, doctor's judgment and the like.
　本化合物を眼球内投与、特に硝子体内投与によって投与する場合、1回あたり０．１μｇ～２０００μｇを投与することができる。この場合の好ましい投与量は、後述の薬理試験において有効であった用量を元に、ヒトと当該病態モデル動物の硝子体容積比を基に算出することができる。硝子体内に投与した物質は、最初に硝子体に分散することから、当該物質の患部付近の組織内濃度は投与量を硝子体容積で除することにより近似的に求めることができる。また、硝子体容積は眼球容積で近似できる。ヒトの硝子体容積は約4.5mLであり、ラットの硝子体容積は約50μLとされている (Oyster C；The Human Eye, 1999年,、Berkwitz BAら；Invest. Ophthalmol. Vis. Sci.　39巻 391ページ、1998年)。すなわち、ヒトの推定臨床用量は、ラットにおける用量を約90倍することにより換算することができる。ヒトにおいては人種、年齢、性別等によって、ラットにおいては系統、週齢、性別等によって平均的な硝子体容積には前述の容積値との差が生じることがあるが、理想的な投与量は臨床試験を行うことによって確認することができる。このような考え方に基づく、本化合物の眼球内投与、特に、硝子体内投与の際の好ましい投与量は1回当たり９０μｇ～９００μｇであり、より好ましくは、1回あたり９０μｇ～５００μｇである。 When the present compound is administered by intraocular administration, particularly by intravitreal administration, 0.1 μg to 2000 μg can be administered per dose. A preferable dose in this case can be calculated based on a vitreous volume ratio between a human and the disease model animal based on a dose effective in a pharmacological test described below. Since the substance administered into the vitreous is first dispersed in the vitreous body, the tissue concentration in the vicinity of the affected part of the substance can be obtained approximately by dividing the dose by the vitreous volume. The vitreous volume can be approximated by the eyeball volume. The volume of human vitreous body is about 4.5 mL, and the vitreous volume of rat is about 50 μL (Oyster® C; The Human Eye, w 1999, Berkwitz BA et al .; Invest. 巻 Ophthalmol. Vis. Sci. Vol. 39 391 pages, 1998). That is, the estimated clinical dose for humans can be converted by multiplying the dose in rats by about 90 times. In humans, the average vitreous volume may differ from the aforementioned volume value depending on race, age, sex, etc., and in rats, the strain, age, sex, etc. Can be confirmed by conducting clinical trials. Based on such a concept, the preferred dosage for intraocular administration, particularly intravitreal administration, of the present compound is 90 μg to 900 μg per dose, and more preferably 90 μg to 500 μg per dose.
　経口投与の場合、一般には、成人に対し１回あたり０．０１～５０００ｍｇ、好ましくは０．１～２５００ｍｇ、より好ましくは０．５～１０００ｍｇを投与することができ、注射剤の場合、一般には、成人に対し1回あたり０．０００１～２０００ｍｇを投与することができる。また、点眼剤又は挿入剤の場合には、１回あたり０．０００００１～１０％（ｗ／ｖ）、好ましくは０．００００１～１％（ｗ／ｖ）、より好ましくは０．０００１～０．１％（ｗ／ｖ）の有効成分濃度のものを投与することができる。さらに、貼布剤の場合は、成人に対し０．０００１～２０００ｍｇを含有する貼布剤を貼布することができ、眼内インプラント用製剤の場合は、成人に対し０．０００１～２０００ｍｇ含有する眼内インプラント用製剤を眼内にインプラントすることができる。 In the case of oral administration, generally 0.01 to 5000 mg, preferably 0.1 to 2500 mg, more preferably 0.5 to 1000 mg per administration can be administered to an adult. In adults, 0.0001 to 2000 mg can be administered at a time. In the case of eye drops or intercalating agents, 0.000001 to 10% (w / v), preferably 0.00001 to 1% (w / v), more preferably 0.0001 to 0.00 per dose. An active ingredient having a concentration of 1% (w / v) can be administered. Furthermore, in the case of a patch, a patch containing 0.0001 to 2000 mg can be applied to an adult. In the case of an intraocular implant preparation, 0.0001 to 2000 mg is included for an adult. An intraocular implant formulation can be implanted in the eye.
　本化合物は後述のように優れた持続性を有するので、治療効果が持続する間は投与する必要はなく、治療効果が減弱した場合に再度投与すればよい。眼球内投与、特に硝子体内投与で投与する場合の本化合物の投与間隔は、少なくとも12週間とすることができる。 Since this compound has excellent persistence as described later, it is not necessary to administer it while the therapeutic effect is sustained, and it may be administered again when the therapeutic effect is attenuated. When administered intraocularly, particularly administered intravitreally, the interval between administrations of the compound can be at least 12 weeks.
　後述の試験を実施したところ、薬理試験において、本化合物であるテムシロリムス（以下、「化合物Ａ」ともいう）及びエベロリムス（以下、「化合物Ｂ」ともいう）が、レーザー誘発ラット脈絡膜血管新生モデルにおいて脈絡膜血管新生を有意に阻害することが示された。また、意外なことに、単回投与後に治療効果の評価を長期間を継続する薬理試験において、化合物Aなどの本化合物は処置後12週においても脈絡膜血管新生抑制効果を有意に維持することが示された。 In the pharmacological test, temsirolimus (hereinafter also referred to as “compound A”) and everolimus (hereinafter also referred to as “compound B”), which are the present compounds, were found to be choroidal in a laser-induced rat choroidal neovascularization model. It has been shown to significantly inhibit angiogenesis. Surprisingly, in a pharmacological study in which the evaluation of the therapeutic effect is continued for a long time after a single administration, this compound such as Compound A can significantly maintain the choroidal neovascularization inhibitory effect even 12 weeks after the treatment. Indicated.
　すなわち、化合物Ａ等に代表される本化合物は、加齢黄斑変性、特に、浸出型加齢黄斑変性、ポリープ状脈絡膜血管症、網膜血管腫状増殖などの血管新生を伴う網脈絡膜疾患の治療剤として有用であり、1回の投与で長期間治療効果が持続するこれらの疾患の治療剤として有用である。 That is, the present compound typified by Compound A and the like is a therapeutic agent for age-related macular degeneration, particularly reticulochoroidal diseases associated with angiogenesis such as exudative age-related macular degeneration, polypoidal choroidal vasculopathy, retinal hemangiomatous proliferation, etc. It is useful as a therapeutic agent for these diseases, where the therapeutic effect is sustained for a long time by a single administration.
　以下に、薬理試験及び製剤例の結果を示すが、これらの例は本発明をよりよく理解するためのものであり、本発明の範囲を限定するものではない。 The results of pharmacological tests and formulation examples are shown below, but these examples are for better understanding of the present invention and do not limit the scope of the present invention.
［薬理試験１］
　レーザー誘発ラット脈絡膜血管新生モデル（Invest. Ophthalmol. Vis. Sci., 40(2), 459-466 (1999)）を用いて、本化合物の有用性を評価した。 [Pharmacological test 1]
The usefulness of this compound was evaluated using a laser-induced rat choroidal neovascularization model (Invest. Ophthalmol. Vis. Sci., 40 (2), 459-466 (1999)).
（クリプトンレーザー誘発ラット脈絡膜血管新生モデル動物の作製方法）
　ラットに５％（Ｗ／Ｖ）塩酸ケタミン注射液および２％塩酸キシラジン注射液の混合液（７：１）１ｍｌ／ｋｇを筋肉内投与して全身麻酔し、０．５％（Ｗ／Ｖ）トロピカミド－０．５％塩酸フェニレフリン点眼液を点眼して散瞳させた後、クリプトンレーザー光凝固装置により光凝固を行った。光凝固は、眼底後局部において、太い網膜血管を避け、焦点を網膜深層に合わせて１眼につき８ヶ所散在状に実施した（凝固条件：スポットサイズ１００μｍ、出力１００Ｗｍ、凝固時間０．１秒）。光凝固後、眼底撮影を行い、レーザー照射部位を確認した。 (Production method of krypton laser-induced rat choroidal neovascularization model animal)
Rats were anesthetized by intramuscular administration of 1 ml / kg of a mixed solution (7: 1) of 5% (W / V) ketamine hydrochloride injection and 2% xylazine hydrochloride injection, and 0.5% (W / V) Tropicamide-0.5% phenylephrine hydrochloride ophthalmic solution was instilled to make mydriasis, and then photocoagulated with a krypton laser photocoagulator. Photocoagulation was carried out at 8 locations per eye, avoiding thick retinal blood vessels in the posterior region of the fundus, focusing on the deep retina (coagulation conditions: spot size 100 μm, output 100 Wm, coagulation time 0.1 seconds). . After photocoagulation, fundus photography was performed to confirm the laser irradiation site.
（薬物投与方法）
　テムシロリムス（以下、「化合物Ａ」ともいう）又はエベロリムス（以下、「化合物Ｂ」ともいう）を０．４％Ｐｏｌｙｓｏｒｂａｔｅ ８０（Ｗ／Ｖ）/２．６％Ｇｌｙｃｅｒｉｎ（Ｗ／Ｖ）溶液に０．２ｍｇ／ｍｌ又は２ｍｇ／ｍｌになるように懸濁させ、それぞれ１回あたり１μｇ／眼又は１０μｇ／眼の用量で、光凝固処置日に１回硝子体内投与した。 (Drug administration method)
Temsirolimus (hereinafter also referred to as “Compound A”) or everolimus (hereinafter also referred to as “Compound B”) was added to a 0.4% Polysorbate 80 (W / V) /2.6% Glycerin (W / V) solution in an amount of 0. The suspension was suspended to 2 mg / ml or 2 mg / ml, and intravitreally administered once on the photocoagulation treatment day at a dose of 1 μg / eye or 10 μg / eye, respectively.
（評価方法）
　光凝固処置後２週間が経過した翌日（すなわち、光凝固処置日をｄａｙ　０としてｄａｙ　１５）に、ラットに５％（Ｗ／Ｖ）ペントバルビタール１ｍｌ／ｋｇを腹腔内投与して全身麻酔し、０．５％（Ｗ／Ｖ）トロピカミド－０．５％塩酸フェニレフリン点眼液を点眼して散瞳させた後、１０％フルオレセイン溶液０．１ｍｌを陰茎静脈から注入して、蛍光眼底造影を行った。蛍光眼底造影で、蛍光漏出が認められなかったスポットを陰性（血管新生なし）、蛍光漏出が認められたスポットを陽性（血管新生あり）と判断した。また、若干の蛍光漏出が認められる光凝固部位は、それが２箇所存在した時に陽性と判定した。その後、式１に従い、レーザー照射８ヶ所のスポットに対する陽性スポット数から脈絡膜血管新生発生率（％）を算出した。統計解析はダネットの多重比較により、基剤投与群に対する各化合物投与群の平均値の差を有意水準５％又は１％で検討した。化合物Ａ及びＢの評価結果（発症率）を図１に示す。なお、アスタリスク１個を付したシンボルは上述の統計解析の結果有意水準５%以下であることを、アスタリスク2個を付したシンボルは有意水準1%以下であることを示す。また、各投与群の例数は７～８である。 (Evaluation methods)
On the next day after 2 weeks from the photocoagulation treatment (that is, day 15 with the photocoagulation treatment day being day 0), the rats were given 5% (W / V) pentobarbital 1 ml / kg intraperitoneally and general anesthetized. After 0.5% (W / V) tropicamide-0.5% phenylephrine hydrochloride ophthalmic solution was instilled to make mydriatic, 0.1 ml of 10% fluorescein solution was injected from the penile vein, and fluorescence fundus imaging was performed. . In the fluorescence fundus angiography, a spot where no fluorescence leakage was observed was judged negative (no angiogenesis), and a spot where fluorescence leakage was found was judged positive (with angiogenesis). Moreover, the photocoagulation site | part by which some fluorescence leakage was recognized was determined to be positive when it existed in two places. Then, according to Formula 1, choroidal neovascularization incidence (%) was calculated from the number of positive spots with respect to 8 spots irradiated with laser. Statistical analysis was conducted by Dunnett's multiple comparison to examine the difference in the average value of each compound administration group with respect to the base administration group at a significance level of 5% or 1%. The evaluation results (onset rates) of compounds A and B are shown in FIG. In addition, the symbol attached with one asterisk indicates that the significance level is 5% or less as a result of the above statistical analysis, and the symbol attached with two asterisks indicates that the significance level is 1% or less. The number of cases in each administration group is 7-8.
［式１］
脈絡膜血管新生発生率（％）＝（陽性スポット数／全光凝固部位数）×１００
（結果）
　図１から明らかなように、化合物Ａ及び化合物Ｂのいずれも、硝子体内投与により、レーザー誘発ラット脈絡膜血管新生モデルにおける光凝固抑制効果を備えることが示された。両化合物においてその効果は用量依存的であり、１μｇ／眼、及び１０μｇ／眼の両方の用量で統計学的に有意であった。 [Formula 1]
Incidence rate of choroidal neovascularization (%) = (number of positive spots / total number of photocoagulation sites) × 100
(result)
As is clear from FIG. 1, both compound A and compound B were shown to have a photocoagulation inhibitory effect in a laser-induced rat choroidal neovascularization model by intravitreal administration. The effect was dose-dependent for both compounds and was statistically significant at both 1 μg / eye and 10 μg / eye dose.
［薬理試験２］
　（クリプトンレーザー誘発ラット脈絡膜血管新生モデルにおける血管新生阻害作用の持続性の検討）
　薬理試験１と同様にクリプトンレーザー誘発ラット脈絡膜血管新生モデル動物を作製し、化合物Ａのクリプトンレーザー誘発ラット脈絡膜血管新生モデル動物における血管新生阻害作用の持続性を検討した。被験薬として化合物Ａを用いた。化合物Ａは実施例１と同様に０．４ｍｇ／ｍｌになるように懸濁させ、２μｇ／眼の用量で光凝固手術日に１回硝子体内投与した。光凝固処置後１，２，４，６，８, １０及び１２週間が経過した日またはその翌日（すなわち、光凝固処置日をｄａｙ　０として、ｄａｙ　７，１４，２８，４２，５６，７０及び８５）に、実施例１と同様に脈絡膜血管新生の発生率を算出した。統計解析はスチューデントのt検定又はアスピン－ウェルチのt検定を用い、基剤投与群に対する平均値の差を有意水準1%で検討した。さらに、式２に従い、評価薬物の抑制率（％）を算出した。図２に化合物Ａの脈絡膜血管新生阻害作用の経時変化を抑制率で示す。なお、アスタリスク2個を付したシンボルは上述の統計解析の結果有意水準1%以下であることを示す。また、各投与群の例数は８である。 [Pharmacological test 2]
(Study of the persistence of angiogenesis inhibitory effect in krypton laser-induced rat choroidal neovascularization model)
Similar to Pharmacological Test 1, krypton laser-induced rat choroidal neovascularization model animals were prepared, and the persistence of the angiogenesis inhibitory action of Compound A in krypton laser-induced rat choroidal neovascularization model animals was examined. Compound A was used as a test drug. Compound A was suspended at 0.4 mg / ml as in Example 1 and administered intravitreally at a dose of 2 μg / eye once on the photocoagulation surgery day. The day after 1, 2, 4, 6, 8, 10 and 12 weeks after photocoagulation treatment or the next day (that is, day 7, 14, 28, 42, 56, 70 and 85), the incidence of choroidal neovascularization was calculated in the same manner as in Example 1. For statistical analysis, Student's t-test or Aspin-Welch's t-test was used, and the difference of the mean value from the base administration group was examined at a significance level of 1%. Furthermore, according to Formula 2, the inhibition rate (%) of the evaluation drug was calculated. FIG. 2 shows the change over time of the choroidal neovascularization inhibitory effect of Compound A in terms of inhibition rate. Symbols with two asterisks indicate a significance level of 1% or less as a result of the statistical analysis described above. The number of cases in each administration group is 8.
［式２］
抑制率（％）＝（Ａ０－ＡＸ）／Ａ０×１００
Ａ０：基剤投与群の脈絡膜血管新生発生率
ＡＸ：薬物投与群の脈絡膜血管新生発生率
（結果）
　レーザー誘発ラット脈絡膜血管新生モデルにおいて、化合物Ａの硝子体内投与により、光凝固処置後１２週間が経過するまで持続的に脈絡膜血管新生を阻害した。化合物Ａの脈絡膜血管新生阻害作用は投与期間を通じて統計学的に有意であった。このことから、化合物Ａの脈絡膜血管新生阻害作用は少なくとも１２週間持続することが示された。 [Formula 2]
Inhibition rate (%) = (A 0 −A X ) / A 0 × 100
A 0 : incidence rate of choroidal neovascularization in base administration group A X : incidence rate of choroidal neovascularization in drug administration group (result)
In a laser-induced rat choroidal neovascularization model, intravitreal administration of Compound A continuously inhibited choroidal neovascularization until 12 weeks after the photocoagulation treatment. The inhibitory effect of Compound A on choroidal neovascularization was statistically significant throughout the administration period. From this, it was shown that the choroidal neovascularization inhibitory action of Compound A lasts for at least 12 weeks.
（考察）
　上述のように、本化合物、特に化合物Ａの脈絡膜血管新生抑制作用は強く、特に優れた持続性を示すという意外な効果が得られた。化合物Ａに代表される本化合物は治療効果が長期間持続する血管新生を伴う脈絡膜疾患の治療剤、特に、少なくとも１２週間効果が持続する治療剤として好適に使用可能である。 (Discussion)
As described above, the present compound, particularly Compound A, has a strong choroidal neovascularization inhibitory effect, and an unexpected effect of exhibiting excellent durability has been obtained. The present compound typified by Compound A can be suitably used as a therapeutic agent for choroidal diseases associated with angiogenesis whose therapeutic effect lasts for a long time, particularly as a therapeutic agent whose effect lasts for at least 12 weeks.
［製剤例］
　製剤例を挙げて本発明の薬剤をさらに具体的に説明するが、本発明はこれらの製剤例にのみ限定されるものではない。 [Formulation example]
The pharmaceutical agent of the present invention will be described more specifically with formulation examples, but the present invention is not limited to these formulation examples.
処方例１　点眼剤
　１００ｍｌ中
　　化合物Ａ　　　　　　　　　　　　　　　　　　　　　１０ｍｇ
　　塩化ナトリウム　　　　　　　　　　　　　　　　　　９００ｍｇ
　　ポリソルベート８０　　　　　　　　　　　　　　　　適量
　　リン酸水素二ナトリウム　　　　　　　　　　　　　　適量
　　リン酸二水素ナトリウム　　　　　　　　　　　　　　適量
　　滅菌精製水　　　　　　　　　　　　　　　　　　　　適量
　滅菌精製水に化合物Ａ及びそれ以外の上記成分を加え、これらを十分に混合して点眼液を調製する。化合物Ａの添加量を変えることにより、濃度が０．０５％（ｗ／ｖ）、０．１％（ｗ／ｖ）、０．５％（ｗ／ｖ）、１％（ｗ／ｖ）の点眼剤を調製できる。 Formulation Example 1 Eyedrops 100mg Compound A 10mg
Sodium chloride 900mg
Polysorbate 80 Appropriate amount Disodium hydrogen phosphate Appropriate amount Sodium dihydrogen phosphate Appropriate amount Sterilized purified water Appropriate amount Add Compound A and the above-mentioned components to sterile purified water, and mix them well to prepare an ophthalmic solution. By changing the amount of compound A added, the concentration of 0.05% (w / v), 0.1% (w / v), 0.5% (w / v), 1% (w / v) Eye drops can be prepared.
処方例２　点眼剤
　１００ｍｌ中
　　化合物Ｂ　　　　　　　　　　　　　　　　　　　　　１０ｍｇ
　　塩化ナトリウム　　　　　　　　　　　　　　　　　　９００ｍｇ
　　ポリソルベート８０　　　　　　　　　　　　　　　　適量
　　リン酸水素二ナトリウム　　　　　　　　　　　　　　適量
　　リン酸二水素ナトリウム　　　　　　　　　　　　　　適量
　　滅菌精製水　　　　　　　　　　　　　　　　　　　　適量
　滅菌精製水に化合物Ｂ及びそれ以外の上記成分を加え、これらを十分に混合して点眼液を調製する。化合物Ｂの添加量を変えることにより、濃度が０．０５％（ｗ／ｖ）、０．１％（ｗ／ｖ）、０．５％（ｗ／ｖ）、１％（ｗ／ｖ）の点眼剤を調製できる。 Formulation Example 2 Eyedrops 10mg Compound B 10mg
Sodium chloride 900mg
Polysorbate 80 Appropriate amount Disodium hydrogen phosphate Appropriate amount Sodium dihydrogen phosphate Appropriate amount Sterilized purified water Appropriate amount Compound B and the other components are added to sterile purified water, and these are mixed well to prepare an ophthalmic solution. By changing the amount of compound B added, the concentrations of 0.05% (w / v), 0.1% (w / v), 0.5% (w / v), 1% (w / v) Eye drops can be prepared.
処方例２　眼軟膏
　１００ｇ中
　　化合物Ｂ　　　　　　　　　　　　　　　　　　　　　０．３ｇ
　　流動パラフィン　　　　　　　　　　　　　　　　　　１０．０ｇ
　　白色ワセリン　　　　　　　　　　　　　　　　　　　適量
　均一に溶融した白色ワセリン及び流動パラフィンに、化合物Ｂを加え、これらを十分に混合した後に徐々に冷却することで眼軟膏を調製する。化合物Ｂの添加量を変えることにより、濃度が０．０５％（ｗ／ｖ）、０．１％（ｗ／ｖ）、０．５％（ｗ／ｖ）、１％（ｗ／ｗ）の眼軟膏を調製できる。 Formulation Example 2 Eye Ointment 100g Compound B 0.3g
Liquid paraffin 10.0g
White petrolatum appropriate amount An ointment is prepared by adding compound B to uniformly melted white petrolatum and liquid paraffin, mixing them well, and then gradually cooling. By changing the amount of compound B added, the concentration of 0.05% (w / v), 0.1% (w / v), 0.5% (w / v), 1% (w / w) An eye ointment can be prepared.
処方例３　錠剤
　１００ｍｇ中
　　化合物Ａ　　　　　　　　　　　　　　　　　　　　　　１ｍｇ
　　乳糖　　　　　　　　　　　　　　　　　　　　　　　　６６．４ｍｇ
　　トウモロコシデンプン　　　　　　　　　　　　　　　　２０ｍｇ
　　カルボキシメチルセルロースカルシウム　　　　　　　　６ｍｇ
　　ヒドロキシプロピルセルロース　　　　　　　　　　　　６ｍｇ
　　ステアリン酸マグネシウム　　　　　　　　　　　　　　０．６ｍｇ
　化合物Ａ、乳糖を混合機中で混合し、その混合物にカルボキシメチルセルロースカルシウム及びヒドロキシプロピルセルロースを加えて造粒し、得られた顆粒を乾燥後整粒し、その整粒顆粒にステアリン酸マグネシウムを加えて混合し、打錠機で打錠する。また、化合物Ａの添加量を変えることにより、１００ｍｇ中の含有量が０．１ｍｇ、１０ｍｇ、５０ｍｇの錠剤を調製できる。 Formulation Example 3 Compound A 1 mg in 100 mg tablet
Lactose 66.4mg
Corn starch 20mg
Carboxymethylcellulose calcium 6mg
Hydroxypropylcellulose 6mg
Magnesium stearate 0.6mg
Compound A and lactose are mixed in a blender, carboxymethylcellulose calcium and hydroxypropylcellulose are added to the mixture and granulated. The resulting granules are dried and sized, and magnesium stearate is added to the sized granules. Mix and compress with a tableting machine. Moreover, the tablet whose content in 100 mg is 0.1 mg, 10 mg, and 50 mg can be prepared by changing the addition amount of the compound A.
処方例４　注射剤又は硝子体内投与剤
　１０ｍｌ中
　　化合物Ａ　　　　　　　　　　　　　　　　　　　　　　１０ｍｇ
　　塩化ナトリウム　　　　　　　　　　　　　　　　　　　９０ｍｇ
　　ポリソルベート８０　　　　　　　　　　　　　　　　　適量
　　滅菌精製水　　　　　　　　　　　　　　　　　　　　　適量
　滅菌精製水に化合物Ａ及びそれ以外の上記成分を加え、充分に混合して溶解又は懸濁し注射剤を調製する。化合物Ａの添加量を変えることにより、１０ｍｌ中の含有量が２ｍｇ、１０ｍｇ、５０ｍｇ、２００ｍｇの注射剤を調製できる。このようにして調製した注射剤は眼内投与のための注射剤、例えば硝子体内投与剤として投与することができる。 Formulation Example 4 Injection 10 or intravitreal administration compound 10 ml of Compound A 10 mg
Sodium chloride 90mg
Polysorbate 80 Appropriate amount Sterilized purified water Appropriate amount Compound A and the above-mentioned other components are added to sterile purified water and mixed well to dissolve or suspend to prepare an injection. By changing the amount of compound A added, an injection with a content of 2 mg, 10 mg, 50 mg, and 200 mg in 10 ml can be prepared. The injection prepared as described above can be administered as an injection for intraocular administration, for example, an intravitreal administration.
処方例５　注射剤又は硝子体内投与剤
　１０ｍｌ中
　　化合物Ｂ　　　　　　　　　　　　　　　　　　　　　　１０ｍｇ
　　グリセロール　　　　　　　　　　　　　　　　　　　　２６０ｍｇ
　　ポリソルベート８０　　　　　　　　　　　　　　　　　適量
　　滅菌精製水　　　　　　　　　　　　　　　　　　　　　適量
　化合物Ｂ及びそれ以外の上記成分を滅菌精製水に加え、充分に混合して溶解又は懸濁し注射剤を調製する。化合物Ｂの添加量を変えることにより、１０ｍｌ中の含有量が２ｍｇ、１０ｍｇ、５０ｍｇ、２００ｍｇの注射剤を調製できる。このようにして調製した注射剤は眼内投与のための注射剤、例えば硝子体内投与剤として投与することができる。 Formulation Example 5 Injection or intravitreal administration compound 10 ml of Compound B 10 mg
Glycerol 260mg
Polysorbate 80 Appropriate amount Sterilized purified water Appropriate amount Compound B and the other components mentioned above are added to sterile purified water, mixed well and dissolved or suspended to prepare an injection. By changing the amount of Compound B added, injections with a content of 2 mg, 10 mg, 50 mg, and 200 mg in 10 ml can be prepared. The injection prepared as described above can be administered as an injection for intraocular administration, for example, an intravitreal administration.
化合物Ａおよび化合物Ｂの用量と脈絡膜血管新生発生率の関係を示すグラフである。2 is a graph showing the relationship between the dose of Compound A and Compound B and the incidence of choroidal neovascularization. 時間と脈絡膜血管新生発生率の関係を示すグラフである。It is a graph which shows the relationship between time and choroidal neovascularization incidence.

Claims (20)

  1. 　テムシロリムス、エベロリムス、ゾタロリムス、デフォロリムス及びこれらの塩からなる群から選択される少なくとも１つの化合物を有効成分として含有する網脈絡膜疾患の治療剤。 A therapeutic agent for retina choroidal disease comprising as an active ingredient at least one compound selected from the group consisting of temsirolimus, everolimus, zotarolimus, deforolimus and salts thereof.
  2. 　網脈絡膜疾患が血管新生を伴う網脈絡膜疾患である請求項１記載の治療剤。 The therapeutic agent according to claim 1, wherein the retina choroid disease is a retina choroid disease accompanied by angiogenesis.
  3. 　網脈絡膜疾患が加齢黄斑変性、ポリープ状脈絡膜血管症、網膜血管腫状増殖、糖尿病網膜症、糖尿病黄斑浮腫、増殖性硝子体網膜症、網膜静脈閉塞症、網膜動脈閉塞症、未熟児網膜症または未熟児網膜症である、請求項２記載の治療剤。 Retinal choroidal disease is age-related macular degeneration, polypoidal choroidal vasculopathy, retinal hemangiomatous proliferation, diabetic retinopathy, diabetic macular edema, proliferative vitreoretinopathy, retinal vein occlusion, retinal artery occlusion, retinopathy of prematurity Or the therapeutic agent of Claim 2 which is retinopathy of prematurity.
  4. 　化合物がテムシロリムス、エベロリムス及びこれらの塩からなる群から選択される、請求項１～３いずれか記載の治療剤。 The therapeutic agent according to any one of claims 1 to 3, wherein the compound is selected from the group consisting of temsirolimus, everolimus and salts thereof.
  5. 　治療効果が長期間持続することを特徴とする、請求項１～４いずれか記載の治療剤。 The therapeutic agent according to any one of claims 1 to 4, wherein the therapeutic effect lasts for a long time.
  6. 　治療効果が少なくとも１２週間持続することを特徴とする、請求項５記載の治療剤。 The therapeutic agent according to claim 5, wherein the therapeutic effect lasts for at least 12 weeks.
  7. 　剤型が点眼剤又は眼軟膏剤である、請求項１～６いずれか記載の治療剤 The therapeutic agent according to any one of claims 1 to 6, wherein the dosage form is an eye drop or an eye ointment.
  8. 　剤型が結膜下投与剤、テノン嚢投与剤又は硝子体内投与剤である請求項１～６いずれか記載の治療剤。 The therapeutic agent according to any one of claims 1 to 6, wherein the dosage form is a subconjunctival administration agent, a tenon sac administration agent, or an intravitreal administration agent.
  9. 　剤型が硝子体内投与剤である請求８記載の治療剤。 The therapeutic agent according to claim 8, wherein the dosage form is an intravitreal agent.
  10. 　１回あたりの投与量が９０μｇ～９００μｇである、請求項９記載の治療剤。 The therapeutic agent according to claim 9, wherein the dose per administration is 90 μg to 900 μg.
  11. 　テムシロリムス、エベロリムス、ゾタロリムス、デフォロリムス及びこれらの塩からなる群から選択される少なくとも１つの化合物を薬理学上有効な量患者に投与することを含む、網脈絡膜疾患の治療方法。 A method for treating choroidal diseases, comprising administering to a patient a pharmacologically effective amount of at least one compound selected from the group consisting of temsirolimus, everolimus, zotarolimus, deforolimus and salts thereof.
  12. 　網脈絡膜疾患が血管新生を伴う網脈絡膜疾患である請求項１１記載の治療方法。 The treatment method according to claim 11, wherein the retina choroid disease is a retina choroid disease accompanied by angiogenesis.
  13. 　網脈絡膜疾患が加齢黄斑変性、ポリープ状脈絡膜血管症、網膜血管腫状増殖、糖尿病網膜症、糖尿病黄斑浮腫、増殖性硝子体網膜症、網膜静脈閉塞症、網膜動脈閉塞症、未熟児網膜症または未熟児網膜症である、請求項１２記載の治療方法。 Retinal choroidal disease is age-related macular degeneration, polypoidal choroidal vasculopathy, retinal hemangiomatous proliferation, diabetic retinopathy, diabetic macular edema, proliferative vitreoretinopathy, retinal vein occlusion, retinal artery occlusion, retinopathy of prematurity Or the treatment method of Claim 12 which is retinopathy of prematurity.
  14. 　化合物がテムシロリムス、エベロリムス及びこれらの塩からなる群から選択される、請求項１１～１３いずれか記載の治療方法。 The method according to any one of claims 11 to 13, wherein the compound is selected from the group consisting of temsirolimus, everolimus and salts thereof.
  15. 　治療効果が長期間持続することを特徴とする、請求項１１～１４いずれか記載の治療方法。 The treatment method according to any one of claims 11 to 14, wherein the therapeutic effect lasts for a long time.
  16. 　治療効果が少なくとも１２週間持続することを特徴とする、請求項１５記載の治療方法。 The method according to claim 15, characterized in that the therapeutic effect lasts for at least 12 weeks.
  17. 　剤型が点眼剤又は眼軟膏剤である、請求項１１～１６いずれか記載の治療方法。 The treatment method according to any one of claims 11 to 16, wherein the dosage form is an eye drop or an eye ointment.
  18. 　剤型が結膜下投与剤、テノン嚢投与剤又は硝子体内投与剤である請求項１１～１６いずれか記載の治療方法。 The method according to any one of claims 11 to 16, wherein the dosage form is a subconjunctival administration agent, a tenon sac administration agent, or an intravitreal administration agent.
  19. 　剤型が硝子体内投与剤である請求１８記載の治療方法。 The treatment method according to claim 18, wherein the dosage form is an intravitreal agent.
  20. 　１回あたりの投与量が９０μｇ～９００μｇである、請求項１９記載の治療方法。 The treatment method according to claim 19, wherein the dose per administration is 90 μg to 900 μg.
PCT/JP2010/056498 2009-04-10 2010-04-12 Therapeutic agent for chorioretinal diseases comprising sirolimus derivative as active ingredient WO2010117077A1 (en)

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EP3629774A4 (en) 2017-05-26 2021-03-03 Mercator Medsystems, Inc. Combination therapy for treatment of restenosis

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