WO2010117077A1 - Agent thérapeutique pour des maladies choriorétiniennes comprenant un dérivé de sirolimus comme principe actif - Google Patents

Agent thérapeutique pour des maladies choriorétiniennes comprenant un dérivé de sirolimus comme principe actif Download PDF

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Publication number
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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English (en)
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.

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Abstract

L'invention porte sur un nouvel agent prophylactique ou thérapeutique pour des maladies choriorétiniennes. Le temsirolinus, l'évérolimus et similaires, qui sont des dérivés du sirolimus, présentent une excellente activité anti-angiogénique dans une rétinine et une choroïde, et sont par conséquent utiles comme agents thérapeutiques pour des maladies choriorétiniennes, telles que la dégénérescence maculaire liée à l'âge.
PCT/JP2010/056498 2009-04-10 2010-04-12 Agent thérapeutique pour des maladies choriorétiniennes comprenant un dérivé de sirolimus comme principe actif WO2010117077A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2015507478A (ja) * 2012-01-04 2015-03-12 クォーク ファーマシューティカルズ インコーポレーティッドＱｕａｒｋ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ，Ｉｎｃ． Ｃａｓｐ２に対する二本鎖ｒｎａ化合物およびその使用
CN107550852A (zh) * 2016-06-30 2018-01-09 山东新时代药业有限公司 一种坦西莫司注射液注射用溶剂及其制备方法

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109996549A (zh) * 2016-09-22 2019-07-09 墨卡托医疗系统公司 使用坦罗莫司治疗再狭窄
CN110996687A (zh) 2017-05-26 2020-04-10 墨卡托医疗系统公司 用于治疗再狭窄的联合疗法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007505906A (ja) * 2003-09-19 2007-03-15 アドバンスト アキュラー システムズ リミテッド マクロライド系抗生物質及び／又はミコフェノール酸含有眼用溶液
JP2008530128A (ja) * 2005-02-09 2008-08-07 マクサイト， インコーポレイテッド 疾患または状態を処置するための液体処方物

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007505906A (ja) * 2003-09-19 2007-03-15 アドバンスト アキュラー システムズ リミテッド マクロライド系抗生物質及び／又はミコフェノール酸含有眼用溶液
JP2008530128A (ja) * 2005-02-09 2008-08-07 マクサイト， インコーポレイテッド 疾患または状態を処置するための液体処方物

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2015507478A (ja) * 2012-01-04 2015-03-12 クォーク ファーマシューティカルズ インコーポレーティッドＱｕａｒｋ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ，Ｉｎｃ． Ｃａｓｐ２に対する二本鎖ｒｎａ化合物およびその使用
CN107550852A (zh) * 2016-06-30 2018-01-09 山东新时代药业有限公司 一种坦西莫司注射液注射用溶剂及其制备方法
CN107550852B (zh) * 2016-06-30 2021-05-14 山东新时代药业有限公司 一种坦西莫司注射液注射用溶剂及其制备方法

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