WO2015065136A1 - Pharmaceutical composition for preventing or treating vascular permeability-related diseases, containing masitinib or pharmaceutically acceptable salt thereof as active ingredient - Google Patents

Pharmaceutical composition for preventing or treating vascular permeability-related diseases, containing masitinib or pharmaceutically acceptable salt thereof as active ingredient Download PDF

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WO2015065136A1
WO2015065136A1 PCT/KR2014/010452 KR2014010452W WO2015065136A1 WO 2015065136 A1 WO2015065136 A1 WO 2015065136A1 KR 2014010452 W KR2014010452 W KR 2014010452W WO 2015065136 A1 WO2015065136 A1 WO 2015065136A1
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vascular permeability
related diseases
pharmaceutical composition
administration
preventing
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Korean (ko)
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서원희
김지연
임지은
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아주대학교산학협력단
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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
    • 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
    • A61K31/4965—Non-condensed pyrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • 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
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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

Definitions

  • the present invention relates to a pharmaceutical composition for the prevention or treatment of vascular permeability-related diseases comprising masityinib or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Blood vessels are vital for the survival and normal functioning of all the cells that make up the human body.
  • the innermost vascular endothelial cells form a single layer that controls the leakage of proteins, fluids and electrolytes in the blood into surrounding tissues.
  • the gap between vascular endothelial cells is very narrow in normal blood vessels, so that the permeability of blood vessels is low, whereas when inflammatory cells infiltrate blood vessels or become hypoxic due to blood vessel damage, various cytokines and vascular endothelial growth factors , VEGF), the gap between vascular endothelial cells is destabilized by the secretion of growth factors, such as VEGF significantly increases vascular permeability. Increased vascular permeability leads to an increase in leakage of fluid to the perivascular tissue.
  • vascular permeability causes various diseases, especially excessive increase in vascular permeability in the retina or choroid is the most common cause of fatal vision loss by promoting bleeding and macular edema. do.
  • Representative diseases with such pathogenesis include diabetic retinopathy (DR), diabetic macular edema (DME), macular edema due to retinal vein occlusion, macular degeneration, Choroidal neovascularization, retinopathy of prematurity (ROP), etc. (Surv Ophthalmol. 2007 Jan; 52 Suppl 1: S3-19).
  • DR diabetic retinopathy
  • DME diabetic macular edema
  • ROP Choroidal neovascularization
  • ROP retinopathy of prematurity
  • Masitinib has been reported to have a therapeutic effect against multiple sclerosis (Vermersch P, BMC Neurol. 2012 (12); 12:36). Clinical trials have also been reported in neurological and inflammatory diseases such as Alzheimer's, rheumatoid arthritis, asthma and mastocytosis (Humbert M, Allergy 2009, 64: 1194-1201). As such, there has been no report on the progress of studies to some extent with regard to other uses of masitinib, and whether it is possible to control vascular permeability with marsitibini.
  • An object of the present invention to provide a pharmaceutical composition for the prevention or treatment of vascular permeability-related diseases comprising masityinib or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a pharmaceutical composition for the prevention or treatment of vascular permeability-related diseases comprising masityinib or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a method for treating a vascular permeability-related disease comprising administering masityib or a pharmaceutically acceptable salt thereof to a subject having a vascular permeability-related disease.
  • pharmaceutically acceptable salts falls within the scope of medical judgment and refers to salts suitable for use in contact with human and / or animal tissues without causing inappropriate toxicity, irritation, allergic reactions, and the like.
  • Such pharmaceutically acceptable salts are well known in the art.
  • Pharmaceutically acceptable salts can be obtained during the final separation and purification of the compounds of the invention, or separately by reacting the free base functional groups with a suitable inorganic acid such as hydrochloric acid, phosphoric acid or sulfuric acid, or by organic acids such as ascorbic acid, citric acid, tartaric acid. , Lactic acid, maleic acid, malonic acid, fumaric acid, glycolic acid, succinic acid, propionic acid, acetic acid, methanesulfonic acid and the like. Acid functional groups can be reacted with organic bases or inorganic bases such as sodium hydroxide, potassium hydroxide or lithium hydroxide.
  • vascular permeability-related disease refers to a disease caused by disruption of normal regulation of vascular permeability, and generally refers to a disease causing bleeding by changing blood vessels and increasing permeability.
  • the vascular permeability-related diseases include diabetic retinopathy, diabetic macular edema, macular edema caused by retinal vein occlusion, macular degeneration, choroidal neovascularization, glaucoma retinitis pigmentosa (ROP), and retinopathy of prematurity.
  • Glaucoma Glaucoma, corneal dystrophy, retinoschises, Stargardt's disease, autosomal dominant druzen, Best's macular dystrophy, cystoid Cystoid macular edema, ischemic retinopathy, inflammation-induced retinal degenerative disease, X-linked juvenile retinoschisis, Malatya leventi Ness (Malattia Leventinese; ML) or Doyne honeycomb retinal dystrophy, and the like, but is not limited thereto.
  • the term "treatment” refers to all actions that are clinically involved in altering the natural process of the individual or cell to be treated, which can be performed during or to prevent clinical pathology. have.
  • the desired therapeutic effect includes preventing the occurrence or recurrence of the disease, alleviating the symptoms, lowering all direct or indirect pathological consequences of the disease, preventing metastasis, reducing the rate of disease progression, and reducing the disease state. Or temporarily alleviate, drive off, or improve the prognosis.
  • the treatment is to improve the course of the vascular permeability-related disease by administering a pharmaceutical composition comprising masityib or a pharmaceutically acceptable salt thereof as an active ingredient to a patient having vascular permeability-related disease. It may be interpreted to include all acts, but it is not particularly limited thereto.
  • the term "prophylaxis" is to administer to the individual expected to develop vascular permeability-related diseases by administering a pharmaceutical composition comprising the masityinib or a pharmaceutically acceptable salt thereof provided in the present invention as an active ingredient It means any action that inhibits or delays the onset of the disease.
  • compositions of the present invention are optionally formulated into a formulation suitable for administration, with pharmaceutically acceptable additives.
  • formulations suitable for oral administration include tablets, capsules, granules, fines and powders, and the like;
  • Formulations suitable for parenteral administration include injections, eye drops, eye ointments, patches, gels and inserts. These formulations can be formulated using common techniques that are universal in the art.
  • the compositions of the present invention can be formulated into preparations prepared by DDS (Drug Delivery System) such as preparations for intraocular implants or microspheres.
  • DDS Drug Delivery System
  • tablets may include, for example, excipients such as lactose, glucose, D-mannitol, dicalcium phosphate anhydrous, starch and sucrose;
  • Disintegrating agents such as carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, crospovidone, starch, partially alphaated starch and low-substituted hydroxypropyl cellulose;
  • Binders such as hydroxypropyl cellulose, ethyl cellulose, gum arabic, starch, partially alphaated starch, polyvinylpyrrolidone and polyvinyl alcohol;
  • Lubricants such as magnesium stearate, calcium stearate, talc, hydrous silicon dioxide and hardened oil;
  • Coating agents such as purified white sugar, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose and polyvinylpyrrolidone;
  • flavoring agents such as citric acid, aspartam
  • Injectables include, for example, isotonic agents such as sodium chloride; Buffering agents such as sodium phosphate; Surfactants such as polyoxyethylene sorbitan monooleate; And an additive selected from thickeners such as methyl cellulose and the like may be used in some cases.
  • Eye drops include, for example, isotonic agents such as sodium chloride, potassium chloride, glycerin, concentrated glycerin, mannitol, sorbitol, boric acid, glucose, and propylene glycol; Buffering agents such as phosphate buffer, acetate buffer, borate buffer, carbonate buffer, citrate buffer, tris buffer, glutamic acid and the like; Surfactants such as polyoxyethylene sorbitan monooleate, polyoxyl stearate 40 and polyoxyethylene cured castor oil; Stabilizers such as sodium citrate and sodium edetate; And additives selected from preservatives such as benzalkonium chloride and paraben, etc., may be used in some cases.
  • isotonic agents such as sodium chloride, potassium chloride, glycerin, concentrated glycerin, mannitol, sorbitol, boric acid, glucose, and propylene glycol
  • Buffering agents such as phosphate buffer, acetate
  • the pH of the eye drops may be within an ophthalmically acceptable range, but usually within the range of 4 to 8 is preferred.
  • ophthalmic ointment can be prepared using a common base such as white petrolatum and liquid paraffin.
  • Formulations administered to the eye, such as eye drops, may be formulated into liquid solutions, including gels, sprays, suspensions, microemulsions, nanoparticles, including creams, foams, emulsions.
  • the dosage and dosage of the eye drops of the present invention vary depending on the symptoms, age, etc. of the patient, and in the case of eye drops and suspensions, usually 2 to 4 drops per day, 1 to 5 drops per drop, and in the case of eye ointment, usually 1 day 3 times, it is used by applying an appropriate amount in the conjunctival sac.
  • Inserts can be prepared by, for example, grinding and mixing biodegradable polymers such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxyvinyl polymer and polyacrylic acid with the compound of the present invention, and then compression molding the powder. Can be. If desired, excipients, binders, stabilizers and pH adjusters can be used. Formulations for intraocular implants can be prepared using biodegradable polymers such as polylactic acid, polyglycolic acid, lactic acid-glycolic acid copolymers and hydroxypropylcellulose. The insert can be formulated into a patch or contact lens.
  • compositions of the invention may be prepared in preparations in immediate release, sustained release, pulsating, or timed release forms. As long as it is a method which can make each said active ingredient have the above-mentioned preferable time difference range, it does not restrict
  • Suitable dosages for preventing or treating a disease include, but are not limited to, the type of disease to be treated, the severity and course of the disease, whether the composition of the invention is administered for prophylactic or therapeutic purposes, conventional therapies, patients It will depend on the clinical history and response to masitibini and the judgment of the attending physician.
  • Masitinib is suitably administered to a patient once or throughout a series of treatment periods.
  • masitibini or a pharmaceutically acceptable salt thereof When masitibini or a pharmaceutically acceptable salt thereof is coadministered with a second therapeutic agent that reduces vascular permeability, the second therapeutic agent may be administered first, followed by the administration of mastitinib. In addition, concomitant administration or first administration of masityib is also contemplated. Suitable dosages for the second therapeutic agent are those currently in use and may be reduced due to the combined action (synergy) of these agents with masityib.
  • the second therapeutic agent is an inhibitor that reduces the expression or activity of VEGF or its receptor (hereinafter referred to as "VEGF inhibitor"), an angiopoietin or an inhibitor that reduces the expression or activity of its receptor, dexamethasone ( Corticosteroid related drugs such as dexamethasone) and triamcinolone, but are not limited thereto.
  • VEGF inhibitor an inhibitor that reduces the expression or activity of VEGF or its receptor
  • angiopoietin or an inhibitor that reduces the expression or activity of its receptor an angiopoietin or an inhibitor that reduces the expression or activity of its receptor
  • dexamethasone Corticosteroid related drugs such as dexamethasone
  • triamcinolone but are not limited thereto.
  • the VEGF inhibitor is a drug that inhibits the promotion of angiogenesis by attenuating the action of vascular endothelial growth factor (VEGF), and may also exhibit pharmacological effects such as vascular permeability inhibition and vascular endothelial cell growth inhibition.
  • VEGF inhibitors include anti-VEGF antibodies, VEGF ligand inhibitors, antagonists of VEGF receptors, nucleic acid medicines related to VEGF, and the like.
  • VEGF ligand inhibitor examples include apribercept (VEGF-Trap) and VEGF-Trap EYE.
  • anti-VEGF antibody examples include bevacizumab sodium and ranibizumab.
  • antagonists of VEGF receptors are sorafenib and sunitinib.
  • nucleic acid medicine related to VEGF examples include paptanib sodium, which is an aptamer drug, and RTP801i-14, which is an siRNA.
  • bevacizumab sodium, ranibizumab, VEGF-Trap, VEGF-Trap EYE and the like non-selectively bind to all VEGFs broadly, thereby inhibiting binding of VEGF to receptors.
  • the patient may be treated with Masitinib from about 1 ⁇ g / kg to about 100 mg / kg, preferably from 0.1 mg / kg to 10 mg / kg.
  • Initial candidate dose for administration to a patient may range from about 1 ⁇ g / kg to 100 mg / kg or more, depending on the factors mentioned above. Repeated administration over several days will continue treatment until the desired disease symptoms are suppressed, depending on the disease. However, other dosages may be used.
  • mastitin is administered at a dose ranging from about 0.1 mg / kg to about 20 mg / kg.
  • a typical vascular permeability related disease as a result of administering masityinib to an animal model induced with diabetic retinopathy, a typical vascular permeability related disease, by confirming that vascular permeability is significantly reduced (see FIG. 3), It has been confirmed that its pharmaceutically acceptable salts have a therapeutic effect on vascular permeability related diseases.
  • the route of administration of the pharmaceutical composition according to the present invention may be one selected from the group consisting of oral, subcutaneous, intraperitoneal, pulmonary, intranasal, intramuscular, intravenous, intraarterial and ocular administration, preferably It may be one selected from the group consisting of oral, intraperitoneal and topical administration, and more preferably, topical administration.
  • the topical administration may be one selected from the group consisting of intraconjunctival administration, intravitreal administration (intravitreal administration), subconjunctival administration, and subtenonal cystic administration, preferably intravitreal administration.
  • masityib or a pharmaceutically acceptable salt thereof can be used for the prevention or treatment of vascular permeability-related diseases. have.
  • the pharmaceutical composition containing masityinib or a pharmaceutically acceptable salt thereof according to the present invention as an active ingredient inhibits vascular permeability, eye diseases caused by vascular permeability can be treated.
  • 1 is a graph showing the effect of masityib on blood glucose in a diabetic retinopathy animal model.
  • FIG. 2 is a graph showing the effect of masityib on body weight in diabetic retinopathy animal model.
  • FIG. 3A and 3B are photographs and graphs showing the results of confirming the preventive effect of masityib on the induction of diabetic retinopathy, a model of increased vascular permeability
  • FIG. 3A is an effect of improving vascular permeability according to the treatment concentration of masitinib.
  • 3B is a graph showing the effect of improving vascular permeability according to the treatment concentration of masityib: DM (Diabetic Mellitus).
  • STZ streptozotocin (Sigma)
  • blood glucose 300 mg / dl or more
  • Increased animals were used as an animal model for diabetic retinopathy.
  • the group not treated with STZ was used as a normal control for diabetic retinopathy animal model (hereinafter referred to as "normal").
  • Diabetic rats 3 days after STZ administration were treated with DMSO as a negative control, and intravitreous injection at a dose of 50 ⁇ g or 100 ⁇ g of masitibib (Selleckchem. Houston, TX, USA) as an experimental group.
  • Blood glucose levels of the animal models were measured on days 8 and 15 of the first day of STZ administration.
  • Body weights of the animal models were measured on days 8 and 15 of the first day of STZ administration.
  • the animal model was anesthetized 12 days after drug administration (day 15 of the first day of STZ), and FITC-labeled dextran (Fluorescein isothiocyanate-dextran) in the heart of the animal model. was injected to allow fluorescent material to flow along the blood. After 30 minutes, the retinas of the animal model were removed and separated, and a flat mounting was performed, and then the degree of distribution of the fluorescent substance in the retina was observed by fluorescence microscopy.
  • FITC-labeled dextran Fluorescein isothiocyanate-dextran
  • Masitinib and sodium chloride are dissolved in sterile purified water to prepare an injection.
  • the injection in 0.1 mg, 10 mg, and 50 mg of content in 10 ml can be prepared.
  • eye drops having a concentration of 0.05% (w / v), 0.3% (w / v), 0.5% (w / v) and 1% (w / v) can be prepared.
  • eye ointments having a concentration of 1% (w / w) and 3% (w / w) can be prepared.
  • the pharmaceutical composition containing masityib or a pharmaceutically acceptable salt thereof according to the present invention as an active ingredient inhibits vascular permeability, it may be usefully used in the field of treating eye diseases caused by vascular permeability.

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Abstract

The present invention relates to a pharmaceutical composition for preventing or treating vascular permeability-related diseases, containing masitinib or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutical composition according to the present invention inhibits vascular permeability, thereby effectively preventing or treating diseases caused by vascular permeability.

Description

마시티닙 또는 이의 약학적으로 허용되는 염을 유효성분으로 포함하는 혈관 투과성 관련 질환의 예방 또는 치료용 약학적 조성물Pharmaceutical composition for the prevention or treatment of vascular permeability-related diseases comprising masityinib or a pharmaceutically acceptable salt thereof as an active ingredient
본 발명은 마시티닙 또는 이의 약학적으로 허용되는 염을 유효성분으로 포함하는 혈관 투과성 관련 질환의 예방 또는 치료용 약학적 조성물에 관한 것이다.The present invention relates to a pharmaceutical composition for the prevention or treatment of vascular permeability-related diseases comprising masityinib or a pharmaceutically acceptable salt thereof as an active ingredient.
혈관은 인체를 구성하는 모든 세포의 생존 및 정상적 기능 유지에 필수적인 기관으로, 특히 혈관의 가장 안쪽을 구성하는 혈관내피세포는 단일층을 이루어 혈액 내의 단백질, 유체 및 전해질이 주변 조직으로 누수되는 것을 조절하는 세포성 장벽을 형성한다. 이러한 혈관내피세포 사이의 간극은 정상 혈관에서는 매우 좁아 혈관의 투과성이 낮은 반면, 혈관에 염증세포가 침윤되거나 혹은 혈관 손상에 의해 저산소 상태가 되면 각종 사이토카인 및 혈관내피세포 성장인자(vascular endothelial growth factor, VEGF)와 같은 성장인자의 분비에 의해 혈관내피세포 사이의 간극이 불안정화되어 혈관투과성이 현저히 상승된다. 혈관 투과성이 증가하면 혈관 주변 조직으로의 체액의 누수가 증가하게 된다. Blood vessels are vital for the survival and normal functioning of all the cells that make up the human body. In particular, the innermost vascular endothelial cells form a single layer that controls the leakage of proteins, fluids and electrolytes in the blood into surrounding tissues. To form a cellular barrier. The gap between vascular endothelial cells is very narrow in normal blood vessels, so that the permeability of blood vessels is low, whereas when inflammatory cells infiltrate blood vessels or become hypoxic due to blood vessel damage, various cytokines and vascular endothelial growth factors , VEGF), the gap between vascular endothelial cells is destabilized by the secretion of growth factors, such as VEGF significantly increases vascular permeability. Increased vascular permeability leads to an increase in leakage of fluid to the perivascular tissue.
과도한 혈관 투과성의 증가는 다양한 질환의 원인이 되며, 특히 망막(retina) 또는 맥락막(choroid)에서의 과도한 혈관투과성 증가는 출혈과 황반 부종(macular edema)을 촉진하여 치명적인 시력상실의 가장 흔한 원인으로 작용한다. 이러한 발병기전을 가지는 대표적인 질환으로 당뇨성 망막병증(diabetic retinopathy, DR), 당뇨 황반부종(diabetic macular edema, DME), 망막정맥폐쇄 (retinal vein occlusion)에 의한 황반 부종, 황반변성(macular degeneration), 맥락막 혈관신생(choroidal neovascularization), 미숙아 망막증(ROP: retinopathy of prematurity) 등이 있다(Surv Ophthalmol. 2007 Jan;52 Suppl 1:S3-19). 현재까지 대부분의 혈관 투과성 조절에 관한 연구는 VEGF 또는 VEGF 수용체에 한정되어 있고, 대부분이 상기 유전자에 대한 저해제 개발에 집중되어 있는 실정이다.Excessive increase in vascular permeability causes various diseases, especially excessive increase in vascular permeability in the retina or choroid is the most common cause of fatal vision loss by promoting bleeding and macular edema. do. Representative diseases with such pathogenesis include diabetic retinopathy (DR), diabetic macular edema (DME), macular edema due to retinal vein occlusion, macular degeneration, Choroidal neovascularization, retinopathy of prematurity (ROP), etc. (Surv Ophthalmol. 2007 Jan; 52 Suppl 1: S3-19). To date, most studies on vascular permeability regulation have been limited to VEGF or VEGF receptors, and most of them have focused on developing inhibitors for the genes.
한편, 마시티닙(masitinib)은 다발성 경화증(multiple sclerosis)에 대해 치료 효과가 있는 것이 보고된 바 있다(Vermersch P, BMC Neurol. 2012 (12);12:36). 알츠하이머, 류마티스성 관절염, 천식 및 비만세포증(mastocytosis)과 같은 신경계 및 염증 질환에서 임상 시도 또한 보고된 바 있다(Humbert M, Allergy 2009, 64:1194-1201). 이와 같이, 마시티닙의 다른 용도에 관련해서는 어느 정도 연구가 진척된 상황이나, 마시티닙으로 혈관 투과성을 조절할 수 있는지 여부에 대해서는 보고된 바가 없다. Masitinib, on the other hand, has been reported to have a therapeutic effect against multiple sclerosis (Vermersch P, BMC Neurol. 2012 (12); 12:36). Clinical trials have also been reported in neurological and inflammatory diseases such as Alzheimer's, rheumatoid arthritis, asthma and mastocytosis (Humbert M, Allergy 2009, 64: 1194-1201). As such, there has been no report on the progress of studies to some extent with regard to other uses of masitinib, and whether it is possible to control vascular permeability with marsitibini.
본 발명의 목적은 마시티닙 또는 이의 약학적으로 허용되는 염을 유효성분으로 포함하는 혈관 투과성 관련 질환의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.An object of the present invention to provide a pharmaceutical composition for the prevention or treatment of vascular permeability-related diseases comprising masityinib or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 다른 목적은 혈관 투과성 관련 질환이 유발된 개체에 마시티닙 또는 이의 약학적으로 허용가능한 염을 투여하는 단계를 포함하는 혈관 투과성 관련 질환의 치료 방법을 제공하는 것이다. It is another object of the present invention to provide a method of treating vascular permeability related diseases, comprising administering masityib or a pharmaceutically acceptable salt thereof to a subject having a vascular permeability related disease.
상기 과제를 해결하기 위하여, 본 발명은 마시티닙 또는 이의 약학적으로 허용되는 염을 유효성분으로 포함하는 혈관 투과성 관련 질환의 예방 또는 치료용 약학적 조성물을 제공한다.In order to solve the above problems, the present invention provides a pharmaceutical composition for the prevention or treatment of vascular permeability-related diseases comprising masityinib or a pharmaceutically acceptable salt thereof as an active ingredient.
아울러, 본 발명은 혈관 투과성 관련 질환이 유발된 개체에 마시티닙 또는 이의 약학적으로 허용가능한 염을 투여하는 단계를 포함하는 혈관 투과성 관련 질환의 치료 방법을 제공한다. In addition, the present invention provides a method for treating a vascular permeability-related disease comprising administering masityib or a pharmaceutically acceptable salt thereof to a subject having a vascular permeability-related disease.
약학적으로 허용되는 염이란 용어는 의학적 판단의 범위 내에 속하며, 부적절한 독성, 자극, 알러지 반응 등을 유발하지 않고 인간 및/또는 동물의 조직에 접촉하여 사용하기에 적합한 염을 나타낸다.The term pharmaceutically acceptable salts falls within the scope of medical judgment and refers to salts suitable for use in contact with human and / or animal tissues without causing inappropriate toxicity, irritation, allergic reactions, and the like.
상기 약학적으로 허용되는 염은 당업계에 잘 알려져 있다. 약학적으로 허용되는 염은 본 발명 화합물의 최종 분리 및 정제 과정 중에 얻을 수 있거나, 또는 별도로 유리 염기 작용기를 적절한 무기산, 예컨대 염산, 인산 또는 황산과 반응시키거나, 유기산, 예컨대 아스코르브산, 시트르산, 타르타르산, 락트산, 말레산, 말론산, 푸마르산, 글리콜산, 숙신산, 프로피온산, 아세트산, 메탄설폰산 등과 반응시켜 얻을 수 있다. 산 작용기는 유기 염기 또는 무기 염기, 예를 들어 수산화나트륨, 수산화칼륨 또는 수산화리튬과 반응시킬 수 있다.Such pharmaceutically acceptable salts are well known in the art. Pharmaceutically acceptable salts can be obtained during the final separation and purification of the compounds of the invention, or separately by reacting the free base functional groups with a suitable inorganic acid such as hydrochloric acid, phosphoric acid or sulfuric acid, or by organic acids such as ascorbic acid, citric acid, tartaric acid. , Lactic acid, maleic acid, malonic acid, fumaric acid, glycolic acid, succinic acid, propionic acid, acetic acid, methanesulfonic acid and the like. Acid functional groups can be reacted with organic bases or inorganic bases such as sodium hydroxide, potassium hydroxide or lithium hydroxide.
본 발명에 있어서, "혈관 투과성 관련 질환"이란 용어는 혈관 투과성의 정상적인 조절이 붕괴되어 일어나는 질환으로, 일반적으로 혈관이 변화되어 투과성이 증가됨으로써 출혈을 일으키는 질병을 의미한다.In the present invention, the term "vascular permeability-related disease" refers to a disease caused by disruption of normal regulation of vascular permeability, and generally refers to a disease causing bleeding by changing blood vessels and increasing permeability.
상기 혈관 투과성 관련 질환으로는 당뇨성 망막병증, 당뇨 황반부종, 망막정맥폐쇄에 의한 황반 부종, 황반변성, 맥락막 혈관신생, 녹내장성 망막색소변성(glaucoma retinitis pigmentosa), 미숙아 망막증(ROP: retinopathy of prematurity), 녹내장, 각막 이영양증(corneal dystrophy), 망막층간분리(retinoschises), 스타가르트병(Stargardt's disease), 상염색체 우성 드루젠(autosomal dominant druzen), 베스트의 황반 이영양증(Best's macular dystrophy), 낭포황반부종(cystoid macular edema), 허혈성 망막병증(ischemic retinopathy), 염증-유도 망막 퇴행성 질환(inflammation-induced retinal degenerative disease), X염색체-관련 연소기 망막층간분리(X-linked juvenile retinoschisis), 말라티아 레벤티네스(Malattia Leventinese; ML) 또는 도인 벌집 모양 망막 이영양증(Doyne honeycomb retinal dystrophy) 등을 들 수 있으나, 이에 한정되지 않는다.The vascular permeability-related diseases include diabetic retinopathy, diabetic macular edema, macular edema caused by retinal vein occlusion, macular degeneration, choroidal neovascularization, glaucoma retinitis pigmentosa (ROP), and retinopathy of prematurity. ), Glaucoma, corneal dystrophy, retinoschises, Stargardt's disease, autosomal dominant druzen, Best's macular dystrophy, cystoid Cystoid macular edema, ischemic retinopathy, inflammation-induced retinal degenerative disease, X-linked juvenile retinoschisis, Malatya leventi Ness (Malattia Leventinese; ML) or Doyne honeycomb retinal dystrophy, and the like, but is not limited thereto.
본 발명에 있어서, "치료"란 용어는 치료하고자 하는 개개인 또는 세포의 천연 과정을 변경시키기 위해 임상적으로 개입하는 모든 행위를 의미하는데, 임상 병리 상태가 진행되는 동안 또는 이를 예방하기 위해 수행할 수 있다. 목적하는 치료 효과에는 질병의 발생 또는 재발을 예방하고, 증상을 완화시키며, 질병에 따른 모든 직접 또는 간접적인 병리학적 결과를 저하시키고, 전이를 예방하며, 질병 진행 속도를 감소시키고, 질병 상태를 경감 또는 일시적 완화시키며, 차도시키거나 예후를 개선시키는 것이 포함된다. 본 발명의 목적상 상기 치료는 혈관 투과성 관련 질환이 발병된 환자에게 마시티닙 또는 이의 약학적으로 허용되는 염을 유효성분으로 포함하는 약학적 조성물을 투여하여 상기 혈관 투과성 관련 질환의 경과를 호전시키는 모든 행위를 포함하는 것으로 해석될 수 있으나, 특별히 이에 제한되지는 않는다.In the present invention, the term "treatment" refers to all actions that are clinically involved in altering the natural process of the individual or cell to be treated, which can be performed during or to prevent clinical pathology. have. The desired therapeutic effect includes preventing the occurrence or recurrence of the disease, alleviating the symptoms, lowering all direct or indirect pathological consequences of the disease, preventing metastasis, reducing the rate of disease progression, and reducing the disease state. Or temporarily alleviate, drive off, or improve the prognosis. For the purpose of the present invention, the treatment is to improve the course of the vascular permeability-related disease by administering a pharmaceutical composition comprising masityib or a pharmaceutically acceptable salt thereof as an active ingredient to a patient having vascular permeability-related disease. It may be interpreted to include all acts, but it is not particularly limited thereto.
본 발명에 있어서, "예방"이란 용어는 혈관 투과성 관련 질환의 발병이 예상되는 개체에게 본 발명에서 제공하는 마시티닙 또는 이의 약학적으로 허용되는 염을 유효성분으로 포함하는 약학적 조성물을 투여하여 상기 질환의 발병을 억제 또는 지연시키는 모든 행위를 의미한다.In the present invention, the term "prophylaxis" is to administer to the individual expected to develop vascular permeability-related diseases by administering a pharmaceutical composition comprising the masityinib or a pharmaceutically acceptable salt thereof provided in the present invention as an active ingredient It means any action that inhibits or delays the onset of the disease.
본 발명의 조성물은 경우에 따라서 약학적으로 허용되는 첨가제와 함께, 투여에 적합한 제형으로 제제화된다. 경구 투여에 적합한 제형의 예는 정제, 캡슐제, 과립제, 세립제 및 산제 등을 포함하고; 비경구 투여에 적합한 제형은 주사제, 점안제, 안연고, 첩부제, 겔제 및 삽입제를 포함한다. 이들 제형은 해당 분야에서 범용되어 있는 일반적인 기술을 이용하여 조제할 수 있다. 또한, 이들 제제 외에, 본 발명의 조성물은 안내 이식물용 제제나 미소구 등의 DDS(Drug delivery System; 약물 전달계)로 제조된 제제로 제제화할 수 있다. The compositions of the present invention are optionally formulated into a formulation suitable for administration, with pharmaceutically acceptable additives. Examples of formulations suitable for oral administration include tablets, capsules, granules, fines and powders, and the like; Formulations suitable for parenteral administration include injections, eye drops, eye ointments, patches, gels and inserts. These formulations can be formulated using common techniques that are universal in the art. In addition to these preparations, the compositions of the present invention can be formulated into preparations prepared by DDS (Drug Delivery System) such as preparations for intraocular implants or microspheres.
예를 들면, 정제는 예컨대 락토스, 글루코스, D-만니톨, 무수인산이칼슘, 전분 및 수크로스 등의 부형제; 카르복시메틸셀룰로스, 카르복시메틸셀룰로스칼슘, 크로스카르멜로스나트륨, 크로스포비돈, 전분, 부분 알파화 전분 및 저치환도 히드록시프로필셀룰로오스 등의 붕괴제; 히드록시프로필셀룰로오스, 에틸셀룰로오스, 아라비아 고무, 전분, 부분 알파화 전분, 폴리비닐피롤리돈 및 폴리비닐알콜 등의 결합제; 스테아르산 마그네슘, 스테아르산 칼슘, 탈크, 함수 이산화규소 및 경화유 등의 활택제; 정제백당, 히드록시프로필메틸셀룰로오스, 히드록시프로필셀룰로오스, 메틸셀룰로오스, 에틸셀룰로오스 및 폴리비닐피롤리돈 등의 코팅제; 및 시트르산, 아스파탐, 아스코르빈산 및 멘톨 등의 착향제로부터 적절히 선택된 첨가제를 사용하여 제조할 수 있다.For example, tablets may include, for example, excipients such as lactose, glucose, D-mannitol, dicalcium phosphate anhydrous, starch and sucrose; Disintegrating agents such as carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, crospovidone, starch, partially alphaated starch and low-substituted hydroxypropyl cellulose; Binders such as hydroxypropyl cellulose, ethyl cellulose, gum arabic, starch, partially alphaated starch, polyvinylpyrrolidone and polyvinyl alcohol; Lubricants such as magnesium stearate, calcium stearate, talc, hydrous silicon dioxide and hardened oil; Coating agents such as purified white sugar, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose and polyvinylpyrrolidone; And flavoring agents such as citric acid, aspartame, ascorbic acid and menthol.
주사제는, 예를 들어 염화나트륨 등의 등장화제; 인산나트륨 등의 완충화제; 폴리옥시에틸렌소르비탄모노올레이트 등의 계면활성제; 및 메틸셀룰로오스 등의 증점제 등으로부터 선택된 첨가제를 경우에 따라 사용하여 조제할수 있다.Injectables include, for example, isotonic agents such as sodium chloride; Buffering agents such as sodium phosphate; Surfactants such as polyoxyethylene sorbitan monooleate; And an additive selected from thickeners such as methyl cellulose and the like may be used in some cases.
점안제는, 예를 들어 염화 나트륨, 염화 칼륨, 글리세린, 농축 글리세린, 만니톨, 소르비톨, 붕산, 글루코오스, 및 프로필렌 글리콜 등의 등장화제; 인산염 완충제, 아세트산염 완충제, 붕산염 완충제, 탄산염 완충제, 시트르산염 완충제, 트리스 완충제, 글루탐산 등의 완충화제; 폴리옥시에틸렌소르비탄모노올레이트, 스테아르산폴리옥실 40 및 폴리옥시에틸렌 경화 피마자유 등의 계면활성제; 시트르산나트륨 및 에데트산나트륨 등의 안정화제; 및 염화벤잘코늄 및 파라벤 등의 보존제 등으로부터 선택되는 첨가제를 경우에 따라 이용하여 조제할 수 있다. 점안제의 pH는 안과적으로 허용되는 범위 내일 수 있지만, 통상 4 내지 8의 범위 내가 바람직하다. 또한, 안연고는 백색 바셀린 및 유동 파라핀 등의 범용되는 기제를 이용하여 조제할 수 있다. 상기 점안제와 같이 눈에 투여하는 제제는 크림, 포옴, 에멀젼을 포함하는 리퀴드 용액, 겔, 스프레이, 현탁액, 마이크로 에멀젼, 나노 입자로 제형화 될 수 있다.Eye drops include, for example, isotonic agents such as sodium chloride, potassium chloride, glycerin, concentrated glycerin, mannitol, sorbitol, boric acid, glucose, and propylene glycol; Buffering agents such as phosphate buffer, acetate buffer, borate buffer, carbonate buffer, citrate buffer, tris buffer, glutamic acid and the like; Surfactants such as polyoxyethylene sorbitan monooleate, polyoxyl stearate 40 and polyoxyethylene cured castor oil; Stabilizers such as sodium citrate and sodium edetate; And additives selected from preservatives such as benzalkonium chloride and paraben, etc., may be used in some cases. The pH of the eye drops may be within an ophthalmically acceptable range, but usually within the range of 4 to 8 is preferred. In addition, ophthalmic ointment can be prepared using a common base such as white petrolatum and liquid paraffin. Formulations administered to the eye, such as eye drops, may be formulated into liquid solutions, including gels, sprays, suspensions, microemulsions, nanoparticles, including creams, foams, emulsions.
본 발명의 점안제의 용법·용량은 환자의 증상, 연령 등에 따라 달라지며, 점안액, 현탁액의 경우에는 통상 1일 2~4회, 1회당 1~5방울이 점안되고, 안연고의 경우는 통상 1일 1~3회, 결막낭 내에 적당량을 도포하여 사용된다.The dosage and dosage of the eye drops of the present invention vary depending on the symptoms, age, etc. of the patient, and in the case of eye drops and suspensions, usually 2 to 4 drops per day, 1 to 5 drops per drop, and in the case of eye ointment, usually 1 day 3 times, it is used by applying an appropriate amount in the conjunctival sac.
삽입제는, 예를 들어 히드록시프로필셀룰로오스, 히드록시프로필메틸셀룰로오스, 카르복시비닐폴리머 및 폴리아크릴산 등의 생체분해성 폴리머를 본 발명의 화합물과 함께 분쇄 및 혼합한 후, 이 분말을 압축성형함으로써 조제할 수 있다. 경우에 따라서, 부형제, 결합제, 안정화제 및 pH 조정제를 이용할 수 있다. 안내 이식물용 제제는 생체분해성 폴리머, 예를 들면 폴리락트산, 폴리글리콜산, 락트산-글리콜산 공중합체 및 히드록시프로필셀룰로오스를 사용하여 제조할 수 있다. 상기 삽입제는 패치 또는 콘택트 렌즈로 제형화 될 수 있다. Inserts can be prepared by, for example, grinding and mixing biodegradable polymers such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxyvinyl polymer and polyacrylic acid with the compound of the present invention, and then compression molding the powder. Can be. If desired, excipients, binders, stabilizers and pH adjusters can be used. Formulations for intraocular implants can be prepared using biodegradable polymers such as polylactic acid, polyglycolic acid, lactic acid-glycolic acid copolymers and hydroxypropylcellulose. The insert can be formulated into a patch or contact lens.
본 발명의 약학적 조성물은 속방형, 서방형, 맥동형, 또는 시간차 방출형 형태로의 제제로 제조될 수 있다. 상기 각 활성 성분이 상술한 바람직한 시간차 범위를 갖도록 할 수 있는 방법이라면 특별히 제한되지 않고 당업계에 공지된 방법을 사용하여 이루어질 수 있다.The pharmaceutical compositions of the invention may be prepared in preparations in immediate release, sustained release, pulsating, or timed release forms. As long as it is a method which can make each said active ingredient have the above-mentioned preferable time difference range, it does not restrict | limit but can be made using methods known in the art.
질병을 예방 또는 치료하는데 적당한 투여량은 치료하고자 하는 질병의 유형, 질병의 중증도 및 과정, 본 발명의 조성물이 예방적 용도로 투여되는지 아니면 치료적 용도로 투여되는지의 여부, 기존의 요법, 환자의 임상 병력 및 마시티닙에 대한 반응, 및 담당 의사의 판단에 좌우될 것이다. 마시티닙은 환자에게 1회 투여하거나 일련의 치료 기간 내내 투여하는 것이 적합하다.Suitable dosages for preventing or treating a disease include, but are not limited to, the type of disease to be treated, the severity and course of the disease, whether the composition of the invention is administered for prophylactic or therapeutic purposes, conventional therapies, patients It will depend on the clinical history and response to masitibini and the judgment of the attending physician. Masitinib is suitably administered to a patient once or throughout a series of treatment periods.
마시티닙 또는 이의 약학적으로 허용가능한 염을 혈관 투과성을 감소시키는 제2 치료제와 함께 공동 투여하는 경우, 이러한 제2 치료제를 먼저 투여한 다음, 마시티닙을 투여할 수 있다. 아울러, 동시 투여하거나 마시티닙을 먼저 투여하는 것 또한 고려된다. 제2 치료제에 대한 적합한 투여량은 현재 사용되고 있는 양이고, 이러한 작용제와 마시티닙의 조합 작용(상승작용)으로 인해 양을 줄일 수도 있다. When masitibini or a pharmaceutically acceptable salt thereof is coadministered with a second therapeutic agent that reduces vascular permeability, the second therapeutic agent may be administered first, followed by the administration of mastitinib. In addition, concomitant administration or first administration of masityib is also contemplated. Suitable dosages for the second therapeutic agent are those currently in use and may be reduced due to the combined action (synergy) of these agents with masityib.
상기 제2 치료제는 VEGF 또는 이의 수용체의 발현 또는 활성을 감소시키는 저해제(이하, "VEGF 저해제"로 기재함), 안지오포이에틴(Angiopoietin) 또는 이의 수용체의 발현 또는 활성을 감소시키는 저해제, 덱사메타손(dexamethasone) 및 트리암시놀론(triamcinolone)과 같은 코르티코스테로이드(corticosteroid) 관련 약물일 수 있으나, 이에 한정되지 않는다.The second therapeutic agent is an inhibitor that reduces the expression or activity of VEGF or its receptor (hereinafter referred to as "VEGF inhibitor"), an angiopoietin or an inhibitor that reduces the expression or activity of its receptor, dexamethasone ( Corticosteroid related drugs such as dexamethasone) and triamcinolone, but are not limited thereto.
상기 VEGF 저해제는 혈관 내피 증식 인자(VEGF)의 작용을 감약(減弱)시킴으로써 혈관 신생의 촉진을 억제하는 약제이며, 이외에 혈관 투과성 억제, 혈관 내피 세포 증식 억제 등의 약리 작용을 나타내는 경우가 있다. VEGF 저해제로서는, 항VEGF 항체, VEGF 리간드 저해제, VEGF 수용체의 길항약 및 VEGF에 관련된 핵산 의약 등을 들 수 있다.The VEGF inhibitor is a drug that inhibits the promotion of angiogenesis by attenuating the action of vascular endothelial growth factor (VEGF), and may also exhibit pharmacological effects such as vascular permeability inhibition and vascular endothelial cell growth inhibition. Examples of VEGF inhibitors include anti-VEGF antibodies, VEGF ligand inhibitors, antagonists of VEGF receptors, nucleic acid medicines related to VEGF, and the like.
상기 VEGF 리간드 저해제의 구체예로서는, 아프리버셉트(VEGF-Trap), 및 VEGF-Trap EYE가 있다. 상기 항VEGF 항체의 구체예로서는, 베바시주맙 나트륨, 라니비주맙이 있다. VEGF 수용체의 길항약의 구체적 예로서는, 소라페닙 및 수니티닙이 있다. 상기 VEGF에 관련된 핵산 의약의 구체예로서는, 앱타머 의약인 페갑타닙 나트륨, 및 siRNA인 RTP801i-14 등이 있다. 또한, 베바시주맙 나트륨, 라니비주맙, VEGF-Trap 및 VEGF-Trap EYE 등은, 비선택적으로 모든 VEGF에 폭넓게 결합함으로써 VEGF의 수용체로의 결합을 저해한다.Specific examples of the VEGF ligand inhibitor include apribercept (VEGF-Trap) and VEGF-Trap EYE. Specific examples of the anti-VEGF antibody include bevacizumab sodium and ranibizumab. Specific examples of antagonists of VEGF receptors are sorafenib and sunitinib. Specific examples of the nucleic acid medicine related to VEGF include paptanib sodium, which is an aptamer drug, and RTP801i-14, which is an siRNA. In addition, bevacizumab sodium, ranibizumab, VEGF-Trap, VEGF-Trap EYE and the like non-selectively bind to all VEGFs broadly, thereby inhibiting binding of VEGF to receptors.
질병의 유형과 중증도에 따라서, 1회 이상의 별도 투여이든지 아니면 연속적인 주입이든지 간에, 마시티닙 약 1 ㎍/kg 내지 약 100 mg/kg, 바람직하게는 0.1 mg/kg 내지 10 mg/kg이 환자에게 투여하기 위한 초기 후보 투여량이다. 전형적인 1일 투여량은 상기 언급된 요인들에 따라서 약 1 ㎍/kg 내지 100 mg/kg 이상의 범위일 수 있다. 수 일에 걸쳐 반복 투여하는 경우에는 질환에 따라서 목적하는 질병 증상 억제가 나타날 때까지 치료를 지속한다. 그러나, 기타 투여량도 사용할 수 있다. 바람직한 구현예에서, 마시티닙을 약 0.1 mg/kg 내지 약 20 mg/kg의 범위 용량으로 투여한다.Depending on the type and severity of the disease, whether it is one or more separate or continuous infusions, the patient may be treated with Masitinib from about 1 μg / kg to about 100 mg / kg, preferably from 0.1 mg / kg to 10 mg / kg. Initial candidate dose for administration to a patient. Typical daily dosages may range from about 1 μg / kg to 100 mg / kg or more, depending on the factors mentioned above. Repeated administration over several days will continue treatment until the desired disease symptoms are suppressed, depending on the disease. However, other dosages may be used. In a preferred embodiment, mastitin is administered at a dose ranging from about 0.1 mg / kg to about 20 mg / kg.
본 발명의 한 구현예에서는 대표적인 혈관 투과성 관련 질환인 당뇨성 망막병증이 유도된 동물모델에 마시티닙을 투여한 결과, 혈관 투과성이 현저하게 감소됨을 확인함으로써(도 3 참조), 마시티닙 또는 그의 약학적으로 허용되는 염이 혈관 투과성 관련 질환의 치료 효과를 가짐을 확인하였다. In one embodiment of the present invention, as a result of administering masityinib to an animal model induced with diabetic retinopathy, a typical vascular permeability related disease, by confirming that vascular permeability is significantly reduced (see FIG. 3), It has been confirmed that its pharmaceutically acceptable salts have a therapeutic effect on vascular permeability related diseases.
본 발명에 따른 약학적 조성물의 투여 경로는 경구, 피하, 복강 내, 폐 내, 비강 내, 근육 내, 정맥 내, 동맥 내 및 안국소 투여로 이루어진 군으로부터 선택된 하나인 것일 수 있고, 바람직하게는 경구, 복강 내 및 안국소 투여로 이루어진 군으로부터 선택된 하나인 것일 수 있으며, 더 바람직하게는 안국소 투여일 수 있다. 상기 안국소 투여는 결막낭 내 투여, 유리체 내 투여(초자체 내 투여), 결막하 투여, 및 테논낭하 투여로 이루어진 군으로부터 선택된 하나인 것일 수 있고, 바람직하게는 유리체 내 투여이다.The route of administration of the pharmaceutical composition according to the present invention may be one selected from the group consisting of oral, subcutaneous, intraperitoneal, pulmonary, intranasal, intramuscular, intravenous, intraarterial and ocular administration, preferably It may be one selected from the group consisting of oral, intraperitoneal and topical administration, and more preferably, topical administration. The topical administration may be one selected from the group consisting of intraconjunctival administration, intravitreal administration (intravitreal administration), subconjunctival administration, and subtenonal cystic administration, preferably intravitreal administration.
본 발명에 따른 약학적 조성물은 당뇨성 망막병증이 유도된 동물모델의 혈관 투과성을 현저하게 감소시키기 때문에, 마시티닙 또는 이의 약학적으로 허용되는 염을 혈관 투과성 관련 질환의 예방 또는 치료에 사용할 수 있다. Since the pharmaceutical composition according to the present invention significantly reduces the vascular permeability of an animal model induced with diabetic retinopathy, masityib or a pharmaceutically acceptable salt thereof can be used for the prevention or treatment of vascular permeability-related diseases. have.
본 발명에 따른 마시티닙 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 약학적 조성물은 혈관 투과성을 억제하므로, 혈관 투과성으로 인해 발생하는 안구 질환을 치료할 수 있다. Since the pharmaceutical composition containing masityinib or a pharmaceutically acceptable salt thereof according to the present invention as an active ingredient inhibits vascular permeability, eye diseases caused by vascular permeability can be treated.
도 1은 당뇨성 망막병증 동물 모델의 혈당에 대한 마시티닙의 효과를 나타낸 그래프이다.1 is a graph showing the effect of masityib on blood glucose in a diabetic retinopathy animal model.
도 2는 당뇨성 망막병증 동물 모델의 체중에 대한 마시티닙의 효과를 나타낸 그래프이다. FIG. 2 is a graph showing the effect of masityib on body weight in diabetic retinopathy animal model.
도 3a 및 3b는 혈관투과성 증가 질환 모델인 당뇨성 망막병증의 유도에 대한 마시티닙의 예방 효과를 확인한 결과를 나타내는 사진 및 그래프로서, 도 3a는 마시티닙의 처리 농도에 따른 혈관 투과성 개선 효과를 나타내는 사진이고, 도 3b는 마시티닙의 처리 농도에 따른 혈관 투과성 질환 개선 효과를 나타내는 그래프이다: DM(Diabetic Mellitus).3A and 3B are photographs and graphs showing the results of confirming the preventive effect of masityib on the induction of diabetic retinopathy, a model of increased vascular permeability, and FIG. 3A is an effect of improving vascular permeability according to the treatment concentration of masitinib. 3B is a graph showing the effect of improving vascular permeability according to the treatment concentration of masityib: DM (Diabetic Mellitus).
이하, 본 발명을 실험예 및 제조예에 의해 상세히 설명한다.Hereinafter, the present invention will be described in detail by the experimental and production examples.
단, 하기 실험예 및 제조예는 본 발명을 예시하기 위한 것일 뿐, 본 발명의 내용이 하기 실험예 및 제조예에 의해 한정되는 것은 아니다.However, the following Experimental Examples and Preparation Examples are only for illustrating the present invention, and the content of the present invention is not limited by the following Experimental Examples and Preparation Examples.
<실험예 1> 당뇨성 망막병증 동물 모델에 대한 마시티닙의 효과Experimental Example 1 Effect of Masityib on Animal Model of Diabetic Retinopathy
스프라그 다울리 랫트(Sprague Dawley rat, SD rat)의 복강에 STZ(streptozotocin, Sigma)를 1일 기준 50 mg/kg(intravitreous injection)의 용량으로 3일 동안 투여한 후 혈당이 300 mg/dl 이상으로 증가한 동물을 당뇨성 망막병증 동물 모델로 사용하였다. 아울러, STZ를 처리하지 않은 군을 당뇨성 망막병증 동물 모델에 대한 정상 대조군으로 사용하였다(이하, "정상"으로 기재함). STZ 투여 후 3일 경과된 당뇨 랫트에 음성 대조군으로써 DMSO를 처리하고, 실험군으로써 마시티닙(Selleckchem. Houston, TX, USA) 50 ㎍ 또는 100 ㎍의 용량으로 초자체 내 투여(intravitreous injection)하였다.In the abdominal cavity of Sprague Dawley rats (SD rats), STZ (streptozotocin (Sigma)) was administered at a dose of 50 mg / kg (intravitreous injection) for 3 days, and then blood glucose was 300 mg / dl or more. Increased animals were used as an animal model for diabetic retinopathy. In addition, the group not treated with STZ was used as a normal control for diabetic retinopathy animal model (hereinafter referred to as "normal"). Diabetic rats 3 days after STZ administration were treated with DMSO as a negative control, and intravitreous injection at a dose of 50 μg or 100 μg of masitibib (Selleckchem. Houston, TX, USA) as an experimental group.
<1-1> 당뇨성 망막병증 동물 모델의 혈당에 대한 마시티닙의 효과<1-1> Effect of Masitinib on Blood Glucose in Animal Models of Diabetic Retinopathy
STZ 최초 투여일 기준 8일, 15일째 상기 동물 모델(정상, 대조군 및 실험군)의 혈당을 측정하였다. Blood glucose levels of the animal models (normal, control and experimental) were measured on days 8 and 15 of the first day of STZ administration.
그 결과, STZ를 처리하지 않은 정상군에 비해서, STZ로 유도된 당뇨성 망막병증 동물 모델의 경우, 마시티닙 투여군과 대조군(DMSO 처리군) 모두 혈당이 높은 것을 확인하였다. 하지만, 마시티닙 투여군과 대조군(DMSO 처리군) 사이의 혈당의 차이는 관찰되지 않았다. 이를 통해, 마시티닙이 직접적으로 혈당에 영향을 미치지 않음을 확인하였다(도 1). As a result, in the STZ-induced diabetic retinopathy animal model, compared with the normal group not treated with STZ, it was confirmed that the blood glucose level was higher in both the masityib-administered group and the control group (DMSO-treated group). However, no difference in blood glucose was observed between the masityib treated group and the control group (DMSO treated group). Through this, it was confirmed that masityib does not directly affect blood glucose (FIG. 1).
<1-2> 당뇨성 망막병증 동물 모델의 체중에 대한 마시티닙의 효과<1-2> Effect of Masitinib on Body Weight in Animal Models of Diabetic Retinopathy
STZ 최초 투여일 기준 8일, 15일째 상기 동물 모델(정상, 대조군 및 실험군)의 체중을 측정하였다.Body weights of the animal models (normal, control and experimental groups) were measured on days 8 and 15 of the first day of STZ administration.
그 결과, STZ로 유도된 당뇨성 망막병증 동물 모델의 경우, 마시티닙 투여군과 대조군 사이의 체중의 차이는 관찰되지 않았다. 이를 통해, 마시티닙이 직접적으로 체중에 영향을 미치지 않음을 확인하였다(도 2). As a result, in the STZ-induced diabetic retinopathy animal model, no weight difference was observed between the masityib-administered group and the control group. Through this, it was confirmed that masityinib does not directly affect the weight (Fig. 2).
<1-3> 당뇨성 망막병증 동물 모델의 혈관 투과성에 대한 마시티닙의 효과<1-3> Effect of Masitinib on Vascular Permeability in Animal Model of Diabetic Retinopathy
망막내 혈관 투과성의 변화를 관찰하기 위하여 약물 투여 후 12일째(STZ 최초 투여일 기준으로 15일째) 상기 동물 모델을 마취시키고, 상기 동물 모델의 심장에 FITC-표지된 덱스트란(Fluorescein isothiocyanate-dextran)을 주사하여 혈액을 따라 형광물질이 흐르도록 하였다. 30분 후, 상기 동물 모델의 망막을 적출하여 분리하고, 평편 마운팅(flat mounting)을 수행한 다음, 형광현미경으로 망막에 존재하는 형광물질의 분포 정도를 관찰하였다. To observe changes in intraretinal vascular permeability, the animal model was anesthetized 12 days after drug administration (day 15 of the first day of STZ), and FITC-labeled dextran (Fluorescein isothiocyanate-dextran) in the heart of the animal model. Was injected to allow fluorescent material to flow along the blood. After 30 minutes, the retinas of the animal model were removed and separated, and a flat mounting was performed, and then the degree of distribution of the fluorescent substance in the retina was observed by fluorescence microscopy.
그 결과, 도 3a 및 도 3b와 같이, 당뇨 랫트(대조군)의 망막에서는 망막혈관의 투과성이 증가하여 혈관 주변 조직으로 형광물질이 누출되어 당뇨성 망막병증이 유발된 것으로 확인되었으나, 마시티닙을 처리한 경우에는 형광물질의 누출 정도가 현저하게 감소되어 당뇨성 망막병증의 발생이 방지 또는 완화되었음을 확인하였다(도 3a 및 도 3b). 상기 결과로부터, 마시티닙이 혈관 투과성이 증가하는 당뇨성 망막병증을 치료 또는 예방할 수 있음을 알 수 있었다.As a result, as shown in Figures 3a and 3b, it was confirmed that diabetic rats (control) retinal blood vessels permeability increased and the fluorescent material leaked to the surrounding tissues to cause diabetic retinopathy, but masitinib In the case of treatment, it was confirmed that leakage of the fluorescent material was significantly reduced to prevent or alleviate the occurrence of diabetic retinopathy (FIGS. 3A and 3B). From the above results, it can be seen that mastitinib can treat or prevent diabetic retinopathy with increased vascular permeability.
<제제예 1> 마시티닙 또는 이의 약학적으로 허용가능한 염을 함유하는 제제의 제조Formulation Example 1 Preparation of a Formulation Containing Masityinib or a Pharmaceutically Acceptable Salt thereof
마시티닙 또는 이의 약학적으로 허용가능한 염을 이용한 대표적인 제제예를 이하에 나타낸다.Representative examples of preparations using masityib or a pharmaceutically acceptable salt thereof are shown below.
<1-1> 주사제<1-1> Injection
10 ㎖ 중In 10 ml
마시티닙 10 ㎎Masityib 10 mg
염화나트륨 90 ㎎Sodium chloride 90 mg
폴리소르베이트 80 적량Polysorbate 80 proper
멸균 정제수 적량Sterile purified water
마시티닙 및 염화나트륨을 멸균 정제수에 용해하여 주사제를 조제한다. 마시티닙의 첨가량을 변경함으로써, 10 ㎖ 중의 함유량이 0.1 ㎎, 10 ㎎, 50 ㎎의 주사제를 조제할 수 있다.Masitinib and sodium chloride are dissolved in sterile purified water to prepare an injection. By changing the addition amount of mastitinib, the injection in 0.1 mg, 10 mg, and 50 mg of content in 10 ml can be prepared.
<1-2> 점안제(1)<1-2> eye drops (1)
100㎖ 중 In 100 ml
마시티닙 10 ㎎Masityib 10 mg
염화나트륨 900 ㎎Sodium chloride 900 mg
멸균 정제수 적량Sterile purified water
마시티닙의 첨가량을 변경함으로써, 농도 0.001%(w/v), 0.03%(w/v), 0.1%(w/v), 0.3%(w/v), 1.0%(w/v)의 점안제를 조제할 수 있다.By changing the amount of marsitib added, concentrations of 0.001% (w / v), 0.03% (w / v), 0.1% (w / v), 0.3% (w / v) and 1.0% (w / v) Eye drops can be prepared.
<1-3> 점안제(2)<1-3> eye drops (2)
100㎖ 중In 100 ml
마시티닙 100 ㎎ Masitinib 100 mg
염화나트륨 800 ㎎ Sodium chloride 800 mg
인산수소이나트륨 100 ㎎ Disodium hydrogen phosphate 100 mg
인산이수소나트륨 적량Sodium dihydrogen phosphate
멸균 정제수 적량Sterile purified water
마시티닙의 첨가량을 변경함으로써, 농도 0.05%(w/v), 0.3%(w/v), 0.5%(w/v), 1%(w/v)의 점안제를 조제할 수 있다.By varying the amount of marcitinib added, eye drops having a concentration of 0.05% (w / v), 0.3% (w / v), 0.5% (w / v) and 1% (w / v) can be prepared.
<1-4> 안연고<1-4> Ahn Ointment
100g 중In 100 g
마시티닙 0.3gMarsitib 0.3g
유동 파라핀 10.0g10.0 g of liquid paraffin
백색 바셀린 적량White petroleum jelly
마시티닙의 첨가량을 변경함으로써, 농도 1%(w/w), 3%(w/w)의 안연고를 조제할 수 있다.By changing the addition amount of masityib, eye ointments having a concentration of 1% (w / w) and 3% (w / w) can be prepared.
<1-5> 정제<1-5> tablet
100 ㎎ 중In 100 mg
마시티닙 1 ㎎ Masityib 1 mg
유당 66.4 ㎎Lactose 66.4 mg
옥수수 전분 20 ㎎Corn starch 20 mg
카르복시메틸셀룰로오스 칼슘 6 ㎎Carboxymethylcellulose Calcium 6 mg
히드록시프로필셀룰로오스 6 ㎎Hydroxypropylcellulose 6 mg
스테아린산마그네슘 0.6 ㎎Magnesium stearate 0.6 mg
마시티닙, 유당을 혼합기 중에서 혼합하고, 여기에 카르복시메틸셀룰로오스 칼슘 및 히드록시프로필셀룰로오스를 첨가하여 이 혼합물을 조립(造粒)하며, 얻어진 과립을 건조한 후 정립하고, 그 정립 과립에 스테아린산마그네슘을 첨가하여 혼합하며, 이 혼합물을 타정기로 타정하였다. 또한, 마시티닙의 첨가량을 변경함으로써, 100 ㎎ 중의 함유량이 0.1 ㎎, 10 ㎎, 50 ㎎인 정제를 조제할 수 있다.Marcitinib and lactose are mixed in a mixer, and carboxymethyl cellulose calcium and hydroxypropyl cellulose are added to granulate the mixture, and the granules obtained are dried and then granulated, and magnesium stearate is added to the granulated granules. It was added and mixed, and the mixture was compressed into tableting machines. 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 masityinib.
본 발명에 따른 마시티닙 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 약학적 조성물은 혈관 투과성을 억제하므로, 혈관 투과성으로 인해 발생하는 안구 질환 치료 분야에서 유용하게 사용할 수 있다.Since the pharmaceutical composition containing masityib or a pharmaceutically acceptable salt thereof according to the present invention as an active ingredient inhibits vascular permeability, it may be usefully used in the field of treating eye diseases caused by vascular permeability.

Claims (13)

  1. 마시티닙 또는 이의 약학적으로 허용되는 염을 유효성분으로 포함하는 혈관 투과성 관련 질환의 예방 또는 치료용 약학적 조성물.Pharmaceutical composition for the prevention or treatment of vascular permeability-related diseases comprising masityib or a pharmaceutically acceptable salt thereof as an active ingredient.
  2. 청구항 1에 있어서,The method according to claim 1,
    상기 혈관 투과성 관련 질환은 당뇨성 망막병증, 당뇨 황반부종, 망막정맥폐쇄에 의한 황반 부종, 황반변성, 맥락막 혈관신생, 녹내장성 망막색소변성, 미숙아 망막증, 녹내장, 각막 이영양증, 망막층간분리, 스타가르트병, 상염색체 우성 드루젠, 베스트의 황반 이영양증, 낭포황반부종, 허혈성 망막병증, 염증-유도 망막 퇴행성 질환, X염색체-관련 연소기 망막층간분리, 말라티아 레벤티네스 및 도인 벌집 모양 망막 이영양증으로 이루어진 군으로부터 선택되는 혈관 투과성 관련 질환의 예방 또는 치료용 약학적 조성물.The vascular permeability-related diseases include diabetic retinopathy, diabetic macular edema, macular edema due to retinal vein occlusion, macular degeneration, choroidal neovascularization, glaucoma retinopathy, glaucoma, corneal dystrophy, retinal detachment, starga With Leut's disease, autosomal dominant drusen, best macular dystrophy, cystic macular edema, ischemic retinopathy, inflammatory-induced retinal degenerative disease, X-chromosome-related combustor retinal detachment, malthia leventine and striated honeycomb retinal dystrophy A pharmaceutical composition for preventing or treating vascular permeability-related diseases selected from the group consisting of.
  3. 청구항 1에 있어서,The method according to claim 1,
    상기 조성물의 투여 경로는 경구, 피하, 복강 내, 폐 내, 비강 내, 근육 내, 정맥 내, 동맥 내 및 안국소 투여로 이루어진 군으로부터 선택되는 혈관 투과성 관련 질환의 예방 또는 치료용 약학적 조성물.The route of administration of the composition is oral, subcutaneous, intraperitoneal, pulmonary, intranasal, intramuscular, intravenous, intraarterial and ocular administration pharmaceutical composition for preventing or treating vascular permeability-related diseases.
  4. 청구항 3에 있어서,The method according to claim 3,
    상기 투여 경로는 경구, 복강 내 및 안국소 투여로 이루어진 군으로부터 선택되는 혈관 투과성 관련 질환의 예방 또는 치료용 약학적 조성물.The administration route is a pharmaceutical composition for preventing or treating vascular permeability-related diseases selected from the group consisting of oral, intraperitoneal and ocular administration.
  5. 청구항 4에 있어서, The method according to claim 4,
    상기 안국소 투여는 결막낭 내 투여, 유리체 내 투여, 결막 하 투여 및 테논낭 하 투여로 이루어진 군으로부터 선택되는 혈관 투과성 관련 질환의 예방 또는 치료용 약학적 조성물.The ophthalmic administration is a pharmaceutical composition for the prevention or treatment of vascular permeability-related diseases selected from the group consisting of intraconjunctival administration, intravitreal administration, subconjunctival administration and subtenonal cyst administration.
  6. 청구항 5에 있어서, The method according to claim 5,
    상기 안국소 투여는 유리체 내 투여인 것인 혈관 투과성 관련 질환의 예방 또는 치료용 약학적 조성물.The ocular topical administration is intravitreal administration of the pharmaceutical composition for preventing or treating vascular permeability-related diseases.
  7. 청구항 1에 있어서, The method according to claim 1,
    상기 마시티닙 또는 이의 약학적으로 허용가능한 염은 1 ㎍/kg 내지 100 mg/kg 용량으로 투여되는 혈관 투과성 관련 질환의 예방 또는 치료용 약학적 조성물.The masitinib or a pharmaceutically acceptable salt thereof is administered at a dose of 1 μg / kg to 100 mg / kg of the pharmaceutical composition for preventing or treating vascular permeability-related diseases.
  8. 청구항 7에 있어서,The method according to claim 7,
    상기 마시티닙 또는 이의 약학적으로 허용가능한 염은 0.1 mg/kg 내지 20 mg/kg 용량으로 투여되는 혈관 투과성 관련 질환의 예방 또는 치료용 약학적 조성물.The mastitinib or a pharmaceutically acceptable salt thereof is administered at a dose of 0.1 mg / kg to 20 mg / kg of a pharmaceutical composition for preventing or treating vascular permeability-related diseases.
  9. 청구항 1에 있어서,The method according to claim 1,
    혈관 투과성을 감소시키는 제2 치료제를 추가로 포함하는 혈관 투과성 관련 질환의 예방 또는 치료용 약학적 조성물.A pharmaceutical composition for preventing or treating vascular permeability-related diseases, further comprising a second therapeutic agent for reducing vascular permeability.
  10. 청구항 9에 있어서,　The method according to claim 9,
    상기 제2 치료제는 VEGF 저해제, 안지오포이에틴 또는 이의 수용체의 발현 또는 활성을 감소시키는 저해제, 및 덱사메타손 및 트리암시놀론과 같은 코르티코스테로이드 관련 약물로 이루어진 군으로부터 선택되는 혈관 투과성 관련 질환의 예방 또는 치료용 약학적 조성물.The second therapeutic agent is a pharmaceutical agent for preventing or treating vascular permeability-related diseases selected from the group consisting of VEGF inhibitors, angiopoietins or inhibitors that reduce the expression or activity of receptors thereof, and corticosteroid-related drugs such as dexamethasone and triamcinolone. Composition.
  11. 혈관 투과성 관련 질환이 유발된 개체에 마시티닙 또는 이의 약학적으로 허용가능한 염을 투여하는 단계를 포함하는 혈관 투과성 관련 질환의 치료 방법.A method of treating vascular permeability related disease, comprising administering masitibini or a pharmaceutically acceptable salt thereof to a subject having a vascular permeability related disease.
  12. 청구항 11에 있어서,The method according to claim 11,
    상기 혈관 투과성 관련 질환은 당뇨성 망막병증, 당뇨 황반부종, 망막정맥폐쇄에 의한 황반 부종, 황반변성, 맥락막 혈관신생, 녹내장성 망막색소변성, 미숙아 망막증, 녹내장, 각막 이영양증, 망막층간분리, 스타가르트병, 상염색체 우성 드루젠, 베스트의 황반 이영양증, 낭포황반부종, 허혈성 망막병증, 염증-유도 망막 퇴행성 질환, X염색체-관련 연소기 망막층간분리, 말라티아 레벤티네스 및 도인 벌집 모양 망막 이영양증으로 이루어진 군으로부터 선택되는 혈관 투과성 관련 질환의 치료 방법.The vascular permeability-related diseases include diabetic retinopathy, diabetic macular edema, macular edema due to retinal vein occlusion, macular degeneration, choroidal neovascularization, glaucoma retinopathy, glaucoma, corneal dystrophy, retinal detachment, starga With Leut's disease, autosomal dominant drusen, best macular dystrophy, cystic macular edema, ischemic retinopathy, inflammatory-induced retinal degenerative disease, X-chromosome-related combustor retinal detachment, malthia leventine and striated honeycomb retinal dystrophy A method of treating vascular permeability related diseases selected from the group consisting of.
  13. 청구항 11에 있어서, The method according to claim 11,
    상기 마시티닙 또는 이의 약학적으로 허용가능한 염은 1 ㎍/kg 내지 100 mg/kg 용량으로 투여되는 혈관 투과성 관련 질환의 치료 방법.The mastitinib or a pharmaceutically acceptable salt thereof is administered at a dose of 1 μg / kg to 100 mg / kg.
PCT/KR2014/010452 2013-11-04 2014-11-03 Pharmaceutical composition for preventing or treating vascular permeability-related diseases, containing masitinib or pharmaceutically acceptable salt thereof as active ingredient WO2015065136A1 (en)

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