KR20150051492A - Pharmaceutical Composition for Preventing or Treating Vascular Permeability Disease Comprising Masitinib or Pharmaceutically Acceptable Salts thereof as an Active Ingredient - Google Patents
Pharmaceutical Composition for Preventing or Treating Vascular Permeability Disease Comprising Masitinib or Pharmaceutically Acceptable Salts thereof as an Active Ingredient Download PDFInfo
- Publication number
- KR20150051492A KR20150051492A KR1020130133014A KR20130133014A KR20150051492A KR 20150051492 A KR20150051492 A KR 20150051492A KR 1020130133014 A KR1020130133014 A KR 1020130133014A KR 20130133014 A KR20130133014 A KR 20130133014A KR 20150051492 A KR20150051492 A KR 20150051492A
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- KR
- South Korea
- Prior art keywords
- vascular permeability
- administration
- pharmaceutically acceptable
- pharmaceutical composition
- acceptable salt
- Prior art date
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Abstract
Description
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 preventing or treating vascular permeability related diseases comprising mastitin 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. The blood vessels are essential for the survival and normal functioning of all the cells constituting the human body. In particular, the innermost vascular endothelial cells constitute a single layer, which regulates the leakage of proteins, fluids and electrolytes in the blood into surrounding tissues To form a cellular barrier. The gap between these endothelial cells is very narrow in the normal vessels and the permeability of the blood vessels is low. However, when inflammatory cells are infiltrated into the blood vessels or become hypoxic by vascular injury, various cytokines and vascular endothelial growth factors , VEGF), the gap between vascular endothelial cells is destabilized and vascular permeability is significantly increased. Increased vascular permeability leads to increased leaking of body fluids to surrounding 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(비특허문헌 1, 비특허문헌 2). 현재까지 대부분의 혈관 투과성 조절에 관한 연구는 VEGF 또는 VEGF 수용체에 한정되어 있고, 대부분이 상기 유전자에 대한 저해제 개발에 집중되어 있는 실정이다.Increased vascular permeability is a cause of various diseases, especially excessive retinal permeability in the retina or choroid promotes hemorrhage and macular edema, which is the most common cause of fatal visual loss do. Typical diseases with this pathogenesis are diabetic retinopathy (DR), diabetic macular edema (DME), macular edema due to retinal vein occlusion, macular degeneration, Choroidal neovascularization, retinopathy of prematurity (ROP), and the like (Non-Patent Document 1 and Non-Patent Document 2). To date, most studies on the regulation of vascular permeability have been limited to VEGF or VEGF receptors, and most of them are concentrated on the development of inhibitors against these genes.
한편, 마시티닙(masitinib)은 다발성 경화증(multiple sclerosis)에 대해 치료 효과가 있는 것이 보고된 바 있다(비특허문헌 3). 알츠하이머, 류마티스성 관절염, 천식 및 비만세포증(mastocytosis)과 같은 신경계 및 염증 질환에서 임상 시도 또한 보고된 바 있다(비특허문헌 4-6). 이와 같이, 마시티닙의 다른 용도에 관련해서는 어느 정도 연구가 진척된 상황이나, 마시티닙으로 혈관 투과성을 조절할 수 있는지 여부에 대해서는 보고된 바가 없다.
On the other hand, masitinib has been reported to have a therapeutic effect on multiple sclerosis (Non-Patent Document 3). Clinical trials have also been reported in neurological and inflammatory diseases such as Alzheimer's, rheumatoid arthritis, asthma and mastocytosis (Non-Patent Documents 4-6). Thus, there has been no report on the extent to which progress has been made in relation to other uses of muscleinib, but whether it can modulate vascular permeability in muscleinib.
본 발명의 목적은 마시티닙 또는 이의 약학적으로 허용되는 염을 유효성분으로 포함하는 혈관 투과성 관련 질환의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.
It is an object of the present invention to provide a pharmaceutical composition for preventing or treating vascular permeability related diseases comprising mastitin or a pharmaceutically acceptable salt thereof as an active ingredient.
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 preventing or treating vascular permeability-related diseases comprising macitanium or a pharmaceutically acceptable salt thereof as an active ingredient.
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 refers to salts which are within the scope of medical judgment and which are suitable for use in contact with the tissues of humans and / or animals without undue toxicity, irritation, allergic response 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. The pharmaceutically acceptable salts may be obtained during the final isolation and purification of the compounds of the present invention or may be obtained by separately reacting free base functional groups with an appropriate inorganic acid such as hydrochloric acid, phosphoric acid or sulfuric acid, or by reacting an organic acid such as ascorbic acid, , Lactic acid, maleic acid, malonic acid, fumaric acid, glycolic acid, succinic acid, propionic acid, acetic acid, methanesulfonic acid and the like. The acid functional group may be reacted with an organic base or an inorganic base, for example 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 the collapse of the normal regulation of vascular permeability, and generally refers to a disease that causes bleeding by increasing blood permeability 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 due to retinal vein occlusion, macular degeneration, choroidal neovascularization, glaucoma retinitis pigmentosa, retinopathy of prematurity (ROP) ), Glaucoma, corneal dystrophy, retinoschisis, Stargardt's disease, autosomal dominant druzen, Best's macular dystrophy, cystoid macular edema, Ischemic retinopathy, inflammation-induced retinal degenerative disease, X-linked juvenile retinoschisis, Malathia retinoschisis, Maltia Leventinese (ML) or Doyne honeycomb retinal dystrophy, but the present invention 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.For purposes of the present invention, the term "treatment" refers to any act that is clinically intervened to alter the natural course of an individual or cell to be treated, and may be performed during or during the course of a clinical pathology have. The desired therapeutic effect is to prevent the occurrence or recurrence of the disease, to alleviate the symptoms, to reduce all direct or indirect pathological consequences of the disease, to prevent metastasis, to reduce the rate of disease progression, Or temporarily alleviating, or improving the prognosis. For the purpose of the present invention, the treatment may include administering to a patient suffering from a vascular permeability-related disease a pharmaceutical composition comprising mastitin or a pharmaceutically acceptable salt thereof as an active ingredient to improve the course of the vascular permeability-related disease But is not 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 "prophylactic" refers to administration of a pharmaceutical composition comprising mastitin or a pharmaceutically acceptable salt thereof as an active ingredient to the subject in which the occurrence of a vascular permeability-related disease is expected to be administered Quot; means all actions that inhibit or delay 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 composition of the present invention, optionally together with pharmaceutically acceptable additives, is formulated into a formulation suitable for administration. Examples of formulations suitable for oral administration include tablets, capsules, granules, fine granules and powders, and the like; Formulations suitable for parenteral administration include injections, eye drops, ointments, patches, gels, and intercalating agents. These formulations may be formulated using conventional techniques commonly used in the art. Furthermore, in addition to these preparations, the composition of the present invention can be formulated into a preparation made from a drug delivery system (DDS) such as a preparation for guinea pig implant and a microsphere.
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, the tablet may contain excipients such as lactose, glucose, D-mannitol, dicalcium phosphate anhydrous, starch and sucrose; Disintegrating agents such as carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, crospovidone, starch, partially alpha-starch and low-substituted hydroxypropylcellulose; Binders such as hydroxypropylcellulose, ethylcellulose, gum arabic, starch, partially-alpha-starch, polyvinylpyrrolidone and polyvinyl alcohol; Lubricants such as magnesium stearate, calcium stearate, talc, hydrous silicon dioxide, and hydrogenated oils; A tablet such as tablets, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, ethylcellulose, and polyvinylpyrrolidone; And flavorings 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.Injection agents include, for example, isotonic agents such as sodium chloride; Buffering agents such as sodium phosphate; Surfactants such as polyoxyethylene sorbitan monooleate; And thickeners such as methylcellulose, and the like can be optionally used.
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 isotonic agents such as, for example, sodium chloride, potassium chloride, glycerin, concentrated glycerin, mannitol, sorbitol, boric acid, glucose, and propylene glycol; Buffers such as phosphate buffers, acetate buffers, borate buffers, carbonate buffers, citrate buffers, Tris buffers, and glutamic acid; Surfactants such as polyoxyethylene sorbitan monooleate, stearic acid polyoxyl 40 and polyoxyethylene hardened castor oil; Stabilizers such as sodium citrate and sodium edetate; And a preservative such as benzalkonium chloride and paraben can be optionally used. The pH of the eye drops may be within the ophthalmically acceptable range, but it is usually in the range of 4 to 8. In addition, the ointment can be prepared using a general-purpose base such as white petrolatum and liquid paraffin. Formulations for ocular administration, such as eye drops, may be formulated as liquid solutions, gels, sprays, suspensions, microemulsions, or nanoparticles, including creams, foams, and 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.Dosage and dosage of the eye drops of the present invention vary depending on the patient's symptoms and age. In the case of eye drops and suspensions, the dose is normally 2 to 4 times per day, 1 to 5 drops per one time, and in the case of ophthalmic solution, ~ 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. The intercalating agent is prepared, for example, by pulverizing and mixing a biodegradable polymer such as hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxyvinyl polymer and polyacrylic acid together with the compound of the present invention and then compressing the powder . Optionally, excipients, binders, stabilizers and pH adjusting agents may be used. The preparations for guinea pig implantation can be produced using biodegradable polymers such as polylactic acid, polyglycolic acid, lactic acid-glycolic acid copolymer, and hydroxypropylcellulose. The intercalating agent may be formulated into a patch or a 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 composition of the present invention may be manufactured into a preparation in the form of immediate-release, sustained-release, pulsatile, or time-release release type. Any method capable of causing each active ingredient to have the above-described preferable time difference range can be achieved by using methods known in the art without any particular limitation.
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.Dosages suitable for the prevention or treatment of the disease will depend upon 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 use, The clinical history and response to the muscle nip, and the judgment of the attending physician. Macitinib is suitable for administration 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 coadministering masticin or a pharmaceutically acceptable salt thereof with a second therapeutic agent that reduces vascular permeability, such second therapeutic agent may be administered first, followed by masitinib. It is also contemplated that co-administration or first administration of masitinib is also contemplated. A suitable dosage for the second therapeutic agent is the amount currently used and the amount may be reduced due to the combined action (synergism) of this agent with muscitinib.
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.Said second therapeutic agent is an inhibitor that reduces the expression or activity of VEGF or its receptor (hereinafter referred to as "VEGF inhibitor"), Angiopoietin or its receptor, dexamethasone dexamethasone), and triamcinolone (corticosteroid-related drugs such as triamcinolone).
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 an agent that inhibits the promotion of angiogenesis by attenuating the action of VEGF, and may also exhibit pharmacological actions such as inhibition of vascular permeability and inhibition of vascular endothelial cell proliferation. VEGF inhibitors include anti-VEGF antibodies, VEGF ligand inhibitors, antagonists of VEGF receptors, and nucleic acid drugs related to VEGF.
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 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 sorapenib and sunitinib. Specific examples of the nucleic acid medicines related to VEGF include pecticum sodium, which is an aptamer medicine, and RTP801i-14, which is siRNA. In addition, bevacizumab sodium, ranibizumab, VEGF-Trap, and VEGF-Trap EYE inhibit the binding of VEGF to the receptor by binding broadly to all VEGFs non-selectively.
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, about 1 μg / kg to about 100 mg / kg, preferably 0.1 mg / kg to 10 mg / kg, of one or more separate doses or continuous infusion, Lt; / RTI > A typical daily dose may range from about 1 [mu] g / kg to 100 mg / kg or more, depending on the factors mentioned above. In the case of repeated administration over several days, the treatment is continued until the desired disease symptom suppression appears depending on the disease. However, other dosages may be used. In a preferred embodiment, maxillipine 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, macitinib is administered to an animal model in which diabetic retinopathy, a representative vascular permeability-related disorder, is induced. As a result, vascular permeability is significantly reduced (see FIG. 3) Its pharmaceutically acceptable salts have therapeutic effects 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, intrapulmonary, intranasal, intramuscular, intravenous, intraarterial and intraocular administration, Oral, intraperitoneal, and topical administration, and more preferably, it may be an intraocular administration. The intraocular administration may be one selected from the group consisting of intraocular conjunctival injection, intravaginal administration (intrarectal administration), subconjunctival administration and subtenon injection, preferably intravenous 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.
Because the pharmaceutical composition according to the present invention significantly reduces the vascular permeability of an animal model in which diabetic retinopathy is induced, macitanium 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.
The pharmaceutical composition containing mastitin or a pharmaceutically acceptable salt thereof according to the present invention as an active ingredient inhibits vascular permeability and thus can treat ocular diseases caused by vascular permeability.
도 1은 당뇨성 망막병증 동물 모델의 혈당에 대한 마시티닙의 효과를 나타낸 그래프이다.
도 2는 당뇨성 망막병증 동물 모델의 체중에 대한 마시티닙의 효과를 나타낸 그래프이다.
도 3은 혈관투과성 증가 질환 모델인 당뇨성 망막병증의 유도에 대한 마시티닙의 예방 효과를 확인한 결과를 나타내는 사진 및 그래프로서, 도 3의 (A)는 마시티닙의 처리 농도에 따른 혈관 투과성 개선 효과를 나타내는 사진이고, 도 3의 (B)는 마시티닙의 처리 농도에 따른 혈관 투과성 질환 개선 효과를 나타내는 그래프이다: DM(Diabetic Mellitus).BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a graph showing the effect of muscitip on blood glucose in an animal model of diabetic retinopathy. FIG.
Figure 2 is a graph showing the effect of muscleinip on body weight of an animal model of diabetic retinopathy.
FIG. 3 is a photograph and a graph showing the results of confirming the preventive effect of masitinib on the induction of diabetic retinopathy, which is a disease model of increased vascular permeability. FIG. 3 (A) is a graph showing blood vessel permeability FIG. 3 (B) is a graph showing the effect of improving the vascular permeability disease according to the treatment concentration of macity nip: DM (Diabetic Mellitus). FIG.
이하, 본 발명을 실험예 및 제조예에 의해 상세히 설명한다.Hereinafter, the present invention will be described in detail with reference to Experimental Examples 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 for illustrating the present invention, and the contents of the present invention are not limited by the following Experimental Examples and Production Examples.
<< 실험예Experimental Example 1> 당뇨성 1> diabetic 망막병증Retinopathy 동물 모델에 대한 For animal models 마시티닙의Maccitnip 효과 effect
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.
When STZ (streptozotocin, Sigma) was administered to the abdominal cavity of Sprague Dawley rats (SD rats) for 3 days at a dose of 50 mg / kg (intravitreous injection) per day, blood glucose level was 300 mg / dl or more Were used as animal models of diabetic retinopathy. In addition, the group not treated with STZ was used as a normal control group for an animal model of diabetic retinopathy (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 in Sachetchem (Houston, Tex., USA) as an experimental group.
<1-1> 당뇨성 <1-1> Diabetic 망막병증Retinopathy 동물 모델의 혈당에 대한 Animal model for blood sugar 마시티닙의Maccitnip 효과 effect
STZ 최초 투여일 기준 8일, 15일째 상기 동물 모델(정상, 대조군 및 실험군)의 혈당을 측정하였다. On the 8th and 15th day of the first administration of STZ, blood glucose levels of the animal models (normal, control and experimental groups) were measured.
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 model animals, compared with the non-STZ-treated normal group, both the macity nip treated group and the control group (DMSO treated group) However, no difference in blood glucose between the casein-treated group and the control group (DMSO-treated group) was observed. As a result, it was confirmed that muscitis nip did not directly affect blood glucose (Fig. 1).
<1-2> 당뇨성 <1-2> Diabetic 망막병증Retinopathy 동물 모델의 체중에 대한 Animal Model for Weight 마시티닙의Maccitnip 효과 effect
STZ 최초 투여일 기준 8일, 15일째 상기 동물 모델(정상, 대조군 및 실험군)의 체중을 측정하였다.On the 8th day and 15th day of the first administration of STZ, the body weight of the animal model (normal, control and experimental groups) was measured.
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 STZ-induced diabetic retinopathy, there was no difference in body weight between the treated group and the control group. Thus, it was confirmed that muscitis nip did not directly affect body weight (Fig. 2).
<1-3> 당뇨성 <1-3> Diabetic 망막병증Retinopathy 동물 모델의 혈관 투과성에 대한 On the vascular permeability of animal models 마시티닙의Maccitnip 효과 effect
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 the change of retinal vascular permeability, the animal model was anesthetized on the 12th day after the administration of the drug (15 days as of the first day of STZ administration), and the FITC-labeled dextran (Fluorescein isothiocyanate-dextran) Was injected to allow the fluorescent material to flow along the blood. After 30 minutes, the retina of the animal model was extracted, separated, flat mounted, and observed for fluorescence distribution in the retina by fluorescence microscopy.
그 결과, 도 3과 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 3). 상기 결과로부터, 마시티닙이 혈관 투과성이 증가하는 당뇨성 망막병증을 치료 또는 예방할 수 있음을 알 수 있었다.
As a result, as shown in FIG. 3, it was confirmed that the retina of the diabetic rat (control group) increased the permeability of the retinal vasculature, resulting in the leakage of the fluorescent material to the surrounding tissue, resulting in diabetic retinopathy. It was confirmed that the leakage of the fluorescent substance was remarkably reduced and the occurrence of diabetic retinopathy was prevented or mitigated (FIG. 3). From the above results, it was found that macity nip can treat or prevent diabetic retinopathy with increased vascular permeability.
<< 제제예Formulation example 1> 1> 마시티닙Maccitnip 또는 이의 약학적으로 허용가능한 염을 함유하는 제제의 제조 Or a pharmaceutically acceptable salt thereof.
마시티닙 또는 이의 약학적으로 허용가능한 염을 이용한 대표적인 제제예를 이하에 나타낸다.Representative formulation examples using masticin or a pharmaceutically acceptable salt thereof are shown below.
<1-1> 주사제<1-1> Injection
10 ㎖ 중In 10 ml
마시티닙 10 ㎎Macit nip 10 mg
염화나트륨 90 ㎎90 mg of sodium chloride
폴리소르베이트 80 적량Polysorbate 80 qs
멸균 정제수 적량Sterile purified water volume
마시티닙 및 염화나트륨을 멸균 정제수에 용해하여 주사제를 조제한다. 마시티닙의 첨가량을 변경함으로써, 10 ㎖ 중의 함유량이 0.1 ㎎, 10 ㎎, 50 ㎎의 주사제를 조제할 수 있다.Injection is prepared by dissolving masitinib and sodium chloride in sterile purified water. By varying the amount of masitinib added, injections of 0.1 mg, 10 mg and 50 mg in 10 ml can be prepared.
<1-2> <1-2> 점안제Eye drops (1)(One)
100㎖ 중 In 100 ml
마시티닙 10 ㎎Macit nip 10 mg
염화나트륨 900 ㎎900 mg of sodium chloride
멸균 정제수 적량Sterile purified water volume
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.(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> <1-3> 점안제Eye drops (2)(2)
100㎖ 중In 100 ml
마시티닙 100 ㎎Macit nip 100 mg
염화나트륨 800 ㎎800 mg of sodium chloride
인산수소이나트륨 100 ㎎100 mg of disodium hydrogen phosphate
인산이수소나트륨 적량Sodium dihydrogenphosphate
멸균 정제수 적량Sterile purified water volume
마시티닙의 첨가량을 변경함으로써, 농도 0.05%(w/v), 0.3%(w/v), 0.5%(w/v), 1%(w/v)의 점안제를 조제할 수 있다.The eyedrops can be prepared at concentrations of 0.05% (w / v), 0.3% (w / v), 0.5% (w / v) and 1% (w / v) by varying the amount of masitinib added.
<1-4> <1-4> 안연고Osteoporosis
100g 중Of 100g
마시티닙 0.3gMachitinib 0.3g
유동 파라핀 10.0gLiquid paraffin 10.0 g
백색 바셀린 적량White petrolatum
마시티닙의 첨가량을 변경함으로써, 농도 1%(w/w), 3%(w/w)의 안연고를 조제할 수 있다.By varying the amount of masitinib added, ointments at concentrations of 1% (w / w) and 3% (w / w) can be prepared.
<1-5> 정제<1-5> Purification
100 ㎎ 중100 mg
마시티닙 1 ㎎1 mg of macitanium
유당 66.4 ㎎Lactose 66.4 mg
옥수수 전분 20 ㎎Corn starch 20 mg
카르복시메틸셀룰로오스 칼슘 6 ㎎Carboxymethylcellulose calcium 6 mg
히드록시프로필셀룰로오스 6 ㎎6 mg of hydroxypropylcellulose
스테아린산마그네슘 0.6 ㎎0.6 mg of magnesium stearate
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.The mixture was granulated by adding carboxymethylcellulose calcium and hydroxypropylcellulose to the mixture, and the resulting granules were dried and sieved. Magnesium stearate was added to the granules, And the mixture was compressed into tablets. Further, it is possible to prepare tablets having a content of 0.1 mg, 10 mg, and 50 mg in 100 mg by changing the addition amount of masitinib.
Claims (10)
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 선택된 것인 혈관 투과성 관련 질환의 예방 또는 치료용 약학적 조성물.The method according to claim 1,
The vascular permeability related diseases include diabetic retinopathy, diabetic macular edema, macular edema due to retinal vein occlusion, macular degeneration, choroidal angiogenesis, glaucoma retinitis pigmentosa, retinopathy of prematurity, glaucoma, corneal dystrophy, Ischemic retinopathy, inflammation-induced retinal degenerative disease, X chromosome-associated burner retinal detachment, Malathia lentinensis, and ischemic retinal dystrophy. Or a pharmaceutically acceptable salt, solvate or prodrug thereof, for the prevention or treatment of vascular permeability related diseases.
상기 조성물의 투여 경로는 경구, 피하, 복강 내, 폐 내, 비강 내, 근육 내, 정맥 내, 동맥 내 및 안국소 투여로 이루어진 군으로부터 선택된 하나인 것인 혈관 투과성 관련 질환의 예방 또는 치료용 약학적 조성물.The method according to claim 1,
Wherein the administration route of the composition is one selected from the group consisting of oral, subcutaneous, intraperitoneal, intrapulmonary, intranasal, intramuscular, intravenous, intraarterial, and topical intravenous administration for the prevention or treatment of vascular permeability related diseases Gt;
상기 투여 경로는 경구, 복강 내 및 안국소 투여로 이루어진 군으로부터 선택된 하나인 것인 혈관 투과성 관련 질환의 예방 또는 치료용 약학적 조성물.The method of claim 3,
Wherein the administration route is one selected from the group consisting of oral, intraperitoneal, and intraocular administration.
상기 안국소 투여는 결막낭 내 투여, 유리체 내 투여, 결막 하 투여 및 테논낭 하 투여로 이루어진 군으로부터 선택된 하나인 것인 혈관 투과성 관련 질환의 예방 또는 치료용 약학적 조성물.The method of claim 4,
Wherein the intraocular injection is one selected from the group consisting of intraocular conjunctiva, intravaginal injection, subconjunctival injection, and intramuscular administration.
상기 안국소 투여는 유리체 내 투여인 것인 혈관 투과성 관련 질환의 예방 또는 치료용 약학적 조성물.The method of claim 5,
Wherein said intraocular administration is intravaginal administration. ≪ RTI ID = 0.0 > 11. < / RTI >
상기 마시티닙 또는 이의 약학적으로 허용가능한 염은 1 ㎍/kg 내지 100 mg/kg 용량으로 투여되는 것인 혈관 투과성 관련 질환의 예방 또는 치료용 약학적 조성물.The method according to claim 1,
Wherein the macitinib or a pharmaceutically acceptable salt thereof is administered at a dose of 1 [mu] g / kg to 100 mg / kg.
상기 마시티닙 또는 이의 약학적으로 허용가능한 염은 0.1 mg/kg 내지 20 mg/kg 용량으로 투여되는 것인 혈관 투과성 관련 질환의 예방 또는 치료용 약학적 조성물.The method of claim 7,
Wherein the macitinib or a pharmaceutically acceptable salt thereof is administered in a dose of 0.1 mg / kg to 20 mg / kg.
혈관 투과성을 감소시키는 제2 치료제를 추가로 포함하는 혈관 투과성 관련 질환의 예방 또는 치료용 약학적 조성물.The method according to claim 1,
A pharmaceutical composition for the prevention or treatment of vascular permeability related diseases, which further comprises a second therapeutic agent which decreases vascular permeability.
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 것인 혈관 투과성 관련 질환의 예방 또는 치료용 약학적 조성물.The method of claim 9,
Wherein said second therapeutic agent is selected from the group consisting of a VEGF inhibitor, an angiopoietin or an inhibitor that decreases the expression or activity of its receptor, and a corticosteroid related drug such as dexamethasone and triamcinolone. A pharmaceutical composition.
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