KR20230037922A - Pharmaceutical composition for preventing or treating cancer comprising nanoparticles loaded with benzimidazole as an active ingredient - Google Patents
Pharmaceutical composition for preventing or treating cancer comprising nanoparticles loaded with benzimidazole as an active ingredient Download PDFInfo
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- KR20230037922A KR20230037922A KR1020210121063A KR20210121063A KR20230037922A KR 20230037922 A KR20230037922 A KR 20230037922A KR 1020210121063 A KR1020210121063 A KR 1020210121063A KR 20210121063 A KR20210121063 A KR 20210121063A KR 20230037922 A KR20230037922 A KR 20230037922A
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- cancer
- nanoparticles
- fenbendazole
- poly
- pharmaceutical composition
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Images
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
- A61K9/5153—Polyesters, e.g. poly(lactide-co-glycolide)
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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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
Description
암 예방 또는 치료를 위한 활성 성분으로서 벤조이미다졸이 탑재된 나노입자를 유효성분으로 포함하는 암의 예방 또는 치료용 약학 조성물 {PHARMACEUTICAL COMPOSITION FOR PREVENTING OR TREATING CANCER COMPRISING NANOPARTICLES LOADED WITH BENZIMIDAZOLE AS AN ACTIVE INGREDIENT}A pharmaceutical composition for preventing or treating cancer comprising nanoparticles loaded with benzoimidazole as an active ingredient as an active ingredient for preventing or treating cancer
벤조이미다졸은 벤젠 고리와 이미다졸 고리가 융합된 두 개의 고리 구조를 특징으로 하는 분자식이 C7H6N₂인 방향족 헤테로고리 유기 화합물이며, 벤조이미다졸은 종종 생체활성을 갖는 바, 다양한 구충제(알벤다졸, 메벤다졸, 트리클라벤다졸 등)으로 사용되고 있다. 그 중 펜벤다졸은 회충, 요충, 편충, 십이지장충, 조충등 기생충 감염을 치료하기 위해 사용하는 구충제로서, 작용기전은 기생충 세포의 골격을 구성하는 미세소관을 형성하는 단백질인 튜불린의 형성을 방해하여 기생충의 장을 구조적으로 퇴행시키는 것이다. 그 결과 영양물질 등의 이동이 어려워져 세포 증식이 억제 되고, 기생충의 포도당 섭취와 소화, 생식 기능이 중단되어 기생충이 사멸하게 된다. 펜벤다졸은 포유류의 포도당 섭취는 억제하지 않고, 사람의 혈당에 영향을 미치지 않는다. 최종 숙주의 소화관에 음식이 존재하더라도 장 기생충 감염 치료 시 약물의 작용에 영향을 미치지 않는다.Benzoimidazole is an aromatic heterocyclic organic compound with a molecular formula of C 7 H 6 N₂ characterized by a two-ring structure in which a benzene ring and an imidazole ring are fused. albendazole, mebendazole, triclabendazole, etc.). Among them, fenbendazole is an antiparasitic agent used to treat parasitic infections such as roundworms, pinworms, whipworms, hookworms, and tapeworms. This is to structurally degenerate the intestinal tract of parasites. As a result, the movement of nutrients becomes difficult, cell proliferation is suppressed, and the parasite's glucose intake, digestion, and reproductive function are stopped, leading to the death of the parasite. Fenbendazole does not suppress mammalian glucose uptake and does not affect blood glucose in humans. The presence of food in the definitive host's digestive tract does not affect the action of the drug in treating intestinal parasitic infections.
항암제 중 암세포의 미세소관을 억제하는 기전을 가진 빈크리스틴, 파클리탁셀 등과 작용기전이 유사하여 오래 전부터 암 치료 가능성에 대한 연구가 진행되고 있는 성분이다. 최근 해외에서 임상시험도 진행되고 있으나, 안전성 및 효능을 충분히 입증하지 못하여 아직까지는 사람의 암 치료를 목적으로 사용하도록 허가되어 있지 않다 (Michelle De Witt, Alexander Gamble, et al. Repurposing Mebendazole as a Replacement for Vincristine for the Treatment of Brain Tumors. Molecular Medicine. 2017; 23: 50-56).Among anticancer drugs, it has a similar mechanism of action to vincristine and paclitaxel, which have a mechanism of inhibiting microtubules of cancer cells, so that research on the possibility of cancer treatment has been ongoing for a long time. Recently, clinical trials are also being conducted overseas, but safety and efficacy have not been sufficiently proven, so it has not yet been approved for human cancer treatment (Michelle De Witt, Alexander Gamble, et al. Repurposing Mebendazole as a Replacement for Vincristine for the Treatment of Brain Tumors. Molecular Medicine. 2017; 23: 50-56).
그러나, 펜벤다졸은 물에 용해되지 않는 불용성의 성질이 있으므로 주사제로 사용하기에 제한적이며, 이를 해결하기 위해서는 펜벤다졸의 가용화 방법을 개선해야 한다. 한편, PLGA 고분자는 생체친화적이며, 체내에서 생분해되는 특성이 있다. 또한, PLGA 고분자는 체내주입에 대하여 독성이 없는 것으로 알려져 있다 (Hee Dong Han, Yeongseon Byeon, et al. Toll-like receptor 3-induced immune response by poly(d,l-lactide-co-glycolide) nanoparticles for dendritic cell-based cancer immunotherapy. International Journal of Nanomedicine 2016:11, 5729-5742). 따라서, PLGA는 다양한 물질을 탑재할 수 있는 고분자 나노입자 형태로 제작이 가능하며 이러한 특징을 이용하여 주사제를 만들고자 하는 시도가 활발하다(Deepak N Kapoor, Amit Bhatia, et al. PLGA: a unique polymer for drug delivery. Therapeutic Delivery 6(1), 41-58, 2015.). However, since fenbendazole is insoluble in water, its use as an injection is limited. In order to solve this problem, a method for solubilizing fenbendazole should be improved. Meanwhile, the PLGA polymer is biocompatible and biodegradable in the body. In addition, PLGA polymer is known to be non-toxic when injected into the body (Hee Dong Han, Yeongseon Byeon, et al. Toll-like receptor 3-induced immune response by poly(d,l-lactide-co-glycolide) nanoparticles for dendritic cell-based cancer immunotherapy.International Journal of Nanomedicine 2016:11, 5729-5742). Therefore, PLGA can be manufactured in the form of polymer nanoparticles that can be loaded with various materials, and attempts to make injections using this feature are active (Deepak N Kapoor, Amit Bhatia, et al. PLGA: a unique polymer for drug delivery. Therapeutic Delivery 6(1), 41-58, 2015.).
본 발명자들은 구충제로 사용되고 있는 펜벤다졸의 항암치료 효능을 평가하고자 하였으며, 이를 위하여 불용성 펜벤다졸을 나노입자에 탑재하여 가용화 하였고, 이를 토대로 펜벤다졸 주사제를 개발하였다. 또한 펜벤다졸 주사제의 항암효능을 평가함으로서 신규 항암치료 후보물질로서 펜벤다졸의 적용범위를 확장하고자 노력하였으며, 이에 본 발명을 완성하였다.The inventors of the present invention tried to evaluate the anti-cancer efficacy of fenbendazole used as an anthelmintic agent. In addition, by evaluating the anticancer efficacy of fenbendazole injections, efforts were made to expand the scope of application of fenbendazole as a novel anticancer treatment candidate, and thus the present invention was completed.
본 발명의 목적은 펜벤다졸의 항암 치료 효과를 제공하는 것이며, 상기 펜벤다졸이 탑재된 나노입자를 제공하여, 암의 예방 또는 치료에 효과적인 약학 조성물을 제공함에 있다.An object of the present invention is to provide anticancer therapeutic effects of fenbendazole, and to provide a pharmaceutical composition effective for preventing or treating cancer by providing nanoparticles loaded with the fenbendazole.
본 발명은 또한, 펜벤다졸을 포함하는 벤조이미다졸의 생체 내 불용성을 해소하고자 생체적합성 고분자에 벤조이미다졸을 탑재한 나노입자의 제조방법을 제공함에 목적이 있다.Another object of the present invention is to provide a method for preparing nanoparticles loaded with benzoimidazole in a biocompatible polymer in order to overcome the insolubility of benzoimidazole containing fenbendazole in vivo.
이하, 본 발명의 바람직한 실시예를 상세히 설명한다. 본 발명의 이점 및 특징, 그리고 그것들을 달성하는 후술되어 있는 실시 예들을 참조하면 명확해질 것이다. 그러나 본 발명은 이하에서 게시되는 실시 예들에 한정되는 것이 아니라 서로 다른 다양한 형태로 구현될 수 있으며, 단지 본 실시예들은 본 발명의 게시가 완전하도록 하고, 본 발명이 속하는 기술분야에서 통상의 지식을 가진 자에게 발명의 범주를 완전하게 알려주기 위해 제공되는 것이며, 본 발명은 청구항의 범주에 의해 정의될 뿐이다. 명세서 전체에 걸쳐 동일 참조 부호는 동일 구성 요소를 지칭한다.Hereinafter, preferred embodiments of the present invention will be described in detail. The advantages and features of the present invention and the embodiments described below will become clear with reference to the embodiments that achieve them. However, the present invention is not limited to the embodiments disclosed below, but may be implemented in various different forms, and only the present embodiments make the disclosure of the present invention complete, and common knowledge in the art to which the present invention belongs It is provided to fully inform the holder of the scope of the invention, and the present invention is only defined by the scope of the claims. Like reference numbers designate like elements throughout the specification.
다른 정의가 없다면, 본 명세서에서 사용되는 모든 용어(기술 및 과학적 용어를 포함)는 본 발명이 속하는 기술분야에서 통상의 지식을 가진 자에게 공통적으로 이해될 수 있는 의미로 사용될 수 있을 것이다. 또 일반적으로 사용되는 사전에 정의되어 있는 용어들은 명백하게 특별히 정의되어 있지 않는 한 이상적으로 또는 과도하게 해석되지 않는다. 본 명세서에서 사용된 용어는 실시예들을 설명하기 위한 것이며 본 발명을 제한하고자 하는 것은 아니다. 본 명세서에서, 단수형은 문구에서 특별히 언급하지 않는 한 복수형도 포함한다.Unless otherwise defined, all terms (including technical and scientific terms) used in this specification may be used in a meaning commonly understood by those of ordinary skill in the art to which the present invention belongs. In addition, terms defined in commonly used dictionaries are not interpreted ideally or excessively unless explicitly specifically defined. Terminology used herein is for describing the embodiments and is not intended to limit the present invention. In this specification, singular forms also include plural forms unless specifically stated otherwise in a phrase.
현재 연구에 따르면, 펜벤다졸을 포함하는 벤조이미다졸은 불용성이기 때문에 주사제로 직접 활용이 불가할 뿐만 아니라, 경구 투여시 종양 세포에 대한 흡수율은 상당히 미비한 수준이다. According to the current study, since benzoimidazole including fenbendazole is insoluble, it cannot be used directly as an injection, and its absorption rate by tumor cells when administered orally is quite insignificant.
이와 같은 문제점을 해결하기 위해 생체적합성 고분자(바람직하게는 PLGA) 나노입자에 불용성 펜벤다졸을 탑재하여 주사제로 활용이 가능하게 제작하였으며, 이는 종양 세포에 대한 흡수율을 개선하여 펜벤다졸을 이용한 항암치료를 가능하게 할 수 있다.In order to solve this problem, biocompatible polymer (preferably PLGA) nanoparticles are loaded with insoluble fenbendazole to make them usable as an injection, which improves the uptake rate into tumor cells and thus anti-cancer using fenbendazole. treatment can be made possible.
상기 목적을 달성하기 위하여, 본 발명은 생체 적합성 고분자 및 상기 생체 적합성 고분자 내에 탑재되는 벤조이미다졸(benzimidazole) 또는 이의 유도체를 포함하는 나노입자 제공한다.In order to achieve the above object, the present invention provides a nanoparticle containing a biocompatible polymer and benzoimidazole or a derivative thereof loaded in the biocompatible polymer.
본 발명의 일 실시예에 따르면 본 발명의 나노입자는 생체 적합성 고분자 내부에 벤조이미다졸을 탑재하여 벤조이미다졸의 불용성을 보완한다.According to one embodiment of the present invention, the nanoparticles of the present invention complement the insolubility of benzoimidazole by loading benzoimidazole inside the biocompatible polymer.
본 발명의 상기 나노입자는, 주사제형으로 이용하기 위해 에멀젼 형태로 이용될 수 있으며, 상기 나노입자의 평균크기는 50 nm 내지 300 nm 으로 형성될 수 있다.The nanoparticles of the present invention may be used in the form of an emulsion for use as an injection, and the average size of the nanoparticles may be formed to be 50 nm to 300 nm.
본 발명은 또한, 상기 나노입자를 포함하는 암의 예방 또는 치료용 약학 조성물을 제공한다.The present invention also provides a pharmaceutical composition for preventing or treating cancer comprising the nanoparticles.
본 명세서에서“암”이란, 제어되지 않은 세포성장으로 특징지어지며, 이러한 비정상적인 세포성장에 의해 종양이라고 불리는 세포 덩어리가 형성되어 주위의 조직으로 침투하고 심한 경우에는 신체의 다른 기관으로 전이되기도 하는 것을 말한다. As used herein, “cancer” is characterized by uncontrolled cell growth, in which a cell mass called a tumor is formed by such abnormal cell growth, penetrates into surrounding tissues, and in severe cases, metastasizes to other organs of the body. say
본 발명에서, 상기 암은 난소암, 구강암, 간암, 위암, 결장암, 유방암, 폐암, 골암, 췌장암, 피부암, 두부암, 경부암, 자궁경부암, 난소암, 대장암, 소장암, 직장암, 난관암, 항문암, 자궁내막암, 질암, 음문암, 호지킨 림프종(Hodgkin's disease), 식도암, 임파선암, 방광암, 담낭암, 내분비선암, 갑상선암, 부갑상선암, 부신암, 연조직 육종, 요도암, 음경암, 전립선암, 만성 백혈병, 급성 백혈병, 림프구 림프종, 신장암, 수뇨관암, 신장세포암, 신장골반암, 중추신경계 종양, 1차 중추신경계 림프종, 척수 종양, 뇌간 신경교종, 뇌하수체 선종 또는 다중약물내성(multiple drug resistance) 암일 수 있으나, 이에 한정되는 것은 아니며, 바람직하게는 난소암을 의미한다.In the present invention, the cancer is ovarian cancer, oral cancer, liver cancer, stomach cancer, colon cancer, breast cancer, lung cancer, bone cancer, pancreatic cancer, skin cancer, head cancer, cervical cancer, cervical cancer, ovarian cancer, colon cancer, small intestine cancer, rectal cancer, fallopian tube cancer, Anal cancer, endometrial cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, lymph gland cancer, bladder cancer, gallbladder cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate Cancer, chronic leukemia, acute leukemia, lymphocytic lymphoma, renal cancer, ureteric cancer, renal cell carcinoma, renal pelvic cancer, central nervous system tumor, primary central nervous system lymphoma, spinal cord tumor, brainstem glioma, pituitary adenoma or multiple drug resistance drug resistance) cancer, but is not limited thereto, and preferably means ovarian cancer.
본 발명의 일 구체예에서 “치료”란, 목적하는 질병의 완화 또는/및 개선을 위해 수행되는 일련의 활동을 의미한다. 본 발명의 목적상 치료는 암세포의 수적 또는 양적 증식을 억제시키거나, 암세포를 사멸시키거나, 암 조직의 성장을 억제시키거나, 암 조직의 크기를 감소시키거나, 암 조직 내의 신생혈관의 발달을 억제시키거나, 암이 또 다른 부위로 침윤 또는 전이되는 것을 억제하는 활동을 포함한다.In one embodiment of the present invention, “treatment” refers to a series of activities performed to alleviate or/and improve a target disease. For the purposes of the present invention, treatment inhibits the numerical or quantitative proliferation of cancer cells, kills cancer cells, inhibits the growth of cancer tissue, reduces the size of cancer tissue, or inhibits the development of new blood vessels in cancer tissue. It includes activities that inhibit or inhibit the invasion or metastasis of cancer to another site.
본 발명의 한 실시예에 따르면, 본 발명의 나노입자를 유효성분으로 함유하는 암의 예방 또는 치료용 약학조성물은 통상적인 방법에 따라 과립제, 산제, 정제, 환제, 캡슐제, 좌제, 겔, 현탁제, 유제, 점적제 또는 액제로 이루어진 군에서 선택된 어느 하나의 제형을 사용할 수 있으며, 본 발명은 상기 나노입자를 형성하여 펜벤다졸의 가용성을 향상시킨 것을 특징으로 하는 바, 가장 바람직하게는 주사제형으로 이용될 수 있다.According to one embodiment of the present invention, a pharmaceutical composition for preventing or treating cancer containing the nanoparticles of the present invention as an active ingredient is granules, powders, tablets, pills, capsules, suppositories, gels, suspensions according to conventional methods. Any one formulation selected from the group consisting of an agent, an emulsion, a drop, or a liquid may be used, and the present invention is characterized by improving the solubility of fenbendazole by forming the nanoparticles, most preferably an injection. can be used as a form.
본 발명의 다른 실시예에 따르면, 본 발명의 상기 나노입자를 유효성분으로 함유하는 암의 예방 또는 치료용 약학조성물은 약학조성물의 제조에 통상적으로 사용하는 적절한 담체, 부형제, 붕해제, 감미제, 피복제, 팽창제, 윤활제, 활택제, 향미제, 항산화제, 완충액, 정균제, 희석제, 분산제, 계면활성제, 결합제 및 윤활제로 이루어진 군에서 선택되는 하나 이상의 첨가제를 추가로 포함할 수 있다.According to another embodiment of the present invention, the pharmaceutical composition for preventing or treating cancer containing the nanoparticles of the present invention as an active ingredient is a suitable carrier, excipient, disintegrant, sweetener, blood It may further include one or more additives selected from the group consisting of replication, swelling agents, lubricants, lubricants, flavoring agents, antioxidants, buffers, bacteriostatic agents, diluents, dispersing agents, surfactants, binders and lubricants.
구체적으로 담체, 부형제 및 희석제는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 사용할 수 있으며, 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 조성물에 적어도 하나 이상의 부형제, 예를 들면, 전분, 칼슘카보네이트, 수크로스 또는 락토오스, 젤라틴 등을 섞어 조제할 수 있다. 또한 단순한 부형제 이외에 마그네슘 스티레이트, 탈크 같은 윤활제들도 사용할 수 있다. 경구를 위한 액상제제로는 현탁제, 내용액제, 유제, 시럽제 등이 있으며 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제, 좌제 등이 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜, 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기재로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다.Specifically, carriers, excipients and diluents are lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline Cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil may be used, and solid dosage forms for oral administration include tablets, pills, powders, granules, and capsules. These solid preparations may be prepared by mixing at least one or more excipients, for example, starch, calcium carbonate, sucrose or lactose, gelatin, etc., with the composition. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Liquid preparations for oral administration include suspensions, solutions for oral use, emulsions, syrups, and the like, and various excipients such as wetting agents, sweeteners, aromatics, and preservatives may be included in addition to commonly used simple diluents such as water and liquid paraffin. Preparations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, suppositories, and the like. Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solvents and suspending agents. As a base material of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin paper, glycerogeratin and the like may be used.
본 발명의 약학 조성물은 추가로 다른 항암제와 병용 투여할 수 있으며, 이를 통해서 암 줄기세포뿐만 아니라 일반적인 암세포까지 효과적으로 치료하는데 사용될 수 있다.The pharmaceutical composition of the present invention can be additionally administered in combination with other anticancer agents, and through this, can be used to effectively treat not only cancer stem cells but also general cancer cells.
여기서 상기 항암제로는 나이트로젠 머스타드, 이마티닙, 옥살리플라틴, 리툭시맙, 엘로티닙, 네라티닙, 라파티닙, 제피티닙, 반데타닙, 니로티닙, 세마사닙, 보수티닙, 악시티닙, 세디라닙, 레스타우르티닙, 트라스투주맙, 게피티니브, 보르테조밉, 수니티닙, 카보플라틴, 소라페닙, 베바시주맙, 시스플라틴, 세툭시맙, 비스쿰알붐, 아스파라기나제, 트레티노인, 하이드록시카바마이드, 다사티닙, 에스트라머스틴, 겜투주맵오조가마이신, 이브리투모맙튜세탄, 헵타플라틴, 메칠아미노레불린산, 암사크린, 알렘투주맙, 프로카르바진, 알프로스타딜, 질산홀뮴키토산, 젬시타빈, 독시플루리딘, 페메트렉세드, 테가푸르, 카페시타빈, 기메라신, 오테라실, 아자시티딘, 메토트렉세이트, 우라실, 시타라빈, 플루오로우라실, 플루다가빈, 에노시타빈, 플루타미드, 데시타빈, 머캅토푸린,티오구아닌, 클라드리빈, 카르모퍼, 랄티트렉세드, 도세탁셀, 파클리탁셀, 이리노테칸, 벨로테칸, 토포테칸, 비노렐빈, 에토포시드, 빈크리스틴, 빈블라스틴, 테니포시드, 독소루비신, 이다루비신, 에피루비신, 미톡산트론, 미토마이신, 블레로마이신, 다우노루비신, 닥티노마이신, 피라루비신, 아클라루비신, 페프로마이신, 템시롤리무스, 테모졸로마이드, 부설판, 이포스파미드, 사이클로포스파미드, 멜파란, 알트레트민, 다카바진, 치오테파, 니무스틴, 클로람부실, 미토락톨, 레우코보린, 트레토닌, 엑스메스탄, 아미노글루테시미드, 아나그렐리드, 나벨빈, 파드라졸, 타목시펜, 토레미펜, 테스토락톤, 아나스트로졸, 레트로졸, 보로졸, 비칼루타미드, 로무스틴 및 카르무스틴으로 이루어진 군에서 선택된 적어도 어느 하나를 사용할 수 있으나, 이에 한정되는 것은 아니다.Here, the anticancer agent is nitrogen mustard, imatinib, oxaliplatin, rituximab, erlotinib, neratinib, lapatinib, gefitinib, vandetanib, nirotinib, semasanib, bosutinib, axitinib, cediranib , lestaurtinib, trastuzumab, gefitinib, bortezomib, sunitinib, carboplatin, sorafenib, bevacizumab, cisplatin, cetuximab, viscum album, asparaginase, tretinoin, hydroxycarba amide, dasatinib, estramustine, gemtuzumab ozogamicin, ibritumomabtucetan, heptaplatin, methylaminolevulinic acid, amsacrine, alemtuzumab, procarbazine, alprostadil, holmium nitrate Chitosan, gemcitabine, doxifluridine, pemetrexed, tegafur, capecitabine, gimeracin, oteracil, azacitidine, methotrexate, uracil, cytarabine, fluorouracil, fludabine, enocy Tabine, flutamide, decitabine, mercaptopurine, thioguanine, cladribine, carmophor, raltitrexed, docetaxel, paclitaxel, irinotecan, belotecan, topotecan, vinorelbine, etoposide, vincristine, bin Blastin, teniposide, doxorubicin, idarubicin, epirubicin, mitoxantrone, mitomycin, bleromycin, daunorubicin, dactinomycin, pirarubicin, aclarubicin, pepromycin, temsy lolimus, temozolomide, busulfan, ifosfamide, cyclophosphamide, melpharan, altretmin, dacarbazine, thiotepa, nimustine, chlorambucil, mitolactol, leucovorin, tretonin, x with mestanes, aminoglutesimide, anagrelide, navelbine, fadrazole, tamoxifen, toremifene, testolactone, anastrozole, letrozole, vorozole, bicalutamide, lomustine, and carmustine At least one selected from the group consisting of may be used, but is not limited thereto.
본 발명의 일실시예에 따르면 상기 약학 조성물은 정맥내, 동맥내, 복강내, 근육내, 동맥내, 복강내, 흉골내, 경피, 비측내, 흡입, 국소, 직장, 경구, 안구내 또는 피내 경로를 통해 통상적인 방식으로 대상체로 투여할 수 있다.According to one embodiment of the present invention, the pharmaceutical composition is intravenous, intraarterial, intraperitoneal, intramuscular, intraarterial, intraperitoneal, intrasternal, transdermal, intranasal, inhalational, topical, rectal, oral, intraocular or intradermal. It can be administered to a subject in a conventional manner via a route.
상기 약학조성물의 바람직한 투여량은 대상체의 상태 및 체중, 질환의 종류 및 정도, 약물 형태, 투여경로 및 기간에 따라 달라질 수 있으며 당업자에 의해 적절하게 선택될 수 있다.A preferred dosage of the pharmaceutical composition may vary depending on the condition and body weight of the subject, the type and severity of the disease, the type of drug, the route and duration of administration, and may be appropriately selected by those skilled in the art.
본 발명의 일실시예에 따르면 이에 제한되는 것은 아니지만 1일 투여량이 50 mg/kg 내지 100 mg/kg일 수 있다. 투여는 하루에 한 번 투여할 수도 있고 수회로 나누어 투여할 수도 있으며, 이에 의해 본 발명의 범위가 제한되는 것은 아니다.According to one embodiment of the present invention, but not limited thereto, the daily dosage may be 50 mg/kg to 100 mg/kg. Administration may be administered once a day or divided into several administrations, and the scope of the present invention is not limited thereby.
본 발명에 있어서, 상기 “대상체”는 인간을 포함하는 포유동물일 수 있으나, 이들 예에 한정되는 것은 아니다.In the present invention, the “subject” may be a mammal including a human, but is not limited to these examples.
본 발명은 또한, 벤조이미다졸(benzimidazole)이 탑재된 나노입자의 제조방법을 제공한다.The present invention also provides a method for preparing nanoparticles loaded with benzimidazole.
본 발명의 상기 나노입자 제조방법은, a) 생체적합성 고분자를 유기 용매에 용해시키는 단계; b) 상기 단계 a)에 따른 용해물에 양친매성 고분자를 혼합하여 에멀젼을 형성시키는 단계; c) 상기 에멀젼을 감압하여 유기 용매를 증발시킨 후 나노 입자를 정제하는 단계를 포함할 수 있다. The method for preparing the nanoparticles of the present invention includes the steps of a) dissolving a biocompatible polymer in an organic solvent; b) forming an emulsion by mixing an amphiphilic polymer with the lysate according to step a); c) depressurizing the emulsion to evaporate the organic solvent, and then purifying the nanoparticles.
본 발명에 따르면, 상기 단계 b)는 초음파 분쇄기를 이용하여 에멀젼을 형성시키는 단계를 포함할 수 있으며, 상기 단계 c)는 원심분리 방식으로 나노입자를 정제하는 것을 포함할 수 있다.According to the present invention, step b) may include forming an emulsion using an ultrasonicator, and step c) may include purifying the nanoparticles by centrifugation.
더욱 구체적으로, 상기 나노 입자의 제조방법은, i) 용매(바람직하게는, DMSO(dimethyl sulfoxide))에 펜벤다졸을 30~50mg/ml, PLGA를 100~500mg/ml의 농도로 용해하는 단계; ii) 상기 단계 i)에서 생성된 두개의 용액을 섞어 유상을 형성하는 단계; iii) 상기 단계 ii)의 용액을 폴리비닐알콜 (PVA) 4% 수용액에 넣고 초음파 분쇄기를 이용해 에멀젼을 형성하는 단계; ⅳ) 상기 단계 iii)의 용액을 evaporator로 감압 증발 단계; ⅴ) 상기 단계 ⅳ)의 용액을 원심분리기로 정제하는 단계를 포함할 수 있다.More specifically, the method for producing the nanoparticles, i) dissolving fenbendazole in a solvent (preferably, DMSO (dimethyl sulfoxide)) at a concentration of 30 to 50 mg / ml and PLGA at a concentration of 100 to 500 mg / ml ; ii) forming an oil phase by mixing the two solutions produced in step i); iii) adding the solution of step ii) to a 4% aqueous solution of polyvinyl alcohol (PVA) and forming an emulsion using a sonicator; iv) evaporating the solution of step iii) under reduced pressure using an evaporator; v) purifying the solution of step iv) using a centrifuge.
또한, 본 발명의 상기 제조방법에 따르면, 상기 나노입자는 생체적합성 고분자 내부에 벤조이미다졸(benzimidazole)이 탑재될 수 있다. In addition, according to the preparation method of the present invention, the nanoparticles may be loaded with benzimidazole inside the biocompatible polymer.
본 발명에서, 상기 양친매성 고분자는, 소듐 콜레이트(sodium cholate), 소듐 디옥시콜레이트(sodium deoxycholate), Span 20(Sorbitan Monolaurate), Span 60(Sorbitan Monostearate), Span 80(Sorbitan Monooleate), Tween 20(Polyoxyethylene(20) Sorbitan Monolaurate), Tween 60(Polyoxyethylene(20) Sorbitan Monostearte), Tween 80(Polyoxyethylene(20) Sorbitan Monolaurate) 또는 DPG(dipotassium glycyrrhizinate)일 수 있으며, 바람직하게는 PVA (Polyvinyl alcohol)이다.In the present invention, the amphiphilic polymer is sodium cholate, sodium deoxycholate, Span 20 (Sorbitan Monolaurate), Span 60 (Sorbitan Monostearate), Span 80 (Sorbitan Monooleate), Tween 20 ( Polyoxyethylene (20) Sorbitan Monolaurate), Tween 60 (Polyoxyethylene (20) Sorbitan Monostearate), Tween 80 (Polyoxyethylene (20) Sorbitan Monolaurate), or DPG (dipotassium glycyrrhizinate), preferably PVA (Polyvinyl alcohol).
본 발명에서, 상기 생체 적합성 고분자에는 PLGA(Poly(lactic acid-co-glycolic acid), 폴리에틸렌글리콜(polyethyleneglycol, PEG), 폴리아크릴아미드(polyacrylamide), 플루로닉(pluronic), 폴리에틸렌옥사이드(poly(ethylene oxide), 폴리프로필렌옥사이드(poly(propylene oxide), 엔-옥틸트리에틸렌글라이콜에테르(n-octyltriethylene glycol ether, 8E3)이 포함될 수 있으며, 이에 한정되는 것은 아니다.In the present invention, the biocompatible polymer includes PLGA (Poly (lactic acid-co-glycolic acid), polyethylene glycol (PEG), polyacrylamide, pluronic, polyethylene oxide (poly (ethylene oxide), poly(propylene oxide), and n-octyltriethylene glycol ether (8E3) may be included, but is not limited thereto.
본 발명에서, 상기 벤조이미다졸은, 펜벤다졸(fenbendazole), 티아벤다졸(Tiabendazole), 캄벤다졸(Cambendazole), 파르벤다졸(Parbendazole), 옥시벤다졸(Oxibendazole), 멘벤다졸(Mebendazole), 플루벤다졸(Flubendazole), 옥스펜다졸(Oxfendazole) 및 알벤다졸(Albendazole) 중 어느 하나일 수 있으며, 이에 한정되는 것은 아니다.In the present invention, the benzoimidazole is fenbendazole, thiabendazole, cambendazole, parbendazole, oxybendazole, mebendazole ), flubendazole, oxfendazole, and albendazole, but not limited thereto.
본 발명에 따르면 상기 나노입자의 제조 방법으로 제조된 나노입자를 제공한다.According to the present invention, nanoparticles prepared by the method for preparing nanoparticles are provided.
본 명세서에서 사용된 “치료 유효량”은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 본 발명에 따른 벤조이미다졸이 탑재된 나노입자의 양을 의미한다. 정확한 양은 치료 조성물의 성분 및 물리적 특징, 의도된 환자 집단, 개개의 환자의 고려사항 등을 포함하지만 이에 제한되지 않는 수많은 인자에 따라 달라질 것이고 당업자가 쉽게 결정할 수 있다. 이들 요인들을 완전하게 고려할 때, 부작용 없이 최대의 효과를 얻기에 충분한 최소량을 투여하는 것이 중요하며, 이 복용량은 분야의 전문가에 의하여 용이하게 결정될 수 있다.As used herein, "therapeutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment, and refers to the amount of nanoparticles loaded with benzoimidazole according to the present invention. The precise amount will depend on numerous factors including, but not limited to, the components and physical characteristics of the therapeutic composition, the intended patient population, individual patient considerations, and the like, and can readily be determined by one skilled in the art. Taking these factors into full consideration, it is important to administer the smallest amount sufficient to obtain the maximum effect without side effects, and this dosage can be readily determined by a person skilled in the art.
본 발명에 따른 벤조이미다졸(펜벤다졸)이 탑재된 생체적합성 고분자(PLGA)의 나노입자는 펜벤다졸의 가용화를 통한 주사제 개발을 가능하게 하며, 암조직에 대한 펜벤다졸의 전달률을 높일 수 있다. The nanoparticles of a biocompatible polymer (PLGA) loaded with benzoimidazole (fenbendazole) according to the present invention enable the development of injections through solubilization of fenbendazole and increase the delivery rate of fenbendazole to cancer tissues. can
본 발명의 나노입자는 수동적 표적지향 방법인 EPR(enhanced permeability and retention) 효과를 통해 암 조직에 선택적으로 축적되어 항암 효과가 뛰어나다.The nanoparticles of the present invention are selectively accumulated in cancer tissues through the enhanced permeability and retention (EPR) effect, which is a passive targeting method, and have excellent anticancer effects.
특히, 본 발명의 제조방법을 통해 제조된 펜벤다졸이 탑재된 PLGA 나노입자는 EPR(enhanced permeability and retention) 효과로 인해 암 조직으로 선택적으로 축적되어 항암 효과가 뛰어날 뿐만 아니라, 항암화학제에 내성을 지니는 암종에 대한 치료가 가능한 이점이 있다.In particular, the PLGA nanoparticles loaded with fenbendazole prepared through the manufacturing method of the present invention are selectively accumulated in cancer tissues due to the EPR (enhanced permeability and retention) effect, and not only have excellent anticancer effects, but also have resistance to anticancer chemicals. It has the advantage of being able to treat carcinomas with .
본 발명에 따른 벤조이미다졸(펜벤다졸)이 탑재된 생체적합성 고분자(PLGA)의 나노입자는 펜벤다졸의 가용화를 통한 주사제 개발을 가능하게 하며, 암조직에 대한 펜벤다졸의 전달률을 높일 수 있다.
본 발명의 나노입자는 수동적 표적지향 방법인 EPR(enhanced permeability and retention) 효과를 통해 암 조직에 선택적으로 축적되어 항암 효과가 뛰어나다.
특히, 본 발명의 제조방법을 통해 제조된 펜벤다졸이 탑재된 PLGA 나노입자는 EPR(enhanced permeability and retention) 효과로 인해 암 조직으로 선택적으로 축적되어 항암 효과가 뛰어날 뿐만 아니라, 항암화학제에 내성을 지니는 암종에 대한 치료가 가능한 이점이 있다.The nanoparticles of a biocompatible polymer (PLGA) loaded with benzoimidazole (fenbendazole) according to the present invention enable the development of injections through solubilization of fenbendazole and increase the delivery rate of fenbendazole to cancer tissues. can
The nanoparticles of the present invention are selectively accumulated in cancer tissues through an enhanced permeability and retention (EPR) effect, which is a passive targeting method, and have excellent anticancer effects.
In particular, the PLGA nanoparticles loaded with fenbendazole prepared through the manufacturing method of the present invention are selectively accumulated in cancer tissues due to the EPR (enhanced permeability and retention) effect, and not only have excellent anticancer effects, but also have resistance to anticancer chemicals. There is an advantage of being able to treat carcinomas with .
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 요지에 따라 본 발명의 범위가 이들 실시예에 의해 제한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail through examples. These examples are only for explaining the present invention in more detail, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples according to the gist of the present invention. .
[실시예 1][Example 1]
펜벤다졸이 탑재된 PLGA 나노입자의 제조 Preparation of PLGA nanoparticles loaded with fenbendazole
PLGA 고분자를 이용하여 펜벤다졸을 함유한 나노입자의 제조는 다음과 같이 실시하였다. O/W의 에멀젼 방법으로 제작되며 유기용매를 증발시켜 나노입자를 제조한다. DMSO(dimethyl sulfoxide)에 용해되어있는 펜벤다졸 (40mg/ml)을 DMSO(dimethyl sulfoxide)에 용해되어있는 PLGA와 섞어 유상을 형성한다. 형성된 유상의 용액을 폴리비닐알콜 (PVA) 4% 수용액에 넣어 초음파 분쇄기를 이용해 에멀젼을 형성한다. 형성된 에멀젼을 증발기를 이용하여 DMSO(dimethyl sulfoxide)를 증발시킨다. 증발 후 남은 나노입자를 원심분리기로 정제하여 최종적으로 펜벤다졸이 탑재된 PLGA 나노입자를 제조하였다.Preparation of nanoparticles containing fenbendazole using PLGA polymer was carried out as follows. It is produced by the O/W emulsion method, and nanoparticles are prepared by evaporating organic solvents. Fenbendazole (40mg/ml) dissolved in DMSO (dimethyl sulfoxide) is mixed with PLGA dissolved in DMSO (dimethyl sulfoxide) to form an oil phase. The formed oily solution was added to a 4% aqueous solution of polyvinyl alcohol (PVA), and an emulsion was formed using a sonicator. DMSO (dimethyl sulfoxide) is evaporated from the formed emulsion using an evaporator. The nanoparticles remaining after evaporation were purified by centrifugation to finally prepare PLGA nanoparticles loaded with fenbendazole.
[실시예 2][Example 2]
펜벤다졸이 탑재된 PLGA 나노입자의 물리적 특성 Physical properties of PLGA nanoparticles loaded with fenbendazole
상기 실시예 1에서 제조한 PLGA 나노입자, 펜벤다졸이 탑재된 PLGA 나노입자의 크기를 광산란장치를 이용하여 측정하였으며, 그 결과를 도 1A에 나타내었다. The size of the PLGA nanoparticles prepared in Example 1 and the PLGA nanoparticles loaded with fenbendazole were measured using a light scattering device, and the results are shown in FIG. 1A.
도 1A에 나타낸 바와 같이, PLGA 나노입자의 크기는 130 nm이었으며, 펜벤다졸이 탑재된 PLGA 나노입자의 크기는 148 nm임을 확인할 수 있다. 본 발명에 따른 나노입자는 바람직하게는 50 nm 내지 300 nm 의 크기를 가질 수 있다.As shown in FIG. 1A, the size of the PLGA nanoparticles was 130 nm, and the size of the PLGA nanoparticles loaded with fenbendazole was 148 nm. Nanoparticles according to the present invention may preferably have a size of 50 nm to 300 nm.
또한 제타 전위 측정기를 이용하여 입자 표면의 전위를 측정하였으며, 그 결과를 도 1B에 나타내었다. 도 1B에 나타낸 바와 같이, PLGA 나노입자의 전위 값은 -26 mV이었으며, 펜벤다졸이 탑재된 PLGA 나노입자의 전위 값은 -30 mV임(바람직하게는 -25mV 내지 -50mV 의 전위 값)을 확인할 수 있다. In addition, the potential of the particle surface was measured using a zeta potential meter, and the results are shown in FIG. 1B. As shown in FIG. 1B, the potential value of the PLGA nanoparticles was -26 mV, and the potential value of the PLGA nanoparticles loaded with fenbendazole was -30 mV (preferably a potential value of -25mV to -50mV). You can check.
펜벤다졸이 탑재된 PLGA 나노입자의 적재효율(loading efficiency)을 UV 분광 광도계를 이용하여 285 nm의 흡광 파장에서 측정하고 이를 도 1C에 나타내었다. 도 1C에 나타낸 바와 같이, 펜벤다졸이 탑재된 PLGA 나노입자 적재효율은 80 %임을 확인할 수 있다.The loading efficiency of the PLGA nanoparticles loaded with fenbendazole was measured at an absorption wavelength of 285 nm using a UV spectrophotometer and is shown in FIG. 1C. As shown in FIG. 1C, it can be seen that the loading efficiency of PLGA nanoparticles loaded with fenbendazole is 80%.
[실시예 3][Example 3]
펜벤다졸이 탑재된 PLGA 나노입자의 항암 치료 효과 확인Confirmation of anticancer treatment effect of PLGA nanoparticles loaded with fenbendazole
펜벤다졸의 항암 치료 효과를 확인하기 위하여, 인간 난소암 세포주인 HeyA8과 HeyA8-MDR을 누드마우스에 직접 주사하여 종양모델을 제작하고, 상기 펜벤다졸이 1mg이 탑재되어있는 나노입자를 마우스에 주사하였다. 실험 종료 시점은 대조군 마우스가 죽기 직전으로 하였다. 실험 종료 시점에 각각의 마우스의 종양 조직을 적출하여 무게를 측정하였다.In order to confirm the anticancer treatment effect of fenbendazole, human ovarian cancer cell lines HeyA8 and HeyA8-MDR were directly injected into nude mice to create tumor models, and nanoparticles loaded with 1 mg of fenbendazole were injected into the mice. Injected. The experiment was terminated immediately before the death of the control mice. At the end of the experiment, the tumor tissues of each mouse were removed and weighed.
도 2에 나타낸 바와 같이, 펜벤다졸이 탑재된 PLGA 나노입자가 종양의 크기를 감소시키는 것을 확인하여 치료효과가 있는 것을 확인하였다.As shown in FIG. 2, it was confirmed that the fenbendazole-loaded PLGA nanoparticles reduced the size of the tumor and thus had a therapeutic effect.
이상 본 발명의 실시예들을 설명하였지만, 본 발명이 속하는 기술분야에서 통상의 지식을 가진 자는 본 발명이 그 기술적 사상이나 필수적인 특징을 변경하지 않고서 다른 구체적인 형태로 실시될 수 있다는 것을 이해할 수 있을 것이다. 그러므로 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적인 것이 아닌 것으로 이해해야만 한다.Although the embodiments of the present invention have been described above, those skilled in the art to which the present invention belongs will understand that the present invention can be implemented in other specific forms without changing the technical spirit or essential features. Therefore, the embodiments described above should be understood as illustrative in all respects and not limiting.
Claims (19)
상기 생체 적합성 고분자 내에 탑재되는 벤조이미다졸(benzimidazole) 또는 이의 유도체;를 포함하는 나노입자.biocompatible polymers; and
Nanoparticles containing; benzoimidazole (benzimidazole) or a derivative thereof loaded in the biocompatible polymer.
상기 생체 적합성 고분자는 PLGA(Poly(lactic acid-co-glycolic acid), 폴리에틸렌글리콜(polyethyleneglycol, PEG), 폴리아크릴아미드(polyacrylamide), 플루로닉(pluronic), 폴리에틸렌옥사이드(poly(ethylene oxide), 폴리프로필렌옥사이드(poly(propylene oxide), 엔-옥틸트리에틸렌글라이콜에테르(n-octyltriethylene glycol ether, 8E3)로 이루어진 군에서 선택된 적어도 어느 하나의 고분자인, 나노입자.According to claim 1,
The biocompatible polymer is PLGA (Poly (lactic acid-co-glycolic acid), polyethylene glycol (polyethylene glycol, PEG), polyacrylamide, pluronic, poly (ethylene oxide), poly At least one polymer selected from the group consisting of poly (propylene oxide) and n-octyltriethylene glycol ether (8E3), nanoparticles.
상기 벤조이미다졸은, 펜벤다졸(fenbendazole), 티아벤다졸(Tiabendazole), 캄벤다졸(Cambendazole), 파르벤다졸(Parbendazole), 옥시벤다졸(Oxibendazole), 멘벤다졸(Mebendazole), 플루벤다졸(Flubendazole), 옥스펜다졸(Oxfendazole), 알벤다졸(Albendazole)로 이루어진 군에서 선택된 적어도 하나의 화합물인, 나노입자.According to claim 1,
The benzoimidazole is fenbendazole, thiabendazole, cambendazole, parbendazole, oxybendazole, mebendazole, flubenda Sol (Flubendazole), oxfendazole (Oxfendazole), at least one compound selected from the group consisting of albendazole (Albendazole), nanoparticles.
상기 나노입자는, -25mV 내지 -50mV의 전위값을 갖는 것인, 나노입자.According to claim 1,
The nanoparticles, nanoparticles having a potential value of -25mV to -50mV.
상기 나노입자는, 50 nm 내지 300 nm 크기인, 나노입자.According to claim 1,
The nanoparticles, nanoparticles of 50 nm to 300 nm in size.
상기 암은 난소암, 구강암, 간암, 위암, 결장암, 유방암, 폐암, 골암, 췌장암, 피부암, 두부암, 경부암, 자궁경부암, 난소암, 대장암, 소장암, 직장암, 난관암, 항문암, 자궁내막암, 질암, 음문암, 호지킨 림프종(Hodgkin's disease), 식도암, 임파선암, 방광암, 담낭암, 내분비선암, 갑상선암, 부갑상선암, 부신암, 연조직 육종, 요도암, 음경암, 전립선암, 만성 백혈병, 급성 백혈병, 림프구 림프종, 신장암, 수뇨관암, 신장세포암, 신장골반암, 중추신경계 종양, 1차 중추신경계 림프종, 척수 종양, 뇌간 신경교종 및 뇌하수체 선종을 포함하는 군에서 선택된 적어도 하나의 질환인, 암의 예방 또는 치료용 약학 조성물.According to claim 6,
The cancer is ovarian cancer, oral cancer, liver cancer, stomach cancer, colon cancer, breast cancer, lung cancer, bone cancer, pancreatic cancer, skin cancer, head cancer, cervical cancer, cervical cancer, ovarian cancer, colon cancer, small intestine cancer, rectal cancer, fallopian tube cancer, anal cancer, uterus Endometrial cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, lymph gland cancer, bladder cancer, gallbladder cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic leukemia , at least one disease selected from the group comprising acute leukemia, lymphocytic lymphoma, renal cancer, ureteric cancer, renal cell carcinoma, renal pelvic cancer, central nervous system tumor, primary central nervous system lymphoma, spinal cord tumor, brainstem glioma, and pituitary adenoma. Phosphorus, a pharmaceutical composition for the prevention or treatment of cancer.
상기 암은 다중약물내성(multiple drug resistance) 암인, 암의 예방 또는 치료용 약학 조성물.According to claim 6,
The cancer is multiple drug resistance (multiple drug resistance) cancer, a pharmaceutical composition for preventing or treating cancer.
상기 조성물은 약제학적으로 허용되는 담체, 부형제 또는 희석제를 추가하여 약제학적 투여형으로 제형화되는 것인, 암의 예방 또는 치료용 약학 조성물.According to claim 6,
The composition is formulated into a pharmaceutical dosage form by adding a pharmaceutically acceptable carrier, excipient or diluent, a pharmaceutical composition for preventing or treating cancer.
상기 조성물은 주사제형인, 암의 예방 또는 치료용 약학 조성물.According to claim 6,
The composition is an injection formulation, a pharmaceutical composition for the prevention or treatment of cancer.
a) 생체적합성 고분자를 유기 용매에 용해시키는 단계;
b) 상기 단계 a)에 따른 용해물에 양친매성 고분자를 혼합하여 에멀젼을 형성시키는 단계;
c) 상기 에멀젼을 감압하여 유기 용매를 증발시킨 후 나노 입자를 정제하는 단계를 포함하고,
상기 나노입자는 생체적합성 고분자 내부에 벤조이미다졸(benzimidazole)이 탑재되는 것인, 나노입자의 제조방법. In the method for producing nanoparticles loaded with benzoimidazole,
a) dissolving the biocompatible polymer in an organic solvent;
b) forming an emulsion by mixing an amphiphilic polymer with the lysate according to step a);
c) reducing the emulsion to evaporate the organic solvent and purifying the nanoparticles;
The nanoparticle is a method for producing nanoparticles, in which benzoimidazole (benzimidazole) is loaded inside the biocompatible polymer.
상기 단계 b)는 초음파 분쇄기를 이용하여 에멀젼을 형성시키는 것인, 나노입자의 제조방법.According to claim 11,
Wherein step b) is to form an emulsion using an ultrasonic mill, a method for producing nanoparticles.
상기 단계 c)는 원심분리 방식으로 나노입자를 정제하는 것인, 나노입자의 제조방법.According to claim 11,
Wherein step c) is to purify the nanoparticles by centrifugation, a method for producing nanoparticles.
상기 생체 적합성 고분자는 PLGA(Poly(lactic acid-co-glycolic acid), 폴리에틸렌글리콜(polyethyleneglycol, PEG), 폴리아크릴아미드(polyacrylamide), 플루로닉(pluronic), 폴리에틸렌옥사이드(poly(ethylene oxide), 폴리프로필렌옥사이드(poly(propylene oxide), 엔-옥틸트리에틸렌글라이콜에테르(n-octyltriethylene glycol ether, 8E3)로 이루어진 군에서 선택된 적어도 어느 하나의 고분자인, 나노입자의 제조방법.According to claim 11,
The biocompatible polymer is PLGA (Poly (lactic acid-co-glycolic acid), polyethylene glycol (polyethylene glycol, PEG), polyacrylamide, pluronic, poly (ethylene oxide), poly A method for producing nanoparticles, which is at least one polymer selected from the group consisting of poly (propylene oxide) and n-octyltriethylene glycol ether (8E3).
상기 벤조이미다졸은, 펜벤다졸(fenbendazole), 티아벤다졸(Tiabendazole), 캄벤다졸(Cambendazole), 파르벤다졸(Parbendazole), 옥시벤다졸(Oxibendazole), 멘벤다졸(Mebendazole), 플루벤다졸(Flubendazole), 옥스펜다졸(Oxfendazole), 알벤다졸(Albendazole)로 이루어진 군에서 선택된 적어도 하나의 화합물인, 나노입자의 제조방법. According to claim 11,
The benzoimidazole is fenbendazole, thiabendazole, cambendazole, parbendazole, oxybendazole, mebendazole, flubenda Sol (Flubendazole), oxfendazole (Oxfendazole), a method for producing at least one compound selected from the group consisting of albendazole, nanoparticles.
상기 양친매성 고분자는 PVA (Polyvinyl alcohol), 소듐 콜레이트(sodium cholate), 소듐 디옥시콜레이트(sodium deoxycholate), Span 20(Sorbitan Monolaurate), Span 60(Sorbitan Monostearate), Span 80(Sorbitan Monooleate), Tween 20(Polyoxyethylene(20) Sorbitan Monolaurate), Tween 60(Polyoxyethylene(20) Sorbitan Monostearte), Tween 80(Polyoxyethylene(20) Sorbitan Monolaurate), DPG(dipotassium glycyrrhizinate) 로 이루어진 군에서 선택된 적어도 하나의 화합물인, 나노입자의 제조방법. According to claim 11,
The amphiphilic polymer is PVA (Polyvinyl alcohol), sodium cholate, sodium deoxycholate, Span 20 (Sorbitan Monolaurate), Span 60 (Sorbitan Monostearate), Span 80 (Sorbitan Monooleate), Tween 20 (Polyoxyethylene (20) Sorbitan Monolaurate), Tween 60 (Polyoxyethylene (20) Sorbitan Monostearate), Tween 80 (Polyoxyethylene (20) Sorbitan Monolaurate), and at least one compound selected from the group consisting of DPG (dipotassium glycyrrhizinate), nanoparticles manufacturing method.
상기 나노입자는, -25mV 내지 -50mV의 전위값을 갖는 것인, 나노입자의 제조방법.According to claim 11,
Wherein the nanoparticles have a potential value of -25mV to -50mV, the method of producing nanoparticles.
상기 나노입자는, 50 nm 내지 300 nm 크기인, 나노입자의 제조방법.According to claim 11,
The nanoparticles are 50 nm to 300 nm in size, the method of producing nanoparticles.
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