KR20210050543A - Methods and compositions for treating neuroblastoma in childhood mammalian body - Google Patents
Methods and compositions for treating neuroblastoma in childhood mammalian body Download PDFInfo
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- KR20210050543A KR20210050543A KR1020217008970A KR20217008970A KR20210050543A KR 20210050543 A KR20210050543 A KR 20210050543A KR 1020217008970 A KR1020217008970 A KR 1020217008970A KR 20217008970 A KR20217008970 A KR 20217008970A KR 20210050543 A KR20210050543 A KR 20210050543A
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- taurolidine
- administered
- tauroridine
- neuroblastoma
- nanoparticles
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
신경모세포종은 주로 어린이에게 영향을 미치는 종양이다. 저도-위험 신경모세포종과 중등도 위험 신경모세포종에 대해 매우 높은 생존율이 보고되었지만, 현재의 치료 표준은 외과적으로 절제가능한 병변의 드문 경우를 제외하고는 치유적이지 않다. 타우로리딘은 항-감염제로 개발되었지만, 세포 배양물과 현재 설치류 암 모델에서 놀라운 종양 용해 활성을 갖는 것으로 밝혀졌다. 본 발명은 유년기 포유동물에서 신경모세포종의 치료를 위한 타우로리딘의 용도에 관한 것이다.Neuroblastoma is a tumor that primarily affects children. Although very high survival rates have been reported for low-risk neuroblastoma and moderate-risk neuroblastoma, current standards of care are not curative except in rare cases of surgically resectable lesions. Tauroridine has been developed as an anti-infective agent, but has been shown to have surprising oncolytic activity in cell cultures and in current rodent cancer models. The present invention relates to the use of tauroridine for the treatment of neuroblastoma in childhood mammals.
Description
계류 중인 선행 특허 출원에 대한 참조References to pending prior patent applications
본 특허 출원은:This patent application is:
(i) 코르메딕스, 인코포레이티드 및 디루치오 로버트(Robert DiLuccio)가 '신경모세포종 및 기타 암의 치료를 위한 치료용 나노 입자'에 대해 2017년 1월 11일에 출원한, 계류 중인 선행 미국 특허출원 제15/403,876호(대리인 관리번호 CORMEDIX-14)의 일부연속(CIP)출원으로서, 이 특허출원은 코르메딕스, 인코포레이티드와 디루치오 로버트가 '신경모세포종의 치료를 위한 나노 입자 시스템'에 대해 2016년 1월 11일에 출원한, 선행 미국 가특허 출원 제62/277,243호(대리인 관리번호 CORMEDIX-14 PROV)에 대한 이익을 주장하며;(i) Pending precedence, filed on January 11, 2017 by Cormedix, Inc. and Robert DiLuccio for'Therapeutic Nanoparticles for the Treatment of Neuroblastoma and Other Cancers' As a partial serial (CIP) application of U.S. Patent Application No. 15/403,876 (Agent Control No. CORMEDIX-14), this patent application is issued by Cormedix, Inc., and DiLucio Robert. Claiming an interest in prior U.S. Provisional Patent Application No. 62/277,243 (attorney control number CORMEDIX-14 PROV), filed Jan. 11, 2016 for'Particle Systems';
(ii) 코르메딕스, 인코포레이티드 및 레이덴버그 브루스(Bruce Reidenberg) 등이 ' 유년기 포유류 신체내의 신경모세포종을 치료하기 위한 방법 및 조성물'에 대해 2018년 8월 28일에 출원한, 계류 중인 선행 미국 가특허 출원 제62/723,592호(대리인 관리번호 CORMEDIX-32 PROV)에 대한 이익을 주장한다.(ii) Pending precedence, filed on August 28, 2018 by Cormedix, Inc. and Bruce Reidenberg et al. for'methods and compositions for the treatment of neuroblastoma in childhood mammalian bodies' Claims an interest in US Provisional Patent Application No. 62/723,592 (Agent Control Number CORMEDIX-32 PROV).
상기 세개의 특허 출원은 본 명세서에 참조로 통합된다.The three patent applications are incorporated herein by reference.
발명의 분야Field of invention
본 발명은 일반적으로 치료 방법 및 조성물에 관한 것이며, 보다 구체적으로는 유년기(juvenile) 포유류 신체내의 신경모세포종을 치료하기 위한 치료 방법 및 조성물에 관한 것이다.The present invention relates generally to treatment methods and compositions, and more particularly to treatment methods and compositions for treating neuroblastoma in a juvenile mammalian body.
신경모세포종(NB; neuroblastoma)은 청소년기에 가장 흔한 두개외 고형암이고 유아기에 가장 흔한 암으로, 미국에서는 연간 약 650건, 영국에서는 연간 100건의 발병율을 나타낸다. 신경모세포종 사례의 거의 절반이 2세 미만의 어린이에게서 발생한다. 이것은 신경내분비 종양으로, 교감 신경계(SNS)의 신경능선 요소(neural crest element)에서 발생한다. 신경모세포종은 가장 빈번하게는 부신 중 하나에서 발생하지만, 목, 가슴, 복부, 또는 골반의 신경 조직에서도 발생할 수 있다. 신경모세포종은 신경 조직에서 발생하지만, 중추 신경계(CNS)의 종양은 아니라는 점에 유의해야 한다.Neuroblastoma (NB) is the most common extracranial solid cancer in adolescence and the most common cancer in infancy. The incidence rate is about 650 cases per year in the United States and 100 cases per year in the United Kingdom. Almost half of neuroblastoma cases occur in children under 2 years of age. It is a neuroendocrine tumor, which occurs in the neural crest element of the sympathetic nervous system (SNS). Neuroblastoma most often occurs in one of the adrenal glands, but can also occur in the nervous tissue of the neck, chest, abdomen, or pelvis. It should be noted that neuroblastoma occurs in nervous tissue, but is not a tumor of the central nervous system (CNS).
신경모세포종은 미분화 상태에서 완전히 양성 세포 모양으로 자발적으로 퇴행하는 것으로 알려진 몇 안되는 인간 악성 종양 중 하나이다.Neuroblastoma is one of the few human malignancies known to spontaneously regress from undifferentiated to completely benign cell shapes.
신경모세포종은 극도의 이질성(heterogeneity)을 나타내는 질병으로, 저도-위험, 중등도-위험, 및 고도-위험의 3가지 위험 범주로 분류된다. 저도-위험 신경모세포종은 영아에서 가장 흔하며 단지 관찰 또는 수술로 양호한 결과를 얻을 수 있는 반면, 고도-위험 신경모세포종은 이용가능한 가장 집중적인 다중-모드(multi-modal) 요법으로도 성공적으로 치료하기 어렵다.Neuroblastoma is a disease exhibiting extreme heterogeneity and is classified into three risk categories: low-risk, moderate-risk, and high-risk. Low-risk neuroblastoma is most common in infants and can only yield good results with observation or surgery, whereas high-risk neuroblastoma is difficult to successfully treat even with the most intensive multi-modal therapy available. .
신경모세포종 병변이 국소화되어 있는 경우, 일반적으로 치유 가능하다. 그러나, 공격적인 다중-모드 요법, 예를 들어, 집중 화학요법, 수술, 방사선 요법, 줄기 세포 이식, 분화제 아이소트레티노인(isotrentinoin)(13-cis-레티노산으로도 지칭됨), 및 빈번하게는 면역요법과 함께 항-GD2 단일클론 항체 요법을 이용한 항-GD2 면역 요법에도 불구하고 질환이 진행된 18개월 이상의 어린이의 장기 생존은 좋지 않다.If the neuroblastoma lesion is localized, it is usually curable. However, aggressive multi-modal therapy, e.g., intensive chemotherapy, surgery, radiation therapy, stem cell transplantation, the differentiation agent isotrentinoin (also referred to as 13-cis-retinoic acid), and often immunity. Despite anti-GD2 immunotherapy using anti-GD2 monoclonal antibody therapy in conjunction with therapy, long-term survival of children over 18 months with advanced disease is poor.
생물학적 및 유전적 특성이 확인되었는데, 이는 고전적인 임상 병기결정에 추가되었을 때, 치료 강도를 계획하기 위해 환자를 위험 그룹에 할당할 수 있게 한다. 이러한 기준에는 환자의 나이, 질병 확산 정도, 현미경적 양상, DNA 배수성 및 N-myc 종양 유전자 증폭(N-myc 조절 마이크로 RNA)을 포함하는 유전적 특징이 포함된다. 이러한 기준은 신경모세포종을 저도-위험, 중등도-위험 및 고도-위험 질병으로 분류하는 데 이용된다. 최근 생물학 연구(COG ANBL00B1)에서는 2,687명의 신경모세포종 환자에 대해 분석하였고도-위험 할당 범위를 결정했다: 신경모세포종 사례의 37%는 저도-위험, 신경모세포종 사례의 18%는 중등도-위험, 및 신경모세포종 사례의 45%는 고도-위험. 고도-위험 및 저도-위험 유형의 신경모세포종이 서로 다른 메커니즘에 의해 유발되고, 단순히 동일한 메커니즘의 2가지 다른 발현 정도가 아니라는 몇 가지 증거가 있음에 주의해야 한다.Biological and genetic characteristics have been identified, which, when added to classical clinical staging, allow patients to be assigned to risk groups to plan the intensity of treatment. These criteria include the age of the patient, the extent of disease spread, microscopic features, DNA ploidy, and genetic features including N-myc oncogene amplification (N-myc regulatory microRNA). These criteria are used to classify neuroblastomas as low-risk, moderate-risk and high-risk diseases. A recent biological study (COG ANBL00B1) analyzed 2,687 neuroblastoma patients and determined the range of risk allocation: 37% of neuroblastoma cases were low-risk, 18% of neuroblastoma cases were moderate-risk, and neuroblastoma. 45% of blastoma cases are high-risk. It should be noted that there is some evidence that high-risk and low-risk types of neuroblastoma are caused by different mechanisms and are not simply two different levels of expression of the same mechanism.
이러한 상이한 위험 범주에 대한 요법은 매우 다르다.The therapies for these different risk categories are very different.
저도-위험 신경모세포종은 전혀 임의의 치료없이 빈번하게 관찰되거나 수술만으로 완치될 수 있다.Low-risk neuroblastoma is frequently observed without any treatment at all or can be cured by surgery alone.
중등도-위험 신경모세포종은 일반적으로 수술과 화학요법으로 치료된다.Moderate-risk neuroblastoma is usually treated with surgery and chemotherapy.
고도-위험 신경모세포종은 일반적으로 집중 화학 요법, 수술, 방사선 요법, 골수/조혈 줄기 세포 이식, 13-시스-레티노산(아이소트레티노인 또는 아큐탄(Accutane))을 사용한 생물학적 기반 요법 및 항체 요법(일반적으로 사이토카인 GM-CSF 및 IL-2. 사이토카인과 함께 투여)으로 치료된다.High-risk neuroblastomas are generally characterized by intensive chemotherapy, surgery, radiation therapy, bone marrow/hematopoietic stem cell transplantation, biological-based therapy with 13-cis-retinoic acid (isotretinoin or Accutane) and antibody therapy (common With cytokines GM-CSF and IL-2.administered with cytokines).
현재 치료를 통해, 저도-위험 신경모세포종 및 중등도-위험 신경모세포종을 지닌 환자는 탁월한 예후를 나타내는데, 저도-위험 신경모세포종에 대한 치료율은 90% 이상이고 중등도-위험 신경모세포종에 대한 치료율은 70-90%이다. 대조적으로, 지난 20년 동안 고도-위험 신경모세포종에 대한 치료는 시간의 약 30%에 대해 완치를 초래했다. 항체 요법의 추가는 고도-위험 신경모세포종의 생존율을 크게 높였다. 2009년 3월에, 226명의 고도-위험 신경모세포종 환자를 대상으로 한 소아종양그룹(COG; Children's Oncology Group) 연구의 초기 분석에 따르면, 항체를 받지 않은 그룹에서의 단지 46%와 비교하여 GM-CSF 및 IL-와 함께 chl4.18 항체를 투여받도록 무작위배정된 그룹의 66%에서는 줄기 세포 이식 2년 경과 후에 생존하고 질병이 없었던 것으로 나타났다. 임상 시험에 등록한 모든 환자가 항체 요법을 받을 수 있도록 무작위 배정은 중단되었다.With current treatment, patients with low-risk neuroblastoma and moderate-risk neuroblastoma have excellent prognosis, with a cure rate of more than 90% for low-risk neuroblastoma and 70-90 for moderate-risk neuroblastoma. %to be. In contrast, treatment for high-risk neuroblastoma over the past 20 years has resulted in cures in about 30% of the time. The addition of antibody therapy significantly increased the survival rate of high-risk neuroblastoma. In March 2009, an initial analysis of a Children's Oncology Group (COG) study of 226 highly-risk neuroblastoma patients showed that GM- In 66% of the group randomized to receive the chl4.18 antibody along with CSF and IL-, it was found that they survived and were disease-free after 2 years of stem cell transplantation. Randomization was discontinued so that all patients enrolled in the clinical trial could receive antibody therapy.
병용되는 화학요법제는 신경모세포종에 대해 효과적인 것으로 밝혀졌다. 유도(induction) 및 줄기 세포 이식 조절에 일반적으로 사용되는 작용제는 백금 화합물(시스플라틴, 카보플라틴), 알킬화제(사이클로포스파미드, 이포스파미드, 멜팔란, 토포아이소머라 제 II 억제제) 및 빈카알칼로이드(빈크리스틴)이다. 유도에서의 일부 새로운 섭생(regimens)에는 재발성 질환에 대해 효과적인 것으로 밝혀진 토포아이소머라제 I 억제제(토포테칸 및 이리노테칸)가 포함된다.Combination chemotherapeutic agents have been shown to be effective against neuroblastoma. Agents commonly used in induction and control of stem cell transplantation include platinum compounds (cisplatin, carboplatin), alkylating agents (cyclophosphamide, ifosfamide, melphalan, topoisomerase II inhibitors), and vinca alkaloids. (Vincristine). Some new regimens in induction include topoisomerase I inhibitors (topotecan and irinotecan) that have been shown to be effective against recurrent disease.
그러나, 유년기 포유류 신체내의 신경모세포종에 대해 효과적인 새로운 방법 및 조성물에 대한 필요성이 존재한다.However, there is a need for new methods and compositions that are effective against neuroblastoma in the childhood mammalian body.
본 발명에 따르면, 타우로리딘의 유년기 포유류 신체내의 신경모세포종을 치료하는 데 사용된다. According to the present invention, taurolidine is used to treat neuroblastoma in childhood mammalian bodies.
타우로리딘은 5mg/kg 내지 280mg/kg의 투여량 범위, 바람직하게는 5mg/kg 내지 60mg/kg의 투여량 범위로 제공된다.Tauroridine is provided in a dosage range of 5 mg/kg to 280 mg/kg, preferably in a dosage range of 5 mg/kg to 60 mg/kg.
이러한 투여량은 개별 환자 반응에 기초하여 유효 기간 동안 1일 1회부터 주간 단위까지 투여한다.These dosages are administered from once daily to weekly for the period of validity based on individual patient response.
타우로리딘은 전신적으로, 바람직하게는 정맥 내 (더욱 바람직함) 또는 근육 내로 전달된다.Tauroridine is delivered systemically, preferably intravenously (more preferably) or intramuscularly.
본 발명의 하나의 바람직한 형태에서, 타우로리딘은 "차폐된 형태"로 전신에 전달되기 때문에, 타우로리딘의 가수 분해는 타우로리딘이 신경모세포종의 부위에 도달할 때까지 지연되며, 그 결과 타우로리딘의 가수분해가 일어난다.In one preferred form of the present invention, since tauroridine is delivered systemically in a "shielded form", the hydrolysis of tauroridine is delayed until it reaches the site of the neuroblastoma, as a result. Hydrolysis of tauroridine occurs.
타우로리딘은 단일 제제로서 또는 하나 이상의 종양 용해제 및/또는 방사선 요법과 조합하여 전달될 수 있다.Tauroridine can be delivered as a single agent or in combination with one or more oncolytic agents and/or radiation therapy.
본 발명의 한 형태에서, 타우로리딘을 유년기 포유 동물에게 투여하는 것을 포함하는, 유년기 포유 동물내에서의 신경모세포종을 치료하는 방법이 제공된다.In one form of the invention, a method of treating a neuroblastoma in a childhood mammal is provided comprising administering tauroridine to the childhood mammal.
본 발명의 한 형태에서, 타우로리딘은 개별 환자 반응에 기초하여 유효 기간 동안 5mg/kg 내지 280mg/kg의 투여량 범위로 투여된다.In one form of the invention, tauroridine is administered in a dosage range of 5 mg/kg to 280 mg/kg for an effective period based on individual patient response.
본 발명의 한 형태에서, 타우로리딘은 5mg/kg 내지 60mg/kg의 투여량 범위로 투여된다.In one form of the invention, tauroridine is administered in a dosage range of 5 mg/kg to 60 mg/kg.
본 발명의 한 형태에서, 투여량은 1일 1회부터 주간 단위까지 투여된다 다.In one form of the invention, the dosage is administered from once a day to weekly units.
본 발명의 한 형태에서, 타우로리딘은 전신 투여된다.In one form of the invention, tauroridine is administered systemically.
본 발명의 한 형태에서, 타우로리딘은 정맥 내로 투여된다.In one form of the invention, tauroridine is administered intravenously.
본 발명의 한 형태에서, 타우로리딘은 근육 내로 투여된다.In one form of the invention, tauroridine is administered intramuscularly.
본 발명의 한 형태에서, 타우로리딘은 나노 입자에 포함되고, 나노 입자는 나노 입자가 종양 부위에 도달할 때까지 타우로리딘의 가수 분해를 지연시키도록 구성된다.In one form of the invention, taurolidine is contained in the nanoparticles, and the nanoparticles are configured to delay the hydrolysis of taurolidine until the nanoparticles reach the tumor site.
본 발명의 한 형태에서, 타우로리딘은 나노 입자에 포함되고, 나노 입자는 타우로리딘 코어 및 외부 코팅을 포함하고, 외부 코팅은 나노 입자가 종양 부위에 도달하기 전에 타우로리딘의 노출을 방지하도록 구성된다.In one form of the invention, taurolidine is contained in the nanoparticles, the nanoparticles comprise a taurolidine core and an outer coating, and the outer coating prevents exposure of taurolidine before the nanoparticles reach the tumor site. Is configured to
본 발명의 한 형태에서, 타우로리딘은 나노 입자에 포함되고, 나노 입자는 타우로리딘 코어 및 외부 코팅을 포함하고, 외부 코팅은 나노 입자가 삽입 부위에서 종양의 부위로 이동할 때에 분해되는 흡수성 중합체 또는 지질을 포함한다. In one form of the invention, taurolidine is contained in the nanoparticles, the nanoparticles comprise a taurolidine core and an outer coating, and the outer coating is an absorbent polymer that decomposes when the nanoparticles move from the insertion site to the site of the tumor. Or lipids.
본 발명의 한 형태에서, 타우로리딘은 타우로리딘의 가수 분해를 지연시키도록 구성된 중합체 시스템을 사용하여 전달된다.In one form of the invention, taurolidine is delivered using a polymer system configured to delay the hydrolysis of taurolidine.
본 발명의 한 형태에서, 타우로리딘은 중합체 시스템을 사용하여 전달되며, 타우로리딘은 타우로리딘의 조기 가수 분해를 지연시키기 위해 폴리에틸렌 글리콜 (PEG)을 사용하여 "페길화"된다.In one form of the present invention, taurolidine is delivered using a polymer system, and taurolidine is "pegylated" using polyethylene glycol (PEG) to delay the premature hydrolysis of taurolidine.
본 발명의 한 형태에서, 타우로리딘은 인간에게 투여된다.In one form of the invention, tauroridine is administered to a human.
본 발명의 한 형태에서, 타우로리딘은 유아, 어린이 및 청소년으로 이루어진 군으로부터 적어도 하나에 투여된다.In one form of the invention, tauroridine is administered to at least one from the group consisting of infants, children and adolescents.
본 발명의 한 형태에서, 타우로리딘은 단일 제제로 투여된다.In one form of the invention, tauroridine is administered as a single agent.
본 발명의 한 형태에서, 타우로리딘은 하나 이상의 종양용해제와 조합시켜 투여된다.In one form of the invention, tauroridine is administered in combination with one or more oncolytic agents.
본 발명의 한 형태에서, 타우로리딘은 적어도 하나의 종양 용해제와 조합시켜 투여되며, 적어도 하나의 종양 용해제는 백금 화합물 (시스플라틴, 카보 플라틴), 알킬화제 (사이클로포스파미드, 이포스파미드, 멜팔란, 토포이소머라제 II 억제제), 빈카 알칼로이드(빈크리스틴) 및 토포이소머라제 I 억제제 (토포테칸 및 이리노테칸)으로 구성된 군에서 선택된다.In one form of the invention, taurolidine is administered in combination with at least one oncolytic agent, and the at least one oncolytic agent is a platinum compound (cisplatin, carboplatin), an alkylating agent (cyclophosphamide, ifosfamide, mel. Palan, topoisomerase II inhibitors), vinca alkaloids (vincristine) and topoisomerase I inhibitors (topotecan and irinotecan).
본 발명의 한 형태에서, 타우로리딘은 방사선 요법과 조합시켜 투여된다. In one form of the invention, tauroridine is administered in combination with radiation therapy.
본 발명의 이들 및 다른 목적 및 특징은 첨부된 도면과 함께 고려되는 본 발명의 바람직한 실시형태에 대한 이하의 상세한 설명에 의해 보다 완전히 개시되거나 명백해질 것이며, 같은 번호는 같은 부분을 지칭하며, 추가로 여기서:
도 1은 백혈병 세포주가 시험관내(in vitro)(생체내(in vivo)가 아님) 건강한 림프구에 비해 타우로리딘의 효과에 더 민감한 것을 보여주는 그래프이고;
도 2는 시험관내(생체내가 아님)에서 건강한 섬유아세포(도면 상의 BJ)와 비교할 때 신경모세포종 세포주가 타우로리딘으로 인한 생존력 감소에 더 민감하다는 것을 보여주는 그래프이며;
도 3 내지 6은 CB57 SCID 마우스에 피하로 이식된 신경모세포종 세포주로부터의 측정가능한 종양을 가진 CB57 SCID 마우스에게 투여된 타우로리딘이 IMR5 종양에서 효능을 나타내며 생체내(시험관내가 아님) SK-N-AS 종양에서 측정가능한 효능을 나타낸다는 것을 보여주는 그래프 또는 사진이고;
도 7 및 8은 신경모세포종에서 유래된 다른 세포주(SK-N-AS)로 마우스를 치료하기 위해 타우로리딘을 투여했을 때 종양 크기의 통계적으로 유의한 감소가 달성되었지만 전체적인 생존은 대조군과 유의하게 차이나지 않음을 보여주는 그래프이다.These and other objects and features of the present invention will be more fully disclosed or made apparent by the following detailed description of the preferred embodiments of the present invention considered together with the accompanying drawings, the same numbers refer to the same parts, and further here:
1 is a graph showing that leukemia cell lines are more sensitive to the effect of taurolidine compared to healthy lymphocytes in vitro (not in vivo);
FIG. 2 is a graph showing that neuroblastoma cell lines are more sensitive to reduced viability due to tauroridine when compared to healthy fibroblasts (BJ on the figure) in vitro (not in vivo);
Figures 3 to 6 show that taurolidine administered to CB57 SCID mice with measurable tumors from a neuroblastoma cell line implanted subcutaneously in CB57 SCID mice shows efficacy in IMR5 tumors and in vivo (not in vitro) SK-N- Are graphs or photographs showing measurable efficacy in AS tumors;
7 and 8 show that when taurolidine was administered to treat mice with another cell line derived from neuroblastoma (SK-N-AS), a statistically significant reduction in tumor size was achieved, but overall survival was significantly compared with that of the control group. This is a graph showing that there is no difference.
타우로리딘은 작용 메커니즘과 항균 스펙트럼이 발표된 잘 알려진 항균제이다. 타우로리딘은 순환이 불안정하여 전신성 감염증에 대해 성공적으로 개발되지 못했다. 타우로리딘은 복막염에 대한 국소 적용 및 카테터-잠금 용액으로 주입될 때 감염 예방에 대한 효능이 입증되었다.Tauroridine is a well-known antibacterial agent for which its mechanism of action and antimicrobial spectrum have been published. Tauroridine has not been successfully developed for systemic infections due to unstable circulation. Tauroridine has proven efficacy for topical application to peritonitis and for preventing infection when infused as a catheter-locking solution.
타우로리딘은 최근에 종양 용해 활성에 대해 조사되었으며, 표준 화학 요법과의 병용으로 또는 단독으로, 배양 중의 세포주에 대한 억제 효과가 있는 것으로 밝혀졌다. 시험관내 억제 농도가 임상적으로 달성 가능하다는 주장에도 불구하고, 유일하게 발표된 인간 약동학 연구에서는 타우로리딘 5 g을 20분 주입으로 정맥 주사했을 때, 건강한 지원자에서 측정가능한 농도의 타우로리딘이 부존재하는 것으로 나타났다. 이것은 포유류 체내에 전신 투여할 때 타우로리딘의 빠른 가수분해로 인한 것이라고 여겨진다.Tauroridine has recently been investigated for oncolytic activity and has been shown to have an inhibitory effect on cell lines in culture, either alone or in combination with standard chemotherapy. Despite claims that in vitro inhibitory concentrations are clinically achievable, the only published human pharmacokinetic study found that a measurable concentration of tauroridine in healthy volunteers when 5 g of tauroridine was intravenously injected as a 20-minute infusion. It was found to be absent. This is believed to be due to the rapid hydrolysis of tauroridine when administered systemically into the mammalian body.
백혈병 세포주는 시험관내에서(생체내가 아님) 건강한 림프구에 비해 타우로리딘의 효과에 더 민감한 것으로 확인되었다. 도 1을 참조.Leukemia cell lines have been found to be more sensitive to the effects of tauroridine compared to healthy lymphocytes in vitro (not in vivo). See Figure 1.
또한, 신경모세포종 세포주는 시험관내에서(생체내가 아님) 건강한 섬유아세포와 비교할 때 타우로리딘으로 인한 생존력에서의 감소에 더 민감하다는 것이 확인되었다. 도 2를 참조.It has also been found that neuroblastoma cell lines are more sensitive to a decrease in viability due to tauroridine when compared to healthy fibroblasts in vitro (not in vivo). See Figure 2.
또한, CB57 SCID 마우스에 피하로 이식된 신경모세포종 세포주로부터의 측정가능한 종양을 가진 CB57 SCID 마우스에게 투여된 타우로리딘은 IMR5 종양에서의 효능 및 생체내 SK-N-AS 종양에서 측정가능한 효능을 나타냈다(시험관내가 아님). 도 3 내지 6을 참조.In addition, taurolidine administered to CB57 SCID mice with measurable tumors from neuroblastoma cell lines implanted subcutaneously into CB57 SCID mice showed efficacy in IMR5 tumors and measurable efficacy in SK-N-AS tumors in vivo. (Not in vitro). See Figures 3 to 6.
종양이 이식된 마우스의 전체 생존율은 대조군과 통계적으로 다르지 않았지만, 또한 신경모세포종에서 유래된 다른 세포주(SK-N-AS)로 마우스를 처치하기 위해 타우로리딘을 투여했을 때, 종양 크기의 통계적으로 유의한 감소가 달성되었다. 도 7 및 도 8을 참조.The overall survival rate of the tumor-transplanted mice was not statistically different from that of the control group, but also when taurolidine was administered to treat mice with another cell line derived from neuroblastoma (SK-N-AS), the tumor size was statistically Significant reduction was achieved. See Figs. 7 and 8.
타우로리딘이 유아기 포유류 신체 내에서의 신경모세포종을 치료하는 데 사용할 수 있다는 것이 밝혀졌다.It has been found that tauroridine can be used to treat neuroblastoma in infant mammalian bodies.
타우로리딘은 5mg/kg 내지 280mg/kg의 투여량 범위, 바람직하게는 5mg/kg 내지 60mg/kg의 투여량 범위로 제공된다. Tauroridine is provided in a dosage range of 5 mg/kg to 280 mg/kg, preferably in a dosage range of 5 mg/kg to 60 mg/kg.
유효 투여량은 다음 공식을 사용하여 유효 마우스 용량에서 인간 등가 용량을 계산하여 계산되었다.The effective dose was calculated by calculating the human equivalent dose from the effective mouse dose using the following formula.
[인간 등가 용량 = 마우스 ㎎/㎏ 용량 x 성인 사람 1명/마우스 12마리 x 어린이 25명 BSA 비율/성인 37명 BSA 비율 = ㎎/㎏ 단위 어린이 용량 (https://www.fda.gov/downloads/drugs/guidances)/ucmO78932.pdf).[Human equivalent dose = mouse mg/kg dose x 1 adult human/12 mice x 25 children BSA ratio/37 adults BSA ratio = Children dose in mg/kg ( https://www.fda.gov/downloads) /drugs/guidances)/ucmO78932.pdf ).
이러한 투여량은 개별 환자 반응에 따라 유효 기간 동안 1일 1 회부터 주간 단위까지 투여된다.These dosages are administered from once daily to weekly units for the period of validity depending on the individual patient response.
타우로리딘은 전신적으로, 바람직하게는 정맥 내 (더욱 바람직함) 또는 근육 내로 전달된다.본 발명의 한 바람직한 형태에서, 타우로리딘은 "차폐된 형태"로 전신에 전달되기 때문에, 타우로리딘의 가수 분해는 타우로리딘이 신경모세포종의 부위에 도달할 때까지 지연되며, 그 결과 타우로리딘의 가수분해가 일어난다.Tauroridine is delivered systemically, preferably intravenously (more preferably) or intramuscularly. In one preferred form of the invention, tauroridine is delivered systemically in a "masked form", so tauroridine is delivered systemically. The hydrolysis of taurolidine is delayed until it reaches the site of the neuroblastoma, resulting in the hydrolysis of tauroridine.
더욱 특히, 본 발명의 하나의 바람직한 형태에서, 타우로리딘은 나노 입자의 형태로 전달되며, 나노 입자는 타우로리딘 코어 및 나노 입자가 종양 부위에 도달하기 전에 타우로리딘의 조기 노출을 방지하도록 구성된 외부 코팅을 포함한다. 외부 코팅은 나노 입자가 삽입 부위에서 종양 부위로 이동할 때에 분해되어 가수분해를 위한 타우로리딘은 종양 부위에서 방출된다. 본 발명의 하나의 바람직한 형태에서, 코팅은 나노 입자가 삽입 부위로부터 종양 부위로 이동함에 따라 분해되는 흡수성 중합체 또는 지질을 포함한다. 예를 들어, 비제한적인 예로서, 코팅은 1-락타이드, 글리콜라이드, e-카프로락톤, p-디옥사논, 및 트리메틸렌 카보네이트로부터 구조화된 중합체로부터 유래된 공중합체 및 다량체의 조합으로부터 생성될 수 있다. 코팅은 또한, 선형 또는 다중-암 구조일 수 있는, 폴리에틸렌 글리콜(PEG)과 같은 글리콜과 연관될 수 있다.More particularly, in one preferred form of the present invention, tauroridine is delivered in the form of nanoparticles, wherein the nanoparticles are used to prevent premature exposure of tauroridine before the taurolidine core and nanoparticles reach the tumor site. Includes a configured outer coating. The outer coating is degraded as the nanoparticles move from the insertion site to the tumor site, and taurolidine for hydrolysis is released from the tumor site. In one preferred form of the invention, the coating comprises an absorbable polymer or lipid that degrades as the nanoparticles migrate from the site of insertion to the site of the tumor. For example, as a non-limiting example, the coating is from a combination of copolymers and multimers derived from polymers structured from 1-lactide, glycolide, e-caprolactone, p-dioxanone, and trimethylene carbonate. Can be created. The coating can also be associated with a glycol, such as polyethylene glycol (PEG), which can be of a linear or multi-arm structure.
필요에 따라, 나노 입자는 부형제(예를 들어, 나노 입자 내의 타우로리딘의 향상된 가수분해 안정성을 제공하기 위한 완충제)를 포함할 수 있다.If desired, the nanoparticles may contain excipients (eg, buffers to provide improved hydrolytic stability of taurolidine in the nanoparticles).
또한, 필요에 따라, 나노 입자는 코팅을 추가로 포함할 수 있으며, 여기서 코팅은 신경모세포종의 치료를 위한 타우로리딘의 효능을 개선하기 위해 신경모세포종의 부위에 나노 입자를 표적화하도록 구성된다. 본 발명의 한 바람직한 형태에서, 코팅은 나노 입자의 특정 조직으로의 전달을 표적화하도록 구성된 결합 분자를 포함한다. 비제한적인 예로서, 나노 입자에 대한 코팅은 나노 입자가 신경 조직(예를 들어, 신경모세포종 종양)에 결합하도록 하기 위한 N-형 칼슘 채널(예를 들어, 항-N-형 칼슘 채널 엑소페이셜(exofacial) Fab 단편)에 대한 단일 클론 항체를 포함한다.In addition, if desired, the nanoparticles may further comprise a coating, wherein the coating is configured to target the nanoparticles to the site of the neuroblastoma to improve the efficacy of tauroridine for the treatment of neuroblastoma. In one preferred form of the invention, the coating comprises a binding molecule configured to target the delivery of the nanoparticles to a specific tissue. As a non-limiting example, the coating on the nanoparticles is an N-type calcium channel (e.g., anti-N-type calcium channel exofacial) to allow the nanoparticles to bind to neural tissue (e.g., neuroblastoma tumor). (exofacial) Fab fragment).
본 발명의 다른 형태에서, 타우로리딘은 타우로리딘의 가수분해를 지연시키고/거나 타우로리딘의 방출 특성을 최적화하도록 구성된 중합체 시스템을 사용하여 전달될 수 있다. 제한적이지 않는 예로서, 타우로리딘은 폴리에틸렌 글리콜(PEG)을 사용하여 "페길화"되어 타우로리딘의 가수분해를 지연시키고/거나 타우로리딘의 방출 특성을 최적화할 수 있다.In another form of the present invention, taurolidine can be delivered using a polymer system configured to delay the hydrolysis of taurolidine and/or optimize the release properties of taurolidine. As a non-limiting example, taurolidine can be "pegylated" with polyethylene glycol (PEG) to delay the hydrolysis of taurolidine and/or optimize the release properties of taurolidine.
타우로리딘은 단일 제제로서 또는 하나 이상의 종양용해제 및/또는 방사선요법과 조합하여 전신적으로 전달될 수 있다. 신경아세포종을 치료하기 위해 유아기 포유동물에 전달하기 위해 타우로리딘과 조합될 수 있는 종양용해제의 예로는 백금 화합물(시스플라틴, 카보플라틴), 알킬화제(사이클로포스파미드, 이포스파미드, 멜팔란, 토포아이소머라제 II 억제제), 빈카 알칼로이드(빈크리스틴), 및 토포아이소머라제 I 억제제(토포테칸 및 이리노테칸)가 있다.Tauroridine can be delivered systemically as a single agent or in combination with one or more oncolytic agents and/or radiotherapy. Examples of oncolytic agents that can be combined with taurolidine for delivery to infant mammals to treat neuroblastoma include platinum compounds (cisplatin, carboplatin), alkylating agents (cyclophosphamide, ifosfamide, melphalan, Topoisomerase II inhibitors), vinca alkaloids (vincristine), and topoisomerase I inhibitors (topotecan and irinotecan).
변형transform
본 발명이 특정의 바람직한 실시형태에 관하여 설명되었지만, 해당 기술 분야의 통상의 기술자는 본 발명이 이에 제한되지 않으며, 본 발명의 범위 내에 포함하면서, 위에서 설명한 바람직한 실시형태에 대한 많은 부가, 삭제, 및 변형이 이루어질 수 있다는 것을 쉽게 이해하고 인식할 것이다.Although the present invention has been described with respect to certain preferred embodiments, those skilled in the art will not limit the invention to this, and, while including within the scope of the present invention, many additions, deletions, and additions to the preferred embodiments described above. It will be easy to understand and recognize that transformation can be made.
Claims (18)
상기 타우로리딘은 개별 환자 반응에 기초하여 유효 기간 동안 1일 1회부터 주간 단위까지 5mg/kg 내지 280mg/kg의 투여량 범위로 투여되는 방법.The method of claim 1,
The method of the taurolidine is administered in a dosage range of 5 mg/kg to 280 mg/kg from once a day to weekly units for an effective period based on individual patient responses.
상기 투여량 범위가 5mg/kg 내지 60mg/kg인 방법.The method of claim 2,
The method in which the dosage range is 5mg/kg to 60mg/kg.
상기 투여량은 1일 1회부터 주간 단위까지 투여하는 것인 방법.The method of claim 1,
The method of administering the dosage from once a day to a weekly unit.
상기 타우로리딘은 전신 투여되는 방법.The method of claim 1,
The method of the taurolidine is administered systemically.
상기 타우로리딘은 정맥 내로 투여되는 방법.The method of claim 5,
The method wherein the taurolidine is administered intravenously.
상기 타우로리딘은 근육 내로 투여되는 방법.The method of claim 5,
The method wherein the taurolidine is administered intramuscularly.
상기 타우로리딘은 나노 입자에 포함되며, 또한 추가로 상기 나노 입자는 나노 입자가 종양 부위에 도달할 때까지 타우로리딘의 가수분해를 지연하도록 구성되는 방법.The method of claim 5,
Wherein the taurolidine is contained in the nanoparticles, and further, the nanoparticles are configured to delay the hydrolysis of taurolidine until the nanoparticles reach the tumor site.
상기 나노 입자는 타우로리딘 코어 및 외부 코팅을 포함하고, 상기 외부 코팅은 나노 입자가 종양의 부위에 도달하기 전에 타우로리딘의 노출을 방지하도록 구성되는 방법.The method of claim 8,
Wherein the nanoparticles comprise a taurolidine core and an outer coating, wherein the outer coating is configured to prevent exposure of tauroridine before the nanoparticles reach the site of the tumor.
상기 외부 코팅은 나노 입자가 삽입 부위에서 종양의 부위로 이동할 때에 분해되는 흡수성 중합체 또는 지질을 포함하는 방법. The method of claim 9,
The outer coating comprises an absorbable polymer or lipid that is degraded when the nanoparticles move from the insertion site to the site of the tumor.
상기 타우로리딘은 타우로리딘의 가수 분해를 지연시키도록 구성된 중합체 시스템을 사용하여 전달되는 방법.The method of claim 5,
The method wherein the tauroridine is delivered using a polymer system configured to delay the hydrolysis of tauroridine.
상기 타우로리딘은 타우로리딘의 조기 가수 분해를 지연시키기 위해 폴리에틸렌 글리콜 (PEG)을 사용하여 "페길화"되는 방법.The method of claim 11,
The method wherein the taurolidine is "pegylated" with polyethylene glycol (PEG) to delay the premature hydrolysis of taurolidine.
상기 타우로리딘은 인간에게 투여하는 것인 방법.The method of claim 1,
The method wherein the taurolidine is administered to a human.
상기 타우로리딘은 유아, 어린이 및 청소년으로 이루어진 군으로부터 적어도 하나에 투여되는 방법.The method of claim 13,
The method of the taurolidine is administered to at least one from the group consisting of infants, children and adolescents.
상기 타우로리딘은 단일 제제로 투여되는 방법.The method of claim 1,
The method of the taurolidine is administered as a single agent.
상기 타우로리딘은 적어도 하나의 종양 용해제와 조합시켜 투여되는 것인 방법.The method of claim 1,
Wherein the taurolidine is administered in combination with at least one oncolytic agent.
상기 적어도 하나의 종양 용해제는 백금 화합물 (시스플라틴, 카보플라틴), 알킬화제 (사이클로포스파미드, 이포스파미드, 멜팔란, 토포이소머라제 II 억제제), 빈카 알칼로이드(빈크리스틴) 및 토포이소머라제 I 억제제 (토포테칸 및 이리노테칸)으로 이루어진 군에서 선택되는 방법.The method of claim 16,
The at least one oncolytic agent is a platinum compound (cisplatin, carboplatin), an alkylating agent (cyclophosphamide, ifosfamide, melphalan, topoisomerase II inhibitor), vinca alkaloid (vincristine) and topoisomerase. I inhibitors (topotecan and irinotecan).
상기 타우로리딘은 방사선 요법과 조합시켜 투여되는 방법.
The method of claim 1,
The method of administering the taurolidine in combination with radiation therapy.
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