KR102600943B1 - Composition for the prevention or treatment of chemotherapy-induced neuropathic pain comprising a dried-ginger extract as an active ingredient - Google Patents
Composition for the prevention or treatment of chemotherapy-induced neuropathic pain comprising a dried-ginger extract as an active ingredient Download PDFInfo
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- KR102600943B1 KR102600943B1 KR1020200189163A KR20200189163A KR102600943B1 KR 102600943 B1 KR102600943 B1 KR 102600943B1 KR 1020200189163 A KR1020200189163 A KR 1020200189163A KR 20200189163 A KR20200189163 A KR 20200189163A KR 102600943 B1 KR102600943 B1 KR 102600943B1
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- South Korea
- Prior art keywords
- present
- health
- neuropathic pain
- anticancer
- extract
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Abstract
본 발명은 종래에 소화기 질환, 항암 또는 항염증 용도로 사용되던 건강(dried ginger)의 열수 추출물을 유효성분으로 포함하는, 화학요법유발 신경병증성 통증의 예방 또는 치료용 약학적 조성물 및 상기 조성물을 이용하여 상기 질환을 예방 또는 치료할 수 있는 방법에 관한 것으로, 건강의 새로운 용도를 제공할 뿐만 아니라, 화학요법유발 신경병증성 통증을 효과적으로 예방 또는 치료할 수 있으므로, 새로운 만성통증 질환의 치료제 개발에도 널리 활용될 수 있다.The present invention provides a pharmaceutical composition for the prevention or treatment of chemotherapy-induced neuropathic pain, comprising as an active ingredient a hot water extract of dried ginger, which has been conventionally used for digestive diseases, anticancer or anti-inflammatory purposes, and the composition. This relates to a method that can prevent or treat the above diseases, and not only provides new uses for health, but can also effectively prevent or treat chemotherapy-induced neuropathic pain, so it is widely used in the development of new treatments for chronic pain diseases. It can be.
Description
본 발명은 건강 추출물을 유효성분으로 포함하는 항암제에 의해 유발되는 신경병증성 통증의 예방 또는 치료용 조성물에 관한 것으로, 보다 구체적으로 본 발명은 종래에 소화기 질환 또는 항암제로 활용되던 건강의 열수 추출물을 유효성분으로 포함하는 항암제에 의해 유발되는 신경병증성 통증의 예방 또는 치료용 약학적 조성물 및 상기 조성물을 이용하여 약제에 의해 유발되는 신경병증성 통증을 치료 또는 예방하는 방법에 관한 것이다.The present invention relates to a composition for preventing or treating neuropathic pain caused by an anticancer agent containing a health extract as an active ingredient. More specifically, the present invention relates to a composition for the prevention or treatment of neuropathic pain caused by an anticancer agent containing a health extract as an active ingredient. It relates to a pharmaceutical composition for preventing or treating neuropathic pain caused by an anticancer drug containing the active ingredient, and a method of treating or preventing neuropathic pain caused by the drug using the composition.
항암화학요법의 부작용 중 하나인 약제에 의해 유발되는 신경병증(Chemotherapy-Induced Peripheral Neuropathy, CIPN)은 말초신경섬유의 손상, 염증, 퇴화로 정의할 수 있다. 약제에 의해 유발되는 신경병증의 증상으로는 운동, 감각신경과 관련한 증상은 손가락, 발가락의 저림(tingling), 둔한 느낌(numbness), 타는 듯한 느낌(burning), 찌르는 느낌(stabbing), 쑤시는 느낌(shooting), 따끔거림(pricking) 등이 있으며, 일반적으로 양측성으로 나타나고, 하지가 더 심하게 나타난다. 증상은 통증을 느낄 정도로 악화될 수 있고 심부건반사 상실, 진동, 온도, 접촉, 위치 감각의 상실로 진행될 수 있으며, 이러한 증상은 급성으로 나타나거나 경미하거나 일시적이며 항암화학요법을 종료한 후 회복되기도 하지만, 일부의 경우 더 악화되는 경우도 있으며 비가역적인 상태로 남을 수 있다.Chemotherapy-Induced Peripheral Neuropathy (CIPN), one of the side effects of chemotherapy, can be defined as damage, inflammation, and degeneration of peripheral nerve fibers. Symptoms of neuropathy caused by drugs include motor and sensory nerve-related symptoms such as tingling, numbness, burning, stabbing, and tingling in fingers and toes. There are shooting, tingling, etc., and it generally appears bilaterally, with the lower extremities being more severe. Symptoms can worsen to the point of pain and can progress to loss of deep tendon reflexes, vibration, temperature, touch, and position sense. These symptoms appear acutely, are mild, or temporary, and may recover after the end of chemotherapy. , in some cases it may worsen and may remain in an irreversible condition.
약제에 의해 유발되는 신경병증은 다양한 원인으로 발생할 수 있는데, 크게는 유전, 만성질환, 환경독소, 알코올 중독, 영양결핍, 그리고 약물 등이다. 약제에 의해 유발되는 신경병증을 경험하는 암 환자들의 경우, 그들이 받았던 항암화학요법이 발생원인이 되는 것으로 알려져 있으며, 일반적으로 사용한 항암제의 누적용량과 관련이 있다. 항암 치료에 의한 경우 약 25%에서 CIPN이 발생할 수 있으며 CIPN의 정도는 항암제 종류, 투여된 용량 및 누적용량에 의하고, 특히 항암제 치료 전에 당뇨병성 신경병증, 알코올성 신경병증, vitamin B12 결핍증 등의 병력이 있던 환자에서 발생 위험이 높다.Neuropathy caused by medications can occur for a variety of reasons, including genetics, chronic diseases, environmental toxins, alcoholism, nutritional deficiencies, and drugs. In the case of cancer patients who experience drug-induced neuropathy, it is known that the chemotherapy they received is the cause, and it is generally related to the cumulative dose of anticancer drugs used. CIPN may occur in approximately 25% of cases due to anticancer treatment, and the degree of CIPN depends on the type of anticancer drug, administered dose, and cumulative dose. In particular, there is a history of diabetic neuropathy, alcoholic neuropathy, and vitamin B12 deficiency before anticancer drug treatment. The risk of occurrence is high in patients who have
항암화학요법에 사용되는 항암제 중 백금계열의 옥살리플라틴은 주요 부작용 중 하나로 신경병증성 통증을 유발하는 것으로 알려져 있는데(Journal of Korean Biological Nursing Science, Vol.20(2): 55-66, 2018), 이러한 부작용은 항암 치료의 중단을 야기할 수 있으며, 통증으로 인해 암치료 환자의 삶의 질을 유의미하게 감소시킬 수 있어 치료가 필요하나, 현재 사용되고 있는 부작용 억제 방법들은 단순하게 치료를 중단하거나, 그 부작용 치료 방법으로 인해 또 다른 부작용을 야기할 수 있어, 항암화학요법에 의해 유발된 신경병증성 통증을 부작용 없이 치료할 수 있는 방법을 개발하기 위한 연구가 필요한 실정이다.Among the anticancer drugs used in chemotherapy, platinum-based oxaliplatin is known to cause neuropathic pain as one of the major side effects (Journal of Korean Biological Nursing Science, Vol.20(2): 55-66, 2018). Side effects can cause discontinuation of anticancer treatment, and pain can significantly reduce the quality of life of cancer treatment patients, so treatment is necessary. However, currently used methods to suppress side effects simply stop treatment or cause side effects. Because the treatment method may cause other side effects, research is needed to develop a method to treat neuropathic pain caused by chemotherapy without side effects.
상기와 같은 배경하에, 본 발명자들은 항암화학요법에 의해 유발된 신경병증성 통증을 치료하기 위한 방법을 연구 노력한 결과, 말린 생강인 건강을 열수로 추출하여 투여하는 경우 항암제에 의해 유발된 신경병증성 통증을 효과적으로 억제할 수 있다는 사실을 확인함으로써 본 발명을 완성하였다.Against the above background, the present inventors have researched a method for treating neuropathic pain induced by anticancer chemotherapy. As a result, when dried ginger, which is healthy, is extracted with hot water and administered, neuropathic pain caused by anticancer drugs can be reduced. The present invention was completed by confirming that pain can be effectively suppressed.
이에, 본 발명은 건강 추출물을 유효성분으로 포함하는, 항암제에 의해 유발된 신경병증성 통증의 예방 또는 치료용 약학적 조성물을 제공하는 것을 목적으로 한다.Accordingly, the purpose of the present invention is to provide a pharmaceutical composition for preventing or treating neuropathic pain caused by anticancer drugs, which contains a health extract as an active ingredient.
또한, 본 발명은 상기 약학적 조성물을 포함하는, 항암제에 의해 유발된 신경병증성 통증의 예방 또는 치료용 항암보조제를 제공하는 것을 다른 목적으로 한다.Another object of the present invention is to provide an anticancer adjuvant for the prevention or treatment of neuropathic pain caused by anticancer agents, comprising the pharmaceutical composition.
또한, 본 발명은 건강 추출물을 유효성분으로 포함하는, 항암제에 의해 유발된 신경병증성 통증의 예방 또는 개선용 건강기능식품 조성물을 제공하는 것을 또 다른 목적으로 한다.Another object of the present invention is to provide a health functional food composition for preventing or improving neuropathic pain caused by anticancer drugs, which contains a health extract as an active ingredient.
그러나 본 발명이 이루고자 하는 기술적 과제는 이상에서 언급한 과제에 제한되지 않으며, 언급되지 않은 또 다른 과제들은 아래의 기재로부터 당업자에게 명확하게 이해될 수 있을 것이다.However, the technical problem to be achieved by the present invention is not limited to the problems mentioned above, and other problems not mentioned will be clearly understood by those skilled in the art from the description below.
상기 목적을 달성하기 위해, 본 발명은 건강 추출물을 유효성분으로 포함하는, 항암제에 의해 유발된 신경병증성 통증의 예방 또는 치료용 약학적 조성물을 제공한다.In order to achieve the above object, the present invention provides a pharmaceutical composition for preventing or treating neuropathic pain caused by anticancer drugs, comprising a health extract as an active ingredient.
본 발명의 일 구현예로, 상기 항암제는 시스플라틴(cisplatin), 카보플라틴(carboplatin), 옥살리플라틴(oxaliplatin), 파클리탁셀(paclitaxel), 도세탁셀(docetaxel), 빈크리스틴(vincristine), 비노렐빈(vinorelbine), 에토포사이드(etoposide), 메토트렉세이트(methotrexate), 탈리도마이드(thalidomide) 및 보테조밉(bortezomib)으로 이루어진 군으로부터 선택되는 어느 하나 이상일 수 있다.In one embodiment of the present invention, the anticancer agent is cisplatin, carboplatin, oxaliplatin, paclitaxel, docetaxel, vincristine, vinorelbine, It may be any one or more selected from the group consisting of etoposide, methotrexate, thalidomide, and bortezomib.
본 발명의 다른 구현예로, 상기 건강 추출물은 물, 탄소수 1 내지 4의 알코올 및 이들의 혼합 용매로 이루어진 군으로부터 선택된 용매로 추출되는 것일 수 있다.In another embodiment of the present invention, the health extract may be extracted with a solvent selected from the group consisting of water, alcohol with 1 to 4 carbon atoms, and mixed solvents thereof.
본 발명의 또 다른 구현예로, 상기 건강 추출물은 100 내지 500mg/kg로 포함되는 것일 수 있다.In another embodiment of the present invention, the health extract may be included in an amount of 100 to 500 mg/kg.
또한, 본 발명은 상기 약학적 조성물을 포함하는, 항암제에 의해 유발된 신경병증성 통증의 예방 또는 치료용 항암보조제를 제공한다.Additionally, the present invention provides an anticancer adjuvant for preventing or treating neuropathic pain caused by anticancer agents, comprising the pharmaceutical composition.
본 발명의 일 구현예로, 상기 항암제는 시스플라틴(cisplatin), 카보플라틴(carboplatin), 옥살리플라틴(oxaliplatin), 파클리탁셀(paclitaxel), 도세탁셀(docetaxel), 빈크리스틴(vincristine), 비노렐빈(vinorelbine), 에토포사이드(etoposide), 메토트렉세이트(methotrexate), 탈리도마이드(thalidomide) 및 보테조밉(bortezomib)으로 이루어진 군으로부터 선택되는 어느 하나 이상일 수 있다.In one embodiment of the present invention, the anticancer agent is cisplatin, carboplatin, oxaliplatin, paclitaxel, docetaxel, vincristine, vinorelbine, It may be any one or more selected from the group consisting of etoposide, methotrexate, thalidomide, and bortezomib.
본 발명의 다른 구현예로, 상기 항암보조제는 항암제와 병용 투여하는 것일 수 있다.In another embodiment of the present invention, the anti-cancer adjuvant may be administered in combination with an anti-cancer agent.
본 발명의 또 다른 구현예로, 상기 병용 투여는 동시에(simultaneous), 별도로(separate) 또는 순차적(sequential)으로 투여되는 것일 수 있다.In another embodiment of the present invention, the combined administration may be administered simultaneously, separately, or sequentially.
또한, 본 발명은 건강 추출물을 유효성분으로 포함하는, 항암제에 의해 유발된 신경병증성 통증 예방 또는 개선용 건강기능식품 조성물을 제공한다.In addition, the present invention provides a health functional food composition for preventing or improving neuropathic pain caused by anticancer drugs, comprising a health extract as an active ingredient.
본 발명의 일 구현예로, 상기 항암제는 시스플라틴(cisplatin), 카보플라틴(carboplatin), 옥살리플라틴(oxaliplatin), 파클리탁셀(paclitaxel), 도세탁셀(docetaxel), 빈크리스틴(vincristine), 비노렐빈(vinorelbine), 에토포사이드(etoposide), 메토트렉세이트(methotrexate), 탈리도마이드(thalidomide) 및 보테조밉(bortezomib)으로 이루어진 군으로부터 선택되는 어느 하나 이상인 것일 수 있다.In one embodiment of the present invention, the anticancer agent includes cisplatin, carboplatin, oxaliplatin, paclitaxel, docetaxel, vincristine, vinorelbine, It may be any one or more selected from the group consisting of etoposide, methotrexate, thalidomide, and bortezomib.
본 발명은 한방에서 소화기 질환, 항암 및 항염증 등의 치료에 사용되고 있으며, 부작용이 거의 없는 것으로 알려진 건강의 신규한 화학요법유발 신경병증의 치료용도에 관한 것으로서, 건강의 열수 추출물을 활용하여 화학요법유발 신경병증을 효과적으로 치료 또는 예방할 수 있으므로, 새로운 만성 통증질환의 치료제 개발에도 널리 활용될 수 있다.The present invention is used in oriental medicine to treat digestive diseases, anti-cancer and anti-inflammatory diseases, and relates to the use of a novel chemotherapy-induced neuropathy in health, which is known to have almost no side effects. Chemotherapy using the thermal water extract of health. Because it can effectively treat or prevent induced neuropathy, it can be widely used in the development of new treatments for chronic pain diseases.
단, 본 발명의 효과는 상기 효과로 한정되는 것은 아니며, 본 발명의 상세한 설명 또는 청구범위에 기재된 발명의 구성으로부터 추론 가능한 모든 효과를 포함하는 것으로 이해되어야 한다.However, the effects of the present invention are not limited to the above effects, and should be understood to include all effects that can be inferred from the configuration of the invention described in the detailed description or claims of the present invention.
도 1은 옥살리플라틴으로 유발된 신경병증성 통증 모델의 냉 이질통의 수준(도 1a) 및 기계적 이질통의 수준(도 1b)를 확인한 결과이다.
도 2는 본 발명의 건강 추출물을 농도를 달리하면서 투여할 때, 냉 이질통 개선 효과를 확인한 결과이다.
도 3은 본 발명의 건강 추출물을 농도를 달리하면서 투여할 때, 기계적 이질통의 개선 효과를 확인한 결과이다.
도 4는 본 발명의 건강 추출물을 투여했을 때 행동 변화를 증류수를 투여한 대조군과 비교하여 확인한 결과로서, 도 4a는 냉 행동(Cold behavior)를 확인한 것이고, 도 4b는 기계적 행동(Mechanical behavior)을 확인한 결과이다.
도 5은 본 발명의 추출물의 작용기전을 확인하기 위해 여러 화합물과 병용 투여했을 때 신경병증성 통증의 개선효과를 확인한 것으로서, 도 5a는 Methysergide와 병용투여 했을 때 냉 이질통의 개선효과를 확인한 것이고, 도 5b는 Methysergide와 병용투여 했을 때 기계적 이질통의 개선효과를 확인한 것이며, 도 5c는 MDL-72222와 병용투여 했을 때 냉 이질통의 개선효과를 확인한 것이고, 도 5d는 MDL-72222와 병용투여 했을 때 기계적 이질통의 개선효과를 확인한 것이다.
도 6은 NAN-190 또는 Ketanserin과 본 발명의 건강 추출물을 병용 투여했을 때 본 발명의 건강 추출물의 신경병증성 통증의 개선효과를 확인한 것으로서, 도 6a는 냉 이질통의 개선효과를 확인한 것이고, 도 6b는 기계적 이질통의 개선효과를 확인한 것이다.
도 7은 본 발명의 건강 추출물의 작용기전을 확인하기 위해 mRNA 수준을 측정한 결과로서, 도 7a는 옥살리플라틴을 처리했을 때, 도 7b는 본 발명의 건강 추출물을 처리했을 때 세로토닌 수용체 1A(5-HT1A)의 mRNA 수준을 측정한 것이다.Figure 1 shows the results of confirming the level of cold allodynia (Figure 1a) and the level of mechanical allodynia (Figure 1b) in the neuropathic pain model induced by oxaliplatin.
Figure 2 shows the results confirming the effect of improving cold allodynia when the health extract of the present invention is administered at different concentrations.
Figure 3 shows the results confirming the effect of improving mechanical allodynia when the health extract of the present invention is administered at different concentrations.
Figure 4 shows the results of confirming behavioral changes when administered the health extract of the present invention compared to the control group administered distilled water. Figure 4a shows cold behavior, and Figure 4b shows mechanical behavior. This is the confirmed result.
Figure 5 confirms the effect of improving neuropathic pain when administered in combination with several compounds to confirm the mechanism of action of the extract of the present invention, and Figure 5a confirms the effect of improving cold allodynia when administered in combination with Methysergide; Figure 5b confirms the improvement effect of mechanical allodynia when administered in combination with Methysergide, Figure 5c confirms the improvement effect of cold allodynia when administered in combination with MDL-72222, and Figure 5d shows the improvement effect of mechanical allodynia when administered in combination with MDL-72222. The effect of improving allodynia was confirmed.
Figure 6 confirms the improvement effect of the health extract of the present invention on neuropathic pain when administered in combination with NAN-190 or Ketanserin and the health extract of the present invention, Figure 6a shows the improvement effect of cold allodynia, Figure 6b confirmed the improvement effect of mechanical allodynia.
Figure 7 shows the results of measuring the mRNA level to confirm the mechanism of action of the health extract of the present invention. Figure 7a shows the level of serotonin receptor 1A (5- The mRNA level of HT1A) was measured.
본 발명자들은 항암화학요법에 의해 유발된 신경병증의 통증을 치료하기 위한 방법을 개발하기 위해 연구 노력한 결과, 말린 생강인 건강을 열수로 추출하여 투여하는 경우 항암제에 의해 유발된 신경병증성 통증을 효과적으로 억제할 수 있다는 사실을 확인하였는바, 이로써 본 발명을 완성하게 되었다.As a result of research efforts to develop a method for treating neuropathic pain caused by anticancer chemotherapy, the present inventors found that extracting dried ginger with hot water and administering it effectively treats neuropathic pain caused by anticancer drugs. It was confirmed that it could be suppressed, thereby completing the present invention.
이에, 본 발명은 건강 추출물을 유효성분으로 포함하는, 항암제에 의해 유발된 신경병증성 통증 예방 또는 치료용 약학적 조성물을 제공한다. 또한 본 발명에 따른 항암제는 이에 제한되는 것은 아니나, 시스플라틴(cisplatin), 카보플라틴(carboplatin), 옥살리플라틴(oxaliplatin), 파클리탁셀(paclitaxel), 도세탁셀(docetaxel), 빈크리스틴(vincristine), 비노렐빈(vinorelbine), 에토포사이드(etoposide), 메토트렉세이트(methotrexate), 탈리도마이드(thalidomide) 및 보테조밉(bortezomib)으로 이루어진 군으로부터 선택되는 어느 하나 이상일 수 있다.Accordingly, the present invention provides a pharmaceutical composition for preventing or treating neuropathic pain caused by an anticancer agent, comprising a health extract as an active ingredient. In addition, the anticancer agent according to the present invention is not limited thereto, but includes cisplatin, carboplatin, oxaliplatin, paclitaxel, docetaxel, vincristine, and vinorelbine. ), etoposide, methotrexate, thalidomide, and bortezomib.
본 발명에 있어서 용어 "건강(dried ginger)"이란, 생강을 말린 것으로서 한약재로서 효과가 생강보다 우수한 것으로 알려져 있어 항염증, 항암, 소화기 질환 치료제 등으로 사용되는 중이며, 그 종류로는 토건강, 일건강, 백강, 재강, 구강 등이 있다. In the present invention, the term "dried ginger" refers to dried ginger, which is known to be more effective than ginger as an herbal medicine, and is used as an anti-inflammatory, anti-cancer, and digestive disease treatment. There are health, white strength, financial strength, oral health, etc.
본 발명에 있어서, 추출물은 천연물로부터 추출물을 추출하는 당업계에 공지된 통상적인 방법에 따라, 즉, 통상적인 온도, 압력의 조건 하에서 통상적인 용매를 사용하여 추출할 수 있다. 예컨대, 본 발명에서, 추출물은 물, 탄소수 1 내지 4의 알코올 및 이들의 혼합용매로부터 선택된 1종 이상의 용매를 이용할 수 있다. 또한, 추출물을 추출하는 방법은 열수 추출, 냉침 추출, 환류 추출, 초음파 추출 등의 다양한 방법을 통하여 추출할 수 있고, 바람직하게는 열수 추출 방법을 사용할 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the extract can be extracted according to a conventional method known in the art for extracting an extract from a natural product, that is, using a conventional solvent under conventional conditions of temperature and pressure. For example, in the present invention, the extract may use one or more solvents selected from water, alcohols having 1 to 4 carbon atoms, and mixed solvents thereof. In addition, the extract can be extracted through various methods such as hot water extraction, cold needle extraction, reflux extraction, and ultrasonic extraction. Preferably, the hot water extraction method can be used, but is not limited thereto.
상기 제조된 추출물은 이후 여과하거나 농축 또는 건조과정을 수행하여 용매를 제거할 수 있으며, 여과, 농축 및 건조를 모두 수행할 수 있다. 예컨대, 여과는 여과지를 이용하거나 감압여과기를 이용할 수 있으며, 농축은 감압 농축기, 건조는 동결건조법 등을 활용하여 수행할 수 있으나, 이것으로 제한되는 것은 아니다.The prepared extract can then be filtered, concentrated, or dried to remove the solvent, and filtration, concentration, and drying can all be performed. For example, filtration can be performed using filter paper or a vacuum filter, concentration can be performed using a vacuum concentrator, and drying can be performed using a freeze-drying method, etc., but is not limited to this.
상기 건강 추출물은 약학적 조성물에 50 내지 550mg/kg로 포함되는 것일 수 있으며, 바람직하게는 100 내지 500mg/kg로 포함되는 것일 수 있다.The health extract may be included in the pharmaceutical composition at 50 to 550 mg/kg, preferably at 100 to 500 mg/kg.
본 발명에서 대상으로 하는 질환인 "항암제에 의해 유발되는 신경병증성 통증"은 항암제 투여에 의해 말초염증이 발생되어 이를 통한 다양한 염증관련 사이토카인의 작용에 의해 만성통증이 발생하는 질환으로, 일반적으로 통증 감각신경세포의 이온통로 등의 변화를 통한 흥분성이 변화되어 통증의 발생이 증가됨으로써 지속적인 만성통증을 일으키는 질병을 의미한다.“Neuropathic pain induced by anticancer drugs,” which is the disease targeted by the present invention, is a disease in which peripheral inflammation occurs due to the administration of anticancer drugs and chronic pain occurs due to the action of various inflammation-related cytokines. It refers to a disease that causes persistent chronic pain by changing excitability through changes in the ion channels of pain sensory nerve cells, thereby increasing the occurrence of pain.
본 발명의 용어 "예방"이란, 약제에 의해 유발되는 신경병증성 통증 및 만성통증의 발병이 예상되는 개체에게 본 발명에서 제공하는 건강 추출물을 유효성분으로 포함하는 약학 조성물을 투여하여 상기 질환의 발병을 억제 또는 지연시키는 모든 행위를 의미한다.The term "prevention" of the present invention refers to the administration of a pharmaceutical composition containing the health extract provided by the present invention as an active ingredient to an individual expected to develop neuropathic pain and chronic pain caused by a drug, thereby causing the development of the disease. refers to any act that suppresses or delays.
본 발명의 용어 "치료"란, 치료하고자 하는 개개인 또는 세포의 천연과정을 변경시키기 위해 임상적으로 개입하는 모든 행위를 의미하는데, 임상 병리 상태가 진행되는 동안 또는 이를 예방하기 위해 수행될 수 있다. 목적하는 치료 효과에는 질병의 발생 또는 재발을 예방하고, 증상을 완화시키며, 질병에 따른 모든 직접 또는 간접적인 병리학적 결과를 저하시키며, 전이를 예방하고, 질병 진행 속도를 감소시키며, 질병 상태를 경감 또는 일시적 완화시키거나, 차도시키며 예후를 개선시키는 것이 포함된다. 본 발명의 목적상 상기 치료는 약제에 의해 유발되는 신경병증성 만성통증이 발병된 환자에게 건강 추출물을 유효성분으로 포함하는 약학 조성물을 투여하여 상기 약제에 의해 유발되는 신경병증의 통증을 호전시키는 모든 행위를 포함하는 것으로 해석될 수 있으나, 특별히 이에 제한되지는 않는다.The term “treatment” of the present invention refers to any clinical intervention to alter the natural processes of the individual or cell to be treated, and may be performed during the course of a clinical pathology or to prevent it. The desired therapeutic effects include preventing the occurrence or recurrence of the disease, alleviating symptoms, reducing all direct or indirect pathological consequences of the disease, preventing metastasis, reducing the rate of disease progression, and alleviating the disease state. Or it includes providing temporary relief, remission, and improving prognosis. For the purpose of the present invention, the treatment refers to any treatment that improves neuropathic pain caused by the drug by administering a pharmaceutical composition containing a health extract as an active ingredient to a patient suffering from neuropathic chronic pain caused by the drug. It may be interpreted to include actions, but is not particularly limited thereto.
본 발명자들은 구체적인 실시예를 통하여 본 발명의 건강 추출물이 항암제에 의해 유발된 신경병증성 통증을을 개선시킬 수 있다는 사실을 확인하였다.Through specific examples, the present inventors have confirmed that the health extract of the present invention can improve neuropathic pain caused by anticancer drugs.
본 발명의 일실시예에서는 옥살리플라틴과 병용하여 본 발명의 건강 추출물을 구강 투여한 결과, 본 발명의 건강 추출물을 신경병증성 통증을 유발하는 항암제와 병용투여 했을 때, 항암제에 의해 유발된 냉 이질통(실시예 2 참조) 및 기계적 이질통(실시예 3 참조)을 유의적으로 감소시킬 수 있는 것을 확인할 수 있었다.In one embodiment of the present invention, as a result of oral administration of the health extract of the present invention in combination with oxaliplatin, when the health extract of the present invention was administered in combination with an anticancer drug that causes neuropathic pain, cold allodynia (cold allodynia) induced by the anticancer drug ( It was confirmed that it was possible to significantly reduce (see Example 2) and mechanical allodynia (see Example 3).
상기와 같은 결과를 통해 본 발명자들은 본 발명의 건강 추출물이 약제에 의해 유발된 신경병증성 통증을 효과적으로 개선시킬 수 있다는 사실을 확인하였다.Through the above results, the present inventors confirmed that the health extract of the present invention can effectively improve neuropathic pain caused by drugs.
또한, 본 발명의 다른 양태로서, 본 발명은 상기 약학적 조성물을 포함하는, 항암제에 의해 유발된 신경병증성 통증의 예방 또는 치료용 항암보조제를 제공한다.In addition, in another aspect of the present invention, the present invention provides an anticancer adjuvant for preventing or treating neuropathic pain caused by an anticancer agent, comprising the pharmaceutical composition.
상기 항암보조제는 항암제와 병용 투여하는 것일 수 있으며, 병용 투여는 동시에(simultaneous), 별도로(separate) 또는 순차적(sequential)으로 투여되는 것일 수 있다.The anticancer adjuvant may be administered in combination with an anticancer agent, and the combined administration may be administered simultaneously, separately, or sequentially.
한편, 본 발명의 약학 조성물은 약학적 조성물의 제조에 통상적으로 사용하는 적절한 담체, 부형제 또는 희석제를 추가로 포함할 수 있다. 약학적으로 허용 가능한 담체를 포함하는 조성물은 경구 또는 비경구의 여러 가지 제형일 수 있다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제될 수 있다. 경구투여를 위한 고형제제에는 정제환제, 산제, 과립제, 캡슐제 등이 포함될 수 있으며, 이러한 고형제제는 하나 이상의 화합물에 적어도 하나 이상의 부형제, 예를 들면, 전분, 탄산칼슘, 수크로오스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제될 수 있다. Meanwhile, the pharmaceutical composition of the present invention may further include an appropriate carrier, excipient, or diluent commonly used in the preparation of pharmaceutical compositions. The composition containing a pharmaceutically acceptable carrier may be in various oral or parenteral dosage forms. When formulated, it can be prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants. Solid preparations for oral administration may include tablets, powders, granules, capsules, etc. These solid preparations include one or more compounds and at least one excipient, such as starch, calcium carbonate, sucrose, or lactose. It can be prepared by mixing (lactose), gelatin, etc.
또한, 단순한 부형제 이외에 스테아린산 마그네슘, 탈크 등과 같은 윤활제들도 사용될 수 있다. 경구투여를 위한 액상제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이 외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제, 좌제가 포함될 수 있다. 비수성용제, 현탁용제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로젤라틴 등이 사용될 수 있다.Additionally, in addition to simple excipients, lubricants such as magnesium stearate, talc, etc. may also be used. Liquid preparations for oral administration include suspensions, oral solutions, emulsions, and syrups. In addition to the commonly used simple diluents such as water and liquid paraffin, they contain various excipients such as wetting agents, sweeteners, fragrances, and preservatives. You can. Preparations for parenteral administration may include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate. As a base for suppositories, witepsol, macrogol, tween 61, cacao, laurel, glycerogelatin, etc. can be used.
또한, 본 발명의 약학적 조성물은 정제, 환제, 산제, 과립제, 캡슐제, 현탁제, 내용액제, 유제, 시럽제, 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제 및 좌제로 이루어진 군으로부터 선택되는 어느 하나의 제형을 가질 수 있다.In addition, the pharmaceutical composition of the present invention includes tablets, pills, powders, granules, capsules, suspensions, oral solutions, emulsions, syrups, sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations and suppositories. It may have any one formulation selected from.
한편, 본 발명의 다른 양태로서, 본 발명은 건강 추출물을 유효성분으로 포함하는 조성물을 개체에 투여하는 단계를 포함하는 약제에 의해 유발되는 신경병증성 통증의 예방 또는 치료 방법을 제공한다.Meanwhile, in another aspect of the present invention, the present invention provides a method for preventing or treating neuropathic pain caused by a drug, comprising administering to an individual a composition containing a health extract as an active ingredient.
본 발명의 용어 "개체"란, 상기 약제에 의해 유발되는 신경병증성 통증이 발병될 가능성이 있거나, 또는 발병된 인간을 포함한 모든 동물을 의미한다. 본 발명의 조성물을 개체에 투여함으로써, 약제에 의해 유발되는 신경병증성 통증을 완화 또는 치료할 수 있다.The term “individual” of the present invention refers to all animals, including humans, that are likely to develop or have developed neuropathic pain caused by the above-mentioned drug. By administering the composition of the present invention to an individual, neuropathic pain caused by drugs can be alleviated or treated.
본 발명에서 용어, "완화"는 본 발명에 따른 조성물의 투여로 약제에 의해 유발되는 신경병증성 통증 및 만성통증이 호전되거나 이롭게 되는 모든 행위를 말한다.In the present invention, the term “alleviation” refers to all actions in which neuropathic pain and chronic pain caused by drugs are improved or beneficial by administration of the composition according to the present invention.
상기 본 발명의 조성물은 약학적으로 유효한 양으로 투여한다.The composition of the present invention is administered in a pharmaceutically effective amount.
본 발명에서 용어 "투여"는 어떠한 적절한 방법으로 대상에게 본 발명의 약학적 조성물을 도입하는 것을 말하며, 투여 경로는 목적 조직에 도달할 수 있는 한 경구 또는 비경구의 다양한 경로를 통하여 투여될 수 있다.In the present invention, the term "administration" refers to introducing the pharmaceutical composition of the present invention to a subject by any appropriate method, and the administration route may be oral or parenteral, as long as it can reach the target tissue.
본 발명의 약학적 조성물은 목적 또는 필요에 따라 당업계에서 사용되는 통상적인 방법, 투여 경로, 투여량에 따라 적절하게 개체에 투여될 수 있다. 투여 경로의 예로는 경구, 비경구, 피하, 복강 내, 폐 내, 및 비강 내로 투여될 수 있으며, 비경구 주입에는 근육 내, 정맥 내, 동맥 내, 복강 내 또는 피하투여가 포함된다.The pharmaceutical composition of the present invention can be appropriately administered to an individual according to the conventional method, administration route, and dosage used in the art, depending on the purpose or need. Examples of routes of administration include oral, parenteral, subcutaneous, intraperitoneal, intrapulmonary, and intranasal administration; parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.
또한 당업계에 공지된 방법에 따라 적절한 투여량 및 투여 횟수가 선택될 수 있으며, 실제로 투여되는 본 발명의 약학적 조성물의 양 및 투여 횟수는 치료하고자 하는 증상의 종류, 투여 경로, 성별, 건강 상태, 식이, 개체의 연령 및 체중, 및 질환의 중증도와 같은 다양한 인자에 의해 적절하게 결정될 수 있다.In addition, the appropriate dosage and number of administrations can be selected according to methods known in the art, and the amount and number of administrations of the pharmaceutical composition of the present invention actually administered are determined by the type of symptom to be treated, administration route, gender, and health condition. , can be appropriately determined by various factors such as diet, age and weight of the individual, and severity of the disease.
본 발명에서의 용어 "약학적으로 유효한 양"은 의학적 용도에 적용 가능한 합리적인 수혜/위험 비율로 약제에 의해 유발되는 신경병증성 통증을 억제 또는 완화하기에 충분한 양을 의미하며, 유효 용량 수준은 개체 종류 및 중증도, 연령, 성별, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출 비율, 치료기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다.As used herein, the term "pharmaceutically effective amount" refers to an amount sufficient to suppress or alleviate neuropathic pain caused by a drug at a reasonable benefit/risk ratio applicable to medical use, and the effective dose level is determined by the individual. It can be determined based on factors including type and severity, age, gender, drug activity, sensitivity to the drug, administration time, administration route and excretion rate, treatment period, concurrently used drugs, and other factors well known in the medical field.
본 발명의 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 종래의 치료제와는 순차적 또는 동시에 투여될 수 있다. 그리고 단일 또는 다중 투여될 수 있다. 상기 요소를 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 당업자에 의해 용이하게 결정될 수 있다.The composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents. And it can be administered single or multiple times. Considering all of the above factors, it is important to administer an amount that can achieve maximum effect with the minimum amount without side effects, and can be easily determined by a person skilled in the art.
본 발명의 또 다른 양태로서, 본 발명은 건강 추출물을 유효성분으로 포함하는, 항암제에 의해 유발된 신경병증성 통증 예방 또는 개선용 건강기능식품 조성물을 제공한다.In another aspect of the present invention, the present invention provides a health functional food composition for preventing or improving neuropathic pain caused by an anticancer agent, comprising a health extract as an active ingredient.
본 발명에서 사용되는 용어, "개선"이란, 치료되는 상태와 관련된 파라미터, 예를 들면 통증 증상의 정도를 적어도 감소시키는 모든 행위를 의미한다.As used herein, the term “improvement” refers to any action that results in at least reducing the degree of a parameter related to the condition being treated, such as pain symptoms.
본 발명의 건강기능식품 조성물에서 유효성분을 식품에 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용될 수 있고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 유효 성분의 혼합량은 그의 사용 목적(예방 또는 개선용)에 따라 적합하게 결정될 수 있다. 일반적으로, 식품 또는 음료의 제조 시에 본 발명의 조성물은 원료에 대하여 15 중량% 이하, 바람직하게는 10 중량% 이하의 양으로 첨가된다. 그러나 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 양은 상기 범위 이하일 수 있다.In the health functional food composition of the present invention, the active ingredients can be added directly to food or used together with other foods or food ingredients, and can be used appropriately according to conventional methods. The mixing amount of the active ingredient can be appropriately determined depending on the purpose of use (prevention or improvement). Generally, when producing food or beverages, the composition of the present invention is added in an amount of 15% by weight or less, preferably 10% by weight or less, based on the raw materials. However, in the case of long-term intake for the purpose of health and hygiene or health control, the amount may be below the above range.
본 발명의 건강기능식품 조성물은 지시된 비율로 필수 성분으로서 상기 유효성분을 함유하는 것 외에 다른 성분에는 특별한 제한이 없으며 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상술한 천연 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등; 디사카라이드, 예를들어 말토오스, 수크로오스 등; 및 폴리사카라이드, 예를 들어 덱스트린, 사이클로덱스트린 등과 같은 통상적인 당, 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 상술한 것 이외의 향미제로서 천연 향미제(타우마틴, 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진등) 및 합성 향미제(사카린, 아스파르탐 등)를 유리하게 사용할 수 있다. 상기 천연 탄수화물의 비율은 당업자의 선택에 의해 적절하게 결정될 수 있다.The health functional food composition of the present invention has no particular restrictions on other ingredients other than containing the above-mentioned active ingredients as essential ingredients in the indicated proportions, and may contain various flavoring agents or natural carbohydrates as additional ingredients like ordinary beverages. there is. Examples of the above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose, etc.; Disaccharides such as maltose, sucrose, etc.; and polysaccharides, such as common sugars such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those mentioned above, natural flavoring agents (thaumatin, stevia extract (e.g., rebaudioside A, glycyrrhizin, etc.)) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. The ratio of the natural carbohydrates can be appropriately determined by the selection of a person skilled in the art.
상기 외에 본 발명의 건강기능식품 조성물은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제(치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 이러한 첨가제의 비율 또한 당업자에 의해 적절히 선택될 수 있다.In addition to the above, the health functional food composition of the present invention contains various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic and natural flavoring agents, colorants and thickening agents (cheese, chocolate, etc.), pectic acid and its salts, It may contain alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc. These ingredients can be used independently or in combination. The proportions of these additives can also be appropriately selected by those skilled in the art.
이하, 본 발명의 이해를 돕기 위하여 바람직한 실시예를 제시한다. 그러나 하기의 실시예는 본 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐, 하기 실시예에 의해 본 발명의 내용이 한정되는 것은 아니다.Below, preferred embodiments are presented to aid understanding of the present invention. However, the following examples are provided only to make the present invention easier to understand, and the content of the present invention is not limited by the following examples.
[실시예][Example]
실시예 1. 실험 준비Example 1. Experimental preparation
1-1. 건강 열수 추출물의 제조1-1. Preparation of health thermal water extract
건강(dried rhizome of Zingiber officinale roscoe, Z officinale) 열수 추출물을 얻기 위해 건강을 증류수(distilled water; DW) 100℃에 3시간 환류 추출한 다음, 추출물을 감압 농축한 후 농축액을 동결건조(-80℃) 하여 건강 추출분말을 얻었다. 추출 수율은 17.53%이였으며 건강 분말은 증류수에 용해하여 마우스에게 투여하였다. To obtain a dried rhizome of Zingiber officinale roscoe, Z officinale, the extract was refluxed in distilled water (DW) at 100°C for 3 hours, the extract was concentrated under reduced pressure, and the concentrate was freeze-dried (-80°C). Thus, a health extract powder was obtained. The extraction yield was 17.53%, and the health powder was dissolved in distilled water and administered to mice.
1-2. 항암제 유발 신경병증성 모델의 제작1-2. Construction of anticancer drug-induced neuropathic model
항암제로 유발된 신경병증성 통증 동물 모델 제작을 위해 백금계열 항암제인 옥살리플라틴을 5% glucose의 용매에 2 mg/ml의 농도로 용해하였으며, 마우스에게 6 mg/kg의 농도로 단일 복강 투여하여 냉 및 기계적 이질통을 유발하였다.To create an animal model of neuropathic pain induced by anticancer drugs, oxaliplatin, a platinum-based anticancer drug, was dissolved in a 5% glucose solvent at a concentration of 2 mg/ml, and administered to mice at a single intraperitoneal concentration of 6 mg/kg to induce cold and Mechanical allodynia was induced.
옥사리플라틴을 투여하여 신경병증성 통증 모델을 제작한 다음, 질환 모델의 제작을 확인하기 위해 냉자극(아세톤)과 Von Frey 테스트를 통해 대조군과 옥살리플라틴을 투여한 실험군 간의 냉 이질통(Cold allodynia)과 기계적 이질통(Mechanical allodynia)을 측정하였다. 실험은 대조군 및 실험군 모두 5회 수행하였으며, 유의값은 * p < 0.05, ** p < 0.01, *** p< 0.001, **** p < 0.0001로 설정하여 이원분산분석(Two-way ANOVA) 수행하였다. 그 결과, 도 1a에 나타낸 바와 같이 투여한 당일(D0)에는 냉 이질통 및 기계적 이질통이 대조군과 비교할 때 유의적인 차이를 보여주지 않았으나, 3일(D3)과 5일(D5)이 경과한 시점부터 냉자극에 대한 반응 횟수가 증가하여 냉 이질통이 증가한 것으로 확인되었고, 기계적 이질통 또한 도 1b에 나타낸 바와 같이 역치값이 옥사리플라틴 투여군에서 유의하게 감소되어 있어 기계적 이질통이 증가됨을 확인하여, 옥살리플라틴을 투여하고 3일이 경과한 마우스 모델의 경우 신경병증성 통증의 개선효과를 확인하기 위한 실험 모델로서 사용될 수 있음을 확인하였다.After creating a neuropathic pain model by administering oxaliplatin, to confirm the creation of the disease model, cold stimulation (acetone) and the Von Frey test were used to determine cold allodynia and cold allodynia between the control group and the experimental group administered oxaliplatin. Mechanical allodynia was measured. The experiment was performed 5 times for both the control and experimental groups, and the significance values were set to * p < 0.05, ** p < 0.01, *** p < 0.001, and **** p < 0.0001, and two-way ANOVA was performed. ) was performed. As a result, as shown in Figure 1a, on the day of administration (D0), there was no significant difference in cold allodynia and mechanical allodynia compared to the control group, but after 3 days (D3) and 5 days (D5), It was confirmed that cold allodynia increased due to an increase in the number of responses to cold stimulation, and mechanical allodynia was also confirmed to be increased as the threshold value of mechanical allodynia was significantly decreased in the oxaliplatin-administered group, as shown in Figure 1b, and oxaliplatin was administered. It was confirmed that the mouse model after 3 days could be used as an experimental model to confirm the improvement effect of neuropathic pain.
실시예 2. 항암제 유발 신경병증성 모델에서 건강 열수 추출물의 냉 이질통 개선효과 확인Example 2. Confirmation of cold allodynia improvement effect of health thermal water extract in anticancer drug-induced neuropathic model
옥살리플라틴을 주입한 뒤 3일이 경과하여 신경병증성 통증 증상이 나타난 마우스 모델에 건강 열수 추출물을 100, 300, 500mg/kg의 농도로 투여한 다음 30, 60, 90분 경과했을 때 냉자극(아세톤)에 의한 반응횟수를 관찰하여 본 발명의 건강 열수 추출물의 시간의 흐름에 따른 냉 이질통 개선효과를 확인하였다. 실험은 대조군(증류수, distilled water 투여)은 10회, 나머지 실험군은 7회에 걸쳐 수행하였으며, 유의값을 * p < 0.05,** p < 0.01, *** p< 0.001, **** p< 0.0001로 설정하여 이원분산분석(Two-way ANOVA)을 수행하였다. 그 결과 도 2에 나타낸 바와 같이, 옥살리플라틴과 증류수(distilled water; DW)을 병용하여 구강투여한 대조군에 비해 옥살리플라틴과 건강 열수 추출물을 병용해서 구강투여한 실험군에서 냉자극에 대한 반응 횟수가 감소되는 것을 확인하였다. Healthy hot water extract was administered at concentrations of 100, 300, and 500 mg/kg to a mouse model that developed neuropathic pain symptoms 3 days after oxaliplatin injection, and then 30, 60, and 90 minutes later, cold stimulation (acetone ) was observed to confirm the effect of improving cold allodynia over time of the healthy hot water extract of the present invention. The experiment was performed 10 times for the control group (distilled water administered) and 7 times for the remaining experimental groups. Significance values are * p < 0.05, ** p < 0.01, *** p < 0.001, **** p Two-way ANOVA was performed by setting <0.0001. As a result, as shown in Figure 2, the number of responses to cold stimulation was reduced in the experimental group orally administered with oxaliplatin and healthy hot water extract compared to the control group administered orally with oxaliplatin and distilled water (DW) in combination. Confirmed.
본 발명자들은 상기와 같은 결과를 통해 본 발명의 건강 열수 추출물이 옥살리플라틴에 의해 유도된 냉 이질통을 효과적으로 감소시킬 수 있다는 사실을 확인하였다. Through the above results, the present inventors confirmed that the healthy thermal water extract of the present invention can effectively reduce cold allodynia induced by oxaliplatin.
실시예 3. 항암제 유발 신경병증성 모델에서 건강 열수 추출물의 기계적 이질통 개선효과 확인Example 3. Confirmation of mechanical allodynia improvement effect of health thermal water extract in anticancer drug-induced neuropathic model
옥살리플라틴을 주입한 뒤 3일이 경과하여 신경병증성 통증 증상이 나타난 마우스 모델에 건강 열수 추출물을 100, 300, 500mg/kg으로 투여한 다음 30, 60, 90분 경과했을 때 Von Frey 테스트를 수행하여 본 발명의 건강 열수 추출물의 시간의 흐름에 따른 기계적 이질통 개선효과를 확인하였다. 실험은 대조군(증류수, distilled water 투여)은 10회, 나머지 실험군은 7회에 걸쳐 진행되었으며, 유의값을 * p < 0.05, ** p < 0.01, *** p< 0.001, **** p< 0.0001로 설정하여 이원분산분석(Two-way ANOVA) 수행하였다. 그 결과 도 3에 나타낸 바와 같이, 옥살리플라틴과 증류수(distilled water; DW)를 병용하여 구강투여한 대조군에 비해 옥살리플라틴과 건강 열수 추출물을 병용해서 구강투여한 군에서 기계적 자극에 대한 역치가 유의적으로 증가하는 것을 확인할 수 있어, 기계적 이질통이 감소하는 것을 확인할 수 있었다. Healthy hot water extract was administered at 100, 300, and 500 mg/kg to a mouse model that showed neuropathic pain symptoms 3 days after oxaliplatin injection, and then 30, 60, and 90 minutes later, the Von Frey test was performed. The effect of the health thermal water extract of the present invention on improving mechanical allodynia over time was confirmed. The experiment was conducted 10 times for the control group (distilled water administered) and 7 times for the remaining experimental groups. Significance values are * p < 0.05, ** p < 0.01, *** p < 0.001, **** p Two-way ANOVA was performed by setting <0.0001. As a result, as shown in Figure 3, the threshold for mechanical stimulation was significantly increased in the group orally administered with oxaliplatin and healthy hot water extract compared to the control group administered orally with oxaliplatin and distilled water (DW) in combination. It was confirmed that mechanical allodynia was reduced.
본 발명자들은 상기와 같은 결과를 통해 본 발명의 건강 열수 추출물이 옥살리플라틴에 의해 유도된 기계적 이질통을 효과적으로 감소시킬 수 있다는 사실을 확인하였다. Through the above results, the present inventors confirmed that the healthy thermal water extract of the present invention can effectively reduce mechanical allodynia induced by oxaliplatin.
실시예 4. 마우스(na 
마우스에 증류수(Distilled water, DW)를 투여한 대조군과 본 발명의 건강 추출물을 투여한 실험군으로 나누어 각각 증류수 또는 건강 추출물을 투여한 다음, 30, 60, 90분이 경과한 시점에서 냉 행동(Cold behavior) 및 기계적 행동(Mechanical behavior)을 관찰하였다. 실험은 대조군 및 실험군 모두 5회 실시하였으며, 유의 값을 * p<0.05로 하여 이원분산분석(Two-way ANOVA) 수행하였다. 그 결과 냉 행동(도 4a)의 반응 횟수 및 기계적 행동(도 4b)의 역치값 모두 대조군과 실험군에서 유의적인 차이를 보여주지 않음을 확인할 수 있었다. Mice were divided into a control group administered distilled water (DW) and an experimental group administered the health extract of the present invention. After administering distilled water or health extract, respectively, cold behavior was observed after 30, 60, and 90 minutes. ) and mechanical behavior were observed. The experiment was conducted five times for both the control and experimental groups, and two-way ANOVA was performed with the significance value set to *p<0.05. As a result, it was confirmed that both the number of responses for cold behavior (Figure 4a) and the threshold value for mechanical behavior (Figure 4b) showed no significant difference between the control and experimental groups.
본 발명자들은 상기와 같은 결과를 통해 본 발명의 건강 추출물이 냉 이질통 및 기계적 이질통을 개선하면서도 행동에 영향을 주지 않는다는 사실을 확인하여 본 발명의 건강 추출물이 항암제에 의해 유도된 신경병증성 통증의 치료에 유용하게 활용될 수 있음을 확인하였다.Through the above results, the present inventors confirmed that the health extract of the present invention improves cold allodynia and mechanical allodynia but does not affect behavior, thereby confirming that the health extract of the present invention is effective in the treatment of neuropathic pain induced by anticancer drugs. It was confirmed that it can be usefully used.
실시예 5. 건강 추출물의 신경병증성 통증 개선 기전 확인Example 5. Confirmation of neuropathic pain improvement mechanism of health extract
5-1. methysergide와 병용 투여에 의한 건강 추출물의 신경병증성 통증 개선 효과 확인5-1. Confirmation of the effect of health extract on improving neuropathic pain by co-administration with methysergide
본 발명의 건강 추출물의 구체적인 작용기전을 확인하기 위해서 4가지 그룹인 인산완충생리식염수(Phosphate-buffered saline, PBS)와 증류수를 투여한 대조군, PBS와 건강 추출물을 투여한 그룹, 세로토닌(5-hydroxytryptamine, 5-HT) 수용체 1번(5-HT1) 및 2번(5-HT2)에 대한 길항 작용을 하는 것으로 알려진 methysergide와 증류수를 투여한 그룹 및 methysergide와 건강 추출물을 투여한 그룹으로 나누어 냉 이질통과 기계적 이질통의 계선효과를 확인하였다. 각 실험은 Methysergide와 증류수를 투여한 그룹에 대해서 5회, 나머지 그룹에 대해 6회 수행하였고, 통계적으로 유의한 정도(* p < 0.05 vs. Oxa + PBS + DW)를 이원분산분석(Two-way ANOVA)과 다중 비교를 위한 Sidak`s post-test를 통해 분석 하였다.In order to confirm the specific mechanism of action of the health extract of the present invention, there were four groups: a control group administered phosphate-buffered saline (PBS) and distilled water, a group administered PBS and the health extract, and a group administered serotonin (5-hydroxytryptamine). , 5-HT) cold allodynia was divided into a group administered methysergide and distilled water, which are known to have antagonistic effects on receptors number 1 (5-HT1) and number 2 (5-HT2), and a group administered methysergide and health extract. The mooring effect of mechanical allodynia was confirmed. Each experiment was performed 5 times for the group administered Methysergide and distilled water and 6 times for the remaining groups, and the level of statistical significance (* p < 0.05 vs. Oxa + PBS + DW) was determined by two-way analysis of variance (Two-way analysis of variance). Analysis was performed using ANOVA) and Sidak's post-test for multiple comparisons.
그 결과, 냉 이질통의 경우 도 5a에 나타낸 바와 같이, PBS와 건강 추출물을 투여한 그룹에서는 유의하게 냉자극(아세톤)에 대한 반응 횟수가 감소하나, methysergide와 같이 건강 추출물을 투여한 경우에는 반응횟수 감소 정도가 유의적으로 저하된 것을 확인할 수 있었고, 기계적 이질통의 경우에도 도 5b에 나타낸 바와 같이, PBS와 건강 추출물을 투여했을 때에 유의하게 증가된 역치 수준이 methysergide와 같이 투여한 경우 그 증가 정도가 유의적으로 감소하는 것을 확인할 수 있었다.As a result, in the case of cold allodynia, as shown in Figure 5a, the number of responses to cold stimulation (acetone) was significantly reduced in the group administered PBS and health extracts, but when health extracts such as methysergide were administered, the number of responses was decreased. It was confirmed that the degree of reduction was significantly reduced, and in the case of mechanical allodynia, as shown in Figure 5b, the significantly increased threshold level when administered with PBS and health extract was significantly increased when administered together with methysergide. A significant decrease was confirmed.
본 발명자들은 상기와 같은 결과를 통해 본 발명의 건강 추출물이 세로토닌계(Serotonergic system), 그 중에서도 세로토닌 수용체 1번 또는 2번을 매개로 하여 신경병증성 통증을 개선한다는 사실을 확인할 수 있었다.Through the above results, the present inventors were able to confirm that the health extract of the present invention improves neuropathic pain through the Serotonergic system, especially serotonin receptor No. 1 or 2.
5-2. MDL-72222와 병용 투여에 의한 건강 추출물의 신경병증성 통증 개선 효과 확인5-2. Confirmation of the effect of health extract on improving neuropathic pain by co-administration with MDL-72222
본 발명 건강 추출물의 작용기전을 확인하기 위해 그룹을 20% DMSO와 증류수를 투여한 대조군, 20% DMSO와 건강 추출물을 투여한 그룹, 세로토닌 수용체 3번의 길항제로 알려진 MDL-72222와 증류수를 투여한 그룹 및 MDL-72222와 건강 추출물을 투여한 그룹과 같이 4가지로 나누어 모든 그룹에 실험을 6회 수행하였고, 유의한 정도(* p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001 vs. 20% Oxa + 20% DMSO +DW)를 이원분산분석(Two-way ANOVA)과 다중 비교를 위한 Sidak`s post-test를 통해 분석 하였다.In order to confirm the mechanism of action of the health extract of the present invention, the groups were divided into a control group administered 20% DMSO and distilled water, a group administered 20% DMSO and the health extract, and a group administered MDL-72222, known as a serotonin receptor number 3 antagonist, and distilled water. And the group administered MDL-72222 and health extract was divided into 4 groups and the experiment was performed 6 times on all groups, and the level of significance (* p < 0.05, ** p < 0.01, *** p < 0.001, * *** p < 0.0001 vs. 20% Oxa + 20% DMSO + DW) was analyzed through two-way ANOVA and Sidak's post-test for multiple comparisons.
그 결과, 냉 이질통의 경우 도 5c에 나타낸 바와 같이, 20% DMSO와 건강 추출물을 투여한 그룹에서는 냉자극에 대한 반응 횟수가 감소하는 것이 확인되었으나, MDL-72222와 증류수 또는 건강 추출물을 병행투여한 실험군은 냉 반응 횟수에서 유의한 차이가 발생하지 않았다. 기계적 이질통의 경우는 5d에 나타낸 바와 같이, 20% DMSO와 건강 추출물을 투여한 그룹에서 역치가 유의하게 증가함을 확인할 수 있었고, MDL-72222와 건강 추출물을 투여한 그룹에서도 역치가 유의한 수준으로 증가함을 확인하였다.As a result, in the case of cold allodynia, as shown in Figure 5c, it was confirmed that the number of responses to cold stimulation was reduced in the group administered 20% DMSO and health extract, but in the group administered MDL-72222 and distilled water or health extract simultaneously There was no significant difference in the number of cold reactions in the experimental group. In the case of mechanical allodynia, as shown in 5d, the threshold was confirmed to be significantly increased in the group administered 20% DMSO and health extract, and the threshold was also significantly increased in the group administered MDL-72222 and health extract. An increase was confirmed.
5-3. Ketanserin 및 NAN-190과의 병용 투여에 의한 건강 추출물의 신경병증성 통증 개선 효과 확인5-3. Confirmation of the effect of health extract on improving neuropathic pain by co-administration with Ketanserin and NAN-190
본 발명 건강 추출물의 작용기전을 확인하기 위해 그룹을 PBS와 증류수를 투여한 그룹, PBS와 건강 추출물을 투여한 그룹, 세로토닌 수용체 1A(5-HT1A) 길항제로 알려진 NAN-190과 증류수를 투여한 그룹, NAN-190과 건강 추출물을 투여한 그룹, 세로토닌 수용체 2A 길항제로 알려진 Ketanserin과 증류수를 투여한 그룹 및 Ketanserin과 건강 추출물을 투여한 그룹으로 6개로 나눈 다음, 냉 이질통과 기계적 이질통의 계선효과를 확인하였다. 실험 결과의 유의 값(* p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001 vs. Oxa + PBS + DW)은 이원분산분석(Two-way ANOVA)과 다중 비교를 위한 Sidak`s post-test를 통해 분석 하였다.In order to confirm the mechanism of action of the health extract of the present invention, the groups were divided into a group administered PBS and distilled water, a group administered PBS and the health extract, and a group administered NAN-190, known as a serotonin receptor 1A (5-HT1A) antagonist, and distilled water. , divided into six groups: a group administered NAN-190 and health extract, a group administered Ketanserin, known as a serotonin receptor 2A antagonist, and distilled water, and a group administered Ketanserin and health extract, and then the mooring effect on cold allodynia and mechanical allodynia was confirmed. did. The significance values of the experimental results (* p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001 vs. Oxa + PBS + DW) were determined using two-way ANOVA and Analysis was performed using Sidak's post-test for multiple comparisons.
그 결과, 냉 이질통의 경우 도 6a에 나타낸 바와 같이, NAN-190과 본 발명의 건강 추출물을 투여한 실험군의 경우 냉 자극에 대한 반응이 유의한 정도의 차이를 보여주지 않았으나, Ketanserin과 본 발명의 건강 추출물을 투여한 그룹의 경우 냉 자극에 대한 반응횟수가 유의한 수준으로 감소하는 것을 확인할 수 있었다.As a result, in the case of cold allodynia, as shown in Figure 6a, there was no significant difference in the response to cold stimulation in the experimental group administered NAN-190 and the health extract of the present invention, but Ketanserin and the health extract of the present invention did not show a significant difference. In the group administered the health extract, it was confirmed that the number of responses to cold stimulation was significantly reduced.
한편, 기계적 이질통의 경우에도 도 6b에 나타낸 바와 같이, NAN-190와 본 발명의 건강 추출물을 투여한 실험군은 역치가 유의한 수준으로 증가하지 않아 기계적 이질통이 개선되지 않음을 확인할 수 있었으나, Ketanserin과 본 발명의 건강 추출물을 투여한 그룹은 역치가 유의한 수준으로 증가하여 기계적 이질통을 개선하는 효과가 있음을 확인할 수 있었다.Meanwhile, in the case of mechanical allodynia, as shown in Figure 6b, the threshold of the experimental group administered NAN-190 and the health extract of the present invention did not increase to a significant level, confirming that mechanical allodynia was not improved, but Ketanserin and The group administered the health extract of the present invention had a significant increase in threshold, confirming the effect of improving mechanical allodynia.
본 발명자들은 상기와 같은 결과를 통해 본 발명의 건강 추출물의 신경병증성 통증 개선효과는 척추의 세로토닌 수용체 1A(Spinal serotonin receptor 1A)를 매개로 한다는 사실을 확인하였다.Through the above results, the present inventors confirmed that the neuropathic pain improvement effect of the health extract of the present invention is mediated by spinal serotonin receptor 1A.
5-4. 세로토닌 수용체 1A의 mRNA 발현 확인5-4. Confirmation of mRNA expression of serotonin receptor 1A
상기 실시예 5-1 내지 5-3의 결과를 통해 본 발명의 건강 추출물의 통증 개선효과가 세로토닌 수용체 1A(5-HT1A)와 관련이 있다는 사실을 확인하였고, 이를 구체적으로 확인하기 위해 5-HT1A 수용체의 mRNA의 발현수준을 RT-PCR로 측정하였다. 그 결과, 도 7a에 나타낸 바와 같이, 세로토닌 수용체 1A의 발현 수준은 옥살리플라틴을 처리했을 때, 유의하게 감소되었으나, 본 발명의 건강 추출물과 병용하여 처리했을 때에는, 도 7b에 나타낸 바와 같이, 옥살리플라틴 단독 처리했을 때, 감소되었던 mRNA가 유의하게 증진되는 것을 확인할 수 있었다.Through the results of Examples 5-1 to 5-3, it was confirmed that the pain-improving effect of the health extract of the present invention is related to serotonin receptor 1A (5-HT1A), and to specifically confirm this, 5-HT1A The expression level of receptor mRNA was measured by RT-PCR. As a result, as shown in Figure 7a, the expression level of serotonin receptor 1A was significantly reduced when treated with oxaliplatin, but when treated in combination with the health extract of the present invention, as shown in Figure 7b, treated with oxaliplatin alone When doing this, it was confirmed that the decreased mRNA was significantly enhanced.
상기 진술한 본 발명의 설명은 예시를 위한 것이며, 본 발명이 속하는 기술분야의 통상의 지식을 가진 자는 본 발명의 기술적 사상이나 필수적인 특징을 변경하지 않고서 다른 구체적인 형태로 쉽게 변형이 가능하다는 것을 이해할 수 있을 것이다. 그러므로 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적이 아닌 것으로 이해해야만 한다.The description of the present invention stated above is for illustrative purposes, and a person skilled in the art to which the present invention pertains can understand that it can be easily modified into other specific forms without changing the technical idea or essential features of the present invention. There will be. Therefore, the embodiments described above should be understood in all respects as illustrative and not restrictive.
Claims (10)
상기 항암제는 시스플라틴(cisplatin), 카보플라틴(carboplatin) 및 옥살리플라틴(oxaliplatin)로 이루어진 군으로부터 선택된 백금계 항암제이고,
상기 통증의 예방 또는 치료는 세로토닌 수용체 1A를 매개로 하는 것임을 특징으로 하는, 약학적 조성물.
A pharmaceutical composition for the prevention or treatment of neuropathic pain caused by anticancer drugs, comprising the thermal water extract of Health alone as an active ingredient,
The anticancer agent is a platinum-based anticancer agent selected from the group consisting of cisplatin, carboplatin, and oxaliplatin,
A pharmaceutical composition, characterized in that the prevention or treatment of pain is mediated by serotonin receptor 1A.
상기 건강 추출물은 100 내지 500mg/kg로 포함되는 것을 특징으로 하는, 약학적 조성물.
According to clause 1,
A pharmaceutical composition, characterized in that the health extract is contained in an amount of 100 to 500 mg/kg.
상기 항암제는 시스플라틴(cisplatin), 카보플라틴(carboplatin) 및 옥살리플라틴(oxaliplatin)로 이루어진 군으로부터 선택된 백금계 항암제이고,
상기 통증의 예방 또는 치료는 세로토닌 수용체 1A를 매개로 하는 것임을 특징으로 하는, 항암보조제.
An anticancer adjuvant for the prevention or treatment of neuropathic pain caused by an anticancer agent, comprising the pharmaceutical composition according to claim 1,
The anticancer agent is a platinum-based anticancer agent selected from the group consisting of cisplatin, carboplatin, and oxaliplatin,
An anticancer adjuvant, characterized in that the prevention or treatment of the pain is mediated by serotonin receptor 1A.
상기 항암보조제는 항암제와 병용 투여하는 것을 특징으로 하는, 항암보조제.
According to clause 5,
The anticancer adjuvant is characterized in that the anticancer adjuvant is administered in combination with an anticancer agent.
상기 병용 투여는 동시에(simultaneous), 별도로(separate) 또는 순차적(seqeuntial)으로 투여되는 것을 특징으로 하는, 항암보조제.
According to clause 7,
The anticancer adjuvant is characterized in that the combined administration is administered simultaneously, separately, or sequentially.
상기 항암제는 시스플라틴(cisplatin), 카보플라틴(carboplatin) 및 옥살리플라틴(oxaliplatin)로 이루어진 군으로부터 선택된 백금계 항암제이고,
상기 통증의 예방 또는 개선은 세로토닌 수용체 1A를 매개로 하는 것임을 특징으로 하는, 건강기능식품 조성물.
A health functional food composition for preventing or improving neuropathic pain caused by anticancer drugs, comprising as an active ingredient the thermal water extract of Health Only,
The anticancer agent is a platinum-based anticancer agent selected from the group consisting of cisplatin, carboplatin, and oxaliplatin,
A health functional food composition, characterized in that the prevention or improvement of the pain is mediated by serotonin receptor 1A.
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