KR102012448B1 - Pharmaceutical composition for preventing or treating of neuropathy comprising trimethobenzamide or pharmaceutically acceptable salt thereof as an active ingredient - Google Patents
Pharmaceutical composition for preventing or treating of neuropathy comprising trimethobenzamide or pharmaceutically acceptable salt thereof as an active ingredient Download PDFInfo
- Publication number
- KR102012448B1 KR102012448B1 KR1020180012940A KR20180012940A KR102012448B1 KR 102012448 B1 KR102012448 B1 KR 102012448B1 KR 1020180012940 A KR1020180012940 A KR 1020180012940A KR 20180012940 A KR20180012940 A KR 20180012940A KR 102012448 B1 KR102012448 B1 KR 102012448B1
- Authority
- KR
- South Korea
- Prior art keywords
- neuropathy
- trimethobenzamide
- pharmaceutically acceptable
- pharmaceutical composition
- acceptable salt
- Prior art date
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Abstract
본 발명은 트리메토벤자미드(trimethobenzamide) 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 신경병증의 예방 또는 치료용 약학적 조성물에 관한 것으로, 상기 트리메토벤자미드는 이를 트라마돌(tramadol)과 병용투여하면, 신경병증 동물모델에서 유의적인 통증억제효과를 나타냄으로써, 신경병증의 치료에 유용하게 사용될 수 있다.The present invention relates to a pharmaceutical composition for the prevention or treatment of neuropathy, which contains trimethobenzamide or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the trimethobenzamide has a tramadol and When administered in combination, it can be usefully used for the treatment of neuropathy by showing a significant pain inhibitory effect in a neuropathy animal model.
Description
본 발명은 트리메토벤자미드 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 신경병증의 예방 또는 치료용 약학적 조성물에 관한 것이다.The present invention relates to a pharmaceutical composition for the prevention or treatment of neuropathy, containing trimethobenzamide or a pharmaceutically acceptable salt thereof as an active ingredient.
당뇨병은 그 발병율이 전 세계적으로 급속히 증가하고 있는 질병으로서, 당뇨병에 의한 재정적, 사회적 비용 부담이 점차 늘어나고 있다. 또한 당뇨병에 의해 수반되는 여러 가지 합병증으로 인한 치사율 역시 증가하고 있으나, 엄격한 혈당의 조절로 병의 진행을 막거나 질병의 진행 속도를 늦출 수 있어, 생활 습관의 변화와 적절한 치료로 혈당을 일정하게 유지하는 것이 중요한 방법으로 생각되고 있다.Diabetes is a rapidly growing disease worldwide, and the financial and social costs of diabetes are increasing. In addition, mortality due to various complications associated with diabetes is also increasing, but strict control of blood sugar can prevent disease progression or slow the progression of the disease, thus keeping blood sugar constant through lifestyle changes and proper treatment. It is thought to be an important way.
신경병증의 가장 주요한 원인 중 하나인 당뇨병성 말초 신경병증(Diabetic peripheral neuropathy)은 당뇨병의 가장 흔한 합병증이며, 당뇨병에 의한 말초신경의 기능장애에 따른 제반 징후, 증상을 의미한다. 이는 당뇨병 환자들의 삶의 질을 저하시키고 사망률을 높이는데, 환자의 나이와 투병 기간에 따라 유병율이 증가한다. 특히, 당뇨병성 말초신경병증은 1형 당뇨병 환자(22.7%)보다 2형 당뇨병 환자(32.1%)에서 많이 나타난다(Primary Care Diabetes, Volume 1, Issue 3, September 2007).Diabetic peripheral neuropathy, one of the major causes of neuropathy, is the most common complication of diabetes and refers to all signs and symptoms of dysfunction of peripheral nerves caused by diabetes. This reduces the quality of life and increases mortality in diabetics, which increases with age and duration of illness. In particular, diabetic peripheral neuropathy is more common in
당뇨병 환자의 약 10%정도는 지속적인 통증을 호소하는데, 이러한 통증은 자발적이거나 자극에 의해 유도될 수 있으며, 난치성일 수도 있다. 이러한 당뇨병성 말초 신경병증에 의한 통증은 보통 밤에 더욱 심해지며 주로 타는 듯한 통증, 찌르는 듯한 통증, 쑤심, 죄는 듯한 느낌 등으로 묘사된다. 또한, 이와 같은 통증은 손보다 발에서 확실히 느껴지며, 때때로 급격한 통증은 체중의 감소나 우울증 등을 유발한다(Pain medicine, Volume 8, Number S2, 2007).About 10% of diabetics complain of persistent pain, which can be spontaneous, stimulated, or refractory. Pain caused by diabetic peripheral neuropathy is usually worse at night and is mainly described as burning pain, stinging pain, tingling, feeling of swelling. In addition, such pain is clearly felt in the foot rather than the hand, and sometimes sudden pain causes weight loss or depression (Pain medicine, Volume 8, Number S2, 2007).
당뇨병성 신경병증의 치료제로서 알파 지방산, 알도스 환원효소 억제제 또는 감마 리놀렌산이 사용된다. 항산화제인 알파 지방산은 산화적 스트레스를 감소시킴으로써, 알도스 환원효소 억제제는 신경 세포 내의 포도당이 폴리올 경로로 들어가는 것을 막아 신경 세포에 손상을 가져오는 솔비톨의 축적을 억제함으로써 병의 진행을 차단한다. 그러나, 알도스 환원효소 억제제의 개발은 부작용과 효과부족 등의 문제로 대부분 개발 단계에서 중단되었으며, 현재 Epalrestat만이 일본에서 사용된다. 한편, 레놀렌산은 신경막을 구성하는 인지질의 성분으로서, 신경 혈류의 항상성 유지를 통해 당뇨병성 신경병증의 몇몇 증상을 개선하는 효과를 나타낸다.Alpha fatty acids, aldose reductase inhibitors or gamma linolenic acid are used as agents for diabetic neuropathy. Alpha fatty acids, antioxidants, reduce oxidative stress, and aldose reductase inhibitors block the progression of the disease by inhibiting the accumulation of sorbitol, which damages nerve cells by preventing glucose from entering the polyol pathway. However, the development of aldose reductase inhibitors has been discontinued at most stages of development due to side effects and lack of effect, and currently only Epalrestat is used in Japan. Lenolenic acid, on the other hand, is a component of the phospholipids that make up the neural membrane, and has an effect of ameliorating some symptoms of diabetic neuropathy through maintaining homeostasis of the blood flow.
한편, 트리메토벤자미드(trimethobenzamide)는 수술 후 또는 위장관염에 의한 구토의 치료에 사용된다. 이는 구토 자극을 중추에 전달함으로써 연수에 있는 화학수용체가 구토 자극을 억제하고 도파민 및 세로토닌 수용체를 길항하는 기능을 통해 작용한다. 또한, 트라마돌(tramadol)은 일반적인 통증에 대한 진통제로 사용되는 화합물로써 특히, 클로로하이드레이트의 형태로 사용된다. 트라마돌은 오피오이드 수용체의 활성화 및 뉴런의 모노아민성 시냅스의 농도를 향상시킴으로써 진통 효과를 나타낸다. 이와 관련하여, 대한민국 특허공개 제10-2008-0005429호는 신경병성 통증의 치료를 위한 트라마돌의 배합물을 개시하고 있다.On the other hand, trimethobenzamide is used for the treatment of vomiting after surgery or gastroenteritis. It acts through the function of chemoreceptors in the soft water to suppress the vomiting stimulation and antagonize dopamine and serotonin receptors by delivering vomiting stimulation to the center. In addition, tramadol is a compound that is used as a painkiller for general pain, in particular in the form of chlorohydrate. Tramadol has an analgesic effect by enhancing the activation of opioid receptors and the concentration of monoamine synapses in neurons. In this regard, Korean Patent Publication No. 10-2008-0005429 discloses a combination of tramadol for the treatment of neuropathic pain.
이에, 본 발명자들은 신경병증의 치료에 사용가능한 약물을 개발하기 위해 노력하던 중, 신경병증 동물모델에 트리메토벤자미드를 단독, 또는 이를 트라마돌과 병용처리하였을 때 유의적인 통증억제 효과가 나타남을 확인함으로써, 본 발명을 완성하였다.Thus, the inventors of the present invention, while trying to develop a drug that can be used for the treatment of neuropathy, it was confirmed that a significant pain inhibitory effect when trimethobenzamide alone or in combination with tramadol in the neuropathy animal model By this, the present invention was completed.
본 발명의 목적은 트리메토벤자미드 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 신경병증의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.It is an object of the present invention to provide a pharmaceutical composition for the prevention or treatment of neuropathy, which contains trimethobenzamide or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 또 다른 목적은 트리메토벤자미드 또는 이의 약학적으로 허용가능한 염과 트라마돌 또는 이의 약학적으로 허용가능한 염을 포함하는 신경병증의 예방 또는 치료용 약학적 키트를 제공하는 것이다.It is still another object of the present invention to provide a pharmaceutical kit for preventing or treating neuropathy, including trimetabenzamide or a pharmaceutically acceptable salt thereof and tramadol or a pharmaceutically acceptable salt thereof.
상기 목적을 달성하기 위하여, 본 발명은 트리메토벤자미드(trimethobenzamide) 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 신경병증의 예방 또는 치료용 약학적 조성물을 제공한다. In order to achieve the above object, the present invention provides a pharmaceutical composition for preventing or treating neuropathy containing trimethobenzamide or a pharmaceutically acceptable salt thereof as an active ingredient.
아울러, 본 발명은 약학적으로 치료가능한 양의 트리메토벤자미드 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 제 1성분; 및 트라마돌 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 제 2성분을 포함하는 신경병증 예방 또는 치료용 약학적 키트를 제공한다.In addition, the present invention comprises a first component containing a pharmaceutically treatable amount of trimethobenzamide or a pharmaceutically acceptable salt thereof as an active ingredient; And it provides a pharmaceutical kit for preventing or treating neuropathy comprising a second component containing tramadol or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 트리메토벤자미드는 이를 트라마돌과 병용투여하면 신경병증 동물모델에서 유의적인 통증억제효과를 나타냄으로써, 신경병증의 치료에 유용하게 사용될 수 있다.The trimethobenzamide of the present invention, when used in combination with tramadol, exhibits a significant pain inhibitory effect in neuropathy animal models, and thus may be usefully used for the treatment of neuropathy.
도 1은 트리메토벤자미드에 의한 신경병증 동물모델에서의 통증완화를 확인한 그래프이다.
도 2는 트리메토벤자미드 및 트라마돌의 각각의 투여 및 병용투여에 의한 신경병증 동물모델에서의 통증완화를 비교 확인한 그래프이다.
도 3은 트리메토벤자미드 및 트라마돌의 병용투여에 의한 신경병증 동물모델에서의 농도 의존적 통증완화를 확인한 그래프이다. 1 is a graph confirming the pain relief in the neuropathy animal model by trimethobenzamide.
FIG. 2 is a graph comparing pain relief in neuropathy animal models by administration and coadministration of trimethobenzamide and tramadol, respectively.
Figure 3 is a graph confirming the concentration-dependent pain relief in neuropathy animal model by the co-administration of trimethobenzamide and tramadol.
이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명은 트리메토벤자미드 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 신경병증의 예방 또는 치료용 약학적 조성물을 제공한다.The present invention provides a pharmaceutical composition for the prevention or treatment of neuropathy, containing trimethobenzamide or a pharmaceutically acceptable salt thereof as an active ingredient.
상기 트리메토벤자미드는 하기 화학식 1을 갖는 화합물일 수 있다:The trimethobenzamide may be a
[화학식 1][Formula 1]
상기 트리메토벤자미드는 당업계에 공지된 방법에 따라 추출 또는 합성되거나 상업적으로 정제된 상태로 구입하여 사용할 수 있다.The trimethobenzamide may be purchased and used in an extracted or synthesized or commercially purified state according to methods known in the art.
상기 약학적 조성물은 트라마돌 또는 이의 약학적으로 허용가능한 염, 또는 이의 혼합물을 더 포함할 수 있다. 상기 트라마돌은 당업계에 공지된 방법에 따라 추출 또는 합성되거나 상업적으로 정제된 상태로 구입하여 사용할 수 있다.The pharmaceutical composition may further comprise tramadol or a pharmaceutically acceptable salt thereof, or a mixture thereof. The tramadol can be purchased and used in an extracted or synthesized or commercially purified state according to methods known in the art.
상기 트라마돌은 하기 화학식 2로 표시되는 화합물일 수 있다:The tramadol may be a compound represented by Formula 2:
[화학식 2][Formula 2]
상기 신경병증은 당뇨병성 신경병증(Diabetic neuropathy), 대상포진후 신경병증, 삼차 신경병증(trigeminal neuropathy), 다발성 말초 신경병증(Peripheral Neuropathies), 단발성 말초 신경병증, 다발성 홑신경염(Mononeuritis multiplex), 자율신경병증, 염증성 신경병증(inflammatory neuropathy), 대사 또는 내분비이상에 의한 신경병증(metabolic or endocrine neuropathy), 중독 또는 약물에 의한 신경병증(toxic or drug-induced neuropathy), 영양신경병증(nutritional neuropathy), 혈관염증신경병증(vasculitic neuropathy), 종양관련신경병증(paraneoplastic neuropathy), 외상신경병증(traumatic neuropathy), 유전신경병증(hereditary neuropathy) 및 특발성 신경병증(idiopathic neuropathy)으로 구성된 군으로부터 선택되는 어느 하나 이상의 신경병증일 수 있으나, 이에 한정되지 않는다. The neuropathy may include diabetic neuropathy, post shingles neuropathy, trigeminal neuropathy, multiple peripheral neuropathies, single peripheral neuropathy, multiple mononeuritis multiplex, autonomic Neuropathy, inflammatory neuropathy, metabolic or endocrine neuropathy, toxic or drug-induced neuropathy, nutritional neuropathy, At least one selected from the group consisting of vasculitic neuropathy, tumor-related neuropathy, traumatic neuropathy, hereditary neuropathy, and idiopathic neuropathy. It may be neuropathy, but is not limited thereto.
본 발명의 구체적인 실시예에서, 본 발명자들은 트리메토벤자미드를 당뇨병성 신경병증성 동물 모델 마우스에 투여했을 때 농도 의존적으로 통증이 완화됨을 확인하였으며(도 1 참조), 트리메토벤자미드를 트라마돌과 병용투여 하였을 때 각각의 투여에 비해 신경병증 억제가 우수함을 확인하였다(도 2 및 3 참조).In a specific embodiment of the present invention, the present inventors confirmed that the pain was alleviated in a concentration-dependent manner when trimethobenzamide was administered to diabetic neuropathic animal model mice (see FIG. 1), and trimethobenzamide was treated with tramadol. When administered in combination, it was confirmed that neuropathy inhibition was superior to that of each administration (see FIGS. 2 and 3).
따라서, 상기 트리메토벤자미드는 트라마돌과 병용투여하여 신경병증의 치료에 사용될 수 있다.Thus, the trimethobenzamide may be used in combination with tramadol to treat neuropathy.
본 발명은 또한 트리메토벤자미드 또는 트라마돌의 약학적으로 허용가능한 염을 제공한다. 약학적으로 허용 가능한 염은 인체에 독성이 낮고 화합물의 생물학적 활성과 물리화학적 성질에 악영향을 주지 않아야 한다. 약학적으로 허용 가능한 염은 약학적으로 사용 가능한 유리산과 트리메토벤자미드 또는 트라마돌의 염기 화합물의 산부가염, 알칼리 금속염(나트륨염 등)과 알칼리 토금속염(칼슘염 등), 유기염기와 트리메토벤자미드 또는 트라마돌의 카르복실산의 유기염기부가염, 아미노산부가염 등이 가능하다. The present invention also provides pharmaceutically acceptable salts of trimethobenzamide or tramadol. Pharmaceutically acceptable salts are low toxic to humans and should not adversely affect the biological activity and physicochemical properties of the compounds. Pharmaceutically acceptable salts include acid addition salts of pharmaceutically usable free acids and base compounds of trimethobenzamide or tramadol, alkali metal salts (such as sodium salts) and alkaline earth metal salts (such as calcium salts), organic bases and trimethobenza Organic base addition salt, amino acid addition salt, etc. of the carboxylic acid of a mid or tramadol are possible.
본 발명에 따르는 화합물의 바람직한 염의 형태로는 무기산 또는 유기산과의 염을 들 수 있다. 이 때, 무기산은 염산, 황산, 질산, 인산, 과염소산, 브롬산 등이 사용될 수 있다. 또한, 유기산은 초산, 메탄설폰산, 에탄설폰산, p-톨루엔설폰산, 푸마린산, 말레산, 말론산, 프탈산, 숙신산, 젖산, 구연산, 시트르산, 글루콘산, 타타르산, 살리실산, 말산, 옥살산, 벤조산, 엠본산, 아스파르트산, 글루탐산 등이 사용될 수 있다. 유기염기부가염 제조에 사용될 수 있는 유기염기는 트리스(하이드록시메틸)메틸아민, 디사이클로헥실아민 등이다. 아미노산부가염기 제조에 사용될 수 있는 아미노산은 알라닌, 글라이신 등의 천연아미노산이다. Preferred salt forms of the compounds according to the invention include salts with inorganic or organic acids. At this time, the inorganic acid may be used hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, bromic acid and the like. Organic acids include acetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, malonic acid, phthalic acid, succinic acid, lactic acid, citric acid, citric acid, gluconic acid, tartaric acid, salicylic acid, malic acid, Oxalic acid, benzoic acid, embonic acid, aspartic acid, glutamic acid and the like can be used. Organic bases that can be used for the preparation of organic base addition salts are tris (hydroxymethyl) methylamine, dicyclohexylamine and the like. Amino acids that can be used to prepare amino acid addition bases are natural amino acids such as alanine, glycine and the like.
이와 같은 염은 통상적인 방법으로 제조될 수 있다. 예를 들어 상기한 트리메토벤자미드 및 트라마돌 또는 이들의 약학적으로 허용가능한 염을 메탄올, 에탄올, 아세톤, 1,4-디옥산과 같은 물과 섞일 수 있는 용매에 녹인 다음에 유리산 또는 유리염기를 가한 후에 결정화시켜 제조할 수 있다. Such salts can be prepared by conventional methods. For example, the above-described trimethobenzamide and tramadol or their pharmaceutically acceptable salts are dissolved in a solvent which can be mixed with water such as methanol, ethanol, acetone, 1,4-dioxane and then free acid or free base. It can be prepared by crystallization after adding.
또한, 본 발명에 따른 화합물들은 비대칭 탄소중심을 가질 수 있으므로 R 또는 S 이성질체, 라세믹 화합물, 개개의 거울상이성질체(enantiomer) 또는 혼합물, 개개의 부분입체이성질체(diastereomer) 또는 혼합물로서 존재할 수 있으며, 이들 모든 입체이성질체(stereoisomer) 및 혼합물은 본 발명의 범위에 포함된다. In addition, the compounds according to the invention may have an asymmetric carbon center so that they may exist as R or S isomers, racemic compounds, individual enantiomers or mixtures, individual diastereomers or mixtures, All stereoisomers and mixtures are included within the scope of the present invention.
또한, 본 발명의 범주에는 트리메토벤자미드 및 트라마돌의 수화물 또는 용매화물의 형태도 포함된다. 이러한 수화물 또는 용매화물은 공지의 방법으로 제조될 수 있으며, 비독성 및 수용성인 것이 바람직하고, 물 또는 알코올계 용매(특히, 에탄올 등)의 분자가 1개 내지 5개 결합된 수화물 또는 용매화물인 것이 바람직하다.In addition, the scope of the present invention also includes the form of a hydrate or solvate of trimethobenzamide and tramadol. Such hydrates or solvates may be prepared by known methods, and are preferably nontoxic and water soluble, and are hydrates or solvates having 1 to 5 molecules of water or alcoholic solvents (especially ethanol, etc.) bound together. It is preferable.
본 발명에 따른 약학적 조성물은 조성물 전체 중량에 대하여 유효성분인 트리메토벤자미드 또는 이의 약학적으로 허용 가능한 염을 10 내지 95 중량%로 포함할 수 있다. 또한, 본 발명의 약학적 조성물은 상기 유효성분 이외에 추가로 동일 또는 유사한 기능을 나타내는 유효성분을 1종 이상 추가로 포함할 수 있다.The pharmaceutical composition according to the present invention may include 10 to 95% by weight of trimethobenzamide or a pharmaceutically acceptable salt thereof as an active ingredient based on the total weight of the composition. In addition, the pharmaceutical composition of the present invention may further include one or more active ingredients exhibiting the same or similar functions in addition to the active ingredient.
본 발명의 약학적 조성물은 통상적으로 사용되는 담체, 희석제, 부형제 또는 이의 혼합물을 포함할 수 있다. 약학적으로 허용가능한 담체는 조성물을 생체 내에 전달하는데 적합한 것이면 모두 사용할 수 있다. 구체적으로, 상기 담체는 Merck Index, 13th ed., Merck & Co. Inc.에 기재된 화합물, 식염수, 멸균수, 링거액, 덱스트로스 용액, 말토덱스트린 용액, 글리세롤, 에탄올 또는 이의 혼합물일 수 있다. 또한, 필요에 따라 항산화제, 완충액, 정균제 등과 같은 통상의 첨가제를 첨가할 수 있다.The pharmaceutical composition of the present invention may include a carrier, diluent, excipient, or mixture thereof commonly used. Pharmaceutically acceptable carriers can be used as long as they are suitable for delivery of the composition in vivo. Specifically, the carrier is Merck Index, 13th ed., Merck & Co. Inc., saline, sterile water, Ringer's solution, dextrose solution, maltodextrin solution, glycerol, ethanol or mixtures thereof. In addition, conventional additives such as antioxidants, buffers, bacteriostatics, etc. may be added as necessary.
상기 조성물을 제제화하는 경우, 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 첨가할 수 있다.When formulating the composition, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, etc. which are commonly used may be added.
본 발명의 조성물은 경구용 제제 또는 비경구용 제제로 제형화될 수 있다. 경구용 제제로는 고형 제제 및 액상 제제가 포함될 수 있다. 상기 고형 제제는 정제, 환제, 산제, 과립제, 캡슐제 또는 트로키제일 수 있고, 이러한 고형 제제는 상기 조성물에 적어도 하나 이상의 부형제를 첨가하여 조제할 수 있다. 상기 부형제는 전분, 탄산칼슘, 수크로스, 락토오스, 젤라틴 또는 이의 혼합물일 수 있다. 또한, 상기 고형 제제는 윤활제를 포함할 수 있고, 그 예로는 마그네슘 스티레이트, 탈크등이 있다. 한편, 상기 액상 제제는 현탁제, 내용액제, 유제 또는 시럽일 수 있다. 이때, 상기 액상 제제에는 습윤제, 감미제, 방향제, 보존제 등과 같은 부경제가 포함될 수 있다.The composition of the present invention may be formulated as an oral or parenteral preparation. Oral formulations may include solid and liquid formulations. The solid preparation may be tablets, pills, powders, granules, capsules or troches, and such solid preparations may be prepared by adding at least one excipient to the composition. The excipient may be starch, calcium carbonate, sucrose, lactose, gelatin or mixtures thereof. In addition, the solid preparation may include a lubricant, for example magnesium styrate, talc and the like. On the other hand, the liquid formulation may be a suspending agent, a solution solution, an emulsion or a syrup. In this case, the liquid formulation may include an economy such as a humectant, a sweetener, a fragrance, a preservative.
상기 비경구용 제제는 주사제, 좌제, 호흡기 흡입용 분말, 스프레이용 에어로졸제, 파우더 및 크림 등을 포함할 수 있다. 상기 주사제는 멸균된 수용액, 비수성용제, 현탁용제, 유제 등을 포함할 수 있다. 이때, 비수성용제 또는 현탁용제로서는 프로필렌글리콜, 올리브 오일과 같은 식물성 기름이나, 에틸올레이트와 같이 주사가능한 에스테르 등이 사용될 수 있다.The parenteral preparations may include injections, suppositories, respiratory inhalation powders, spray aerosols, powders and creams, and the like. The injection may include a sterile aqueous solution, a non-aqueous solvent, a suspension solvent, an emulsion, and the like. In this case, as the non-aqueous solvent or suspending solvent, vegetable oils such as propylene glycol and olive oil, or injectable esters such as ethyl oleate may be used.
아울러, 본 발명은 약학적으로 치료가능한 양의 트리메토벤자미드 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 제 1성분; 및 트라마돌 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 제 2성분을 포함하는 신경병증의 예방 또는 치료용 약학적 키트를 제공한다.In addition, the present invention comprises a first component containing a pharmaceutically treatable amount of trimethobenzamide or a pharmaceutically acceptable salt thereof as an active ingredient; And it provides a pharmaceutical kit for preventing or treating neuropathy comprising a second component containing tramadol or a pharmaceutically acceptable salt thereof as an active ingredient.
상기 신경병증은 당뇨병성 신경병증(Diabetic neuropathy), 대상포진후 신경병증, 삼차 신경병증(trigeminal neuropathy), 다발성 말초 신경병증(Peripheral Neuropathies), 단발성 말초 신경병증, 다발성 홑신경염(Mononeuritis multiplex), 자율신경병증, 염증성 신경병증(inflammatory neuropathy), 대사 또는 내분비이상에 의한 신경병증(metabolic or endocrine neuropathy), 중독 또는 약물에 의한 신경병증(toxic or drug-induced neuropathy), 영양신경병증(nutritional neuropathy), 혈관염증신경병증(vasculitic neuropathy), 종양관련신경병증(paraneoplastic neuropathy), 외상신경병증(traumatic neuropathy), 유전신경병증(hereditary neuropathy) 및 특발성 신경병증(idiopathic neuropathy)으로 구성된 군으로부터 선택되는 어느 하나 이상의 신경병증일 수 있으나, 이에 한정되지 않는다. The neuropathy may include diabetic neuropathy, post shingles neuropathy, trigeminal neuropathy, multiple peripheral neuropathies, single peripheral neuropathy, multiple mononeuritis multiplex, autonomic Neuropathy, inflammatory neuropathy, metabolic or endocrine neuropathy, toxic or drug-induced neuropathy, nutritional neuropathy, At least one selected from the group consisting of vasculitic neuropathy, tumor-related neuropathy, traumatic neuropathy, hereditary neuropathy, and idiopathic neuropathy. It may be neuropathy, but is not limited thereto.
상기 약학적 키트에 포함되는 트리메토벤자미드 또는 이의 약학적으로 허용가능한 염, 트라마돌 또는 이의 약학적으로 허용가능한 염을 상술한 바와 같은 특징을 가질 수 있다.Trimethobenzamide or a pharmaceutically acceptable salt thereof, tramadol or a pharmaceutically acceptable salt thereof included in the pharmaceutical kit may have the characteristics as described above.
본 발명의 약학적 키트는 신경병증의 예방 또는 치료를 위하여 제 1성분 및 제 2성분이 순차 또는 동시에 투여될 수 있다. 상기 약학적 키트에 포함된 제 1성분 및 제 2성분을 병용투여함으로써 신경병증을 완화시킬 수 있다.In the pharmaceutical kit of the present invention, the first component and the second component may be administered sequentially or simultaneously for the prevention or treatment of neuropathy. Neuropathy can be alleviated by co-administration of the first component and the second component included in the pharmaceutical kit.
본 발명의 키트에 포함되는 제 1성분 및 제 2성분은 목적하는 방법에 따라 경구 또는 비경구로 투여될 수 있다. 비경구 투여는 복강내, 직장내, 피하, 정맥, 근육내 또는 흉부내 주사 방식을 포함할 수 있다. The first component and the second component included in the kit of the present invention may be administered orally or parenterally according to the desired method. Parenteral administration can include intraperitoneal, rectal, subcutaneous, intravenous, intramuscular or intrathoracic injection modes.
제 1성분 및 제 2성분의 약학적으로 치료가능한 양은 질환의 종류, 중증도, 약물의 활성, 약물에 대한 환자의 민감도, 투여 시간, 투여 경로, 치료기간, 동시에 사용되는 약물 등에 따라 달리질 수 있다. 그러나, 바람직한 효과를 위해서, 본 발명에 따른 제 1성분은 30 내지 90 mg/kg, 구체적으로 40 내지 80 mg/kg, 더욱 구체적으로 50 내지 70 mg/kg의 양으로 투여될 수 있다. 본 발명의 일 실시예에서, 상기 제 1성분은 60 mg/kg의 양으로 투여될 수 있다. 한편, 제 2성분은 5 내지 35 mg/kg, 구체적으로 10 내지 30 mg/kg, 더욱 구체적으로 15 내지 25 mg/kg의 양으로 투여될 수 있다. 본 발명의 일실시예에서, 상기 제2성분은 20 mg/kg의 양으로 투여될 수 있다.Pharmaceutically treatable amounts of the first and second components may vary depending on the type of disease, the severity, the activity of the drug, the patient's sensitivity to the drug, the time of administration, the route of administration, the duration of treatment, the drug being used simultaneously, and the like. . However, for the desired effect, the first component according to the invention can be administered in an amount of 30 to 90 mg / kg, specifically 40 to 80 mg / kg, more specifically 50 to 70 mg / kg. In one embodiment of the invention, the first component may be administered in an amount of 60 mg / kg. On the other hand, the second component may be administered in an amount of 5 to 35 mg / kg, specifically 10 to 30 mg / kg, more specifically 15 to 25 mg / kg. In one embodiment of the present invention, the second component may be administered in an amount of 20 mg / kg.
본 발명의 구체적인 실시예에서, 본 발명자들은 트리메토벤자미드를 당뇨병성 신경병증성 동물 모델 마우스에 투여했을 때 농도 의존적으로 통증이 완화됨을 확인하였으며(도 1 참조), 트리메토벤자미드를 트라마돌과 병용투여 하였을 때 각각의 투여에 비해 신경병증 억제가 우수함을 확인하였다(도 2 및 3 참조).In a specific embodiment of the present invention, the present inventors confirmed that the pain was alleviated in a concentration-dependent manner when trimethobenzamide was administered to diabetic neuropathic animal model mice (see FIG. 1), and trimethobenzamide was treated with tramadol. When administered in combination, it was confirmed that neuropathy inhibition was superior to that of each administration (see FIGS. 2 and 3).
따라서, 상기 트리메토벤자미드는 트라마돌과 병용투여하여 신경병증의 치료에 사용될 수 있다. Thus, the trimethobenzamide may be used in combination with tramadol to treat neuropathy.
이하, 본 발명을 하기 실시예에 의해 상세히 설명한다.Hereinafter, the present invention will be described in detail by the following examples.
단, 하기 실시예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 실시예에 의해 한정되는 것은 아니다.However, the following examples are merely to illustrate the invention, but the content of the present invention is not limited by the following examples.
신경병증 동물모델의 제작Production of neuropathy animal model
먼저, 스트렙토조신(streptozocin)을 투여하여 신경병증 동물모델을 제작하였다. 구체적으로, 4주령의 ICR 마우스에 75 mg/kg의 스트렙토조토신을 복강내로 투여하였다. 투여 5주 후, 혈당 수치 및 Von Frey 필라멘트 자극 시험을 통해 신경병증의 발현을 확인한 후 하기 실험에 이용하였다.First, streptozocin was administered to prepare a neuropathy animal model. Specifically, 75 mg / kg of streptozotocin was intraperitoneally administered to 4 week old ICR mice. After 5 weeks of administration, the expression of neuropathy was confirmed by blood glucose level and Von Frey filament stimulation test, and then used in the following experiment.
<< 시험예Test Example 1> 1> 트리메토벤자미드에To trimethobenzamide 의한 신경병증 억제 확인 Confirmation of neuropathy suppression
<실시예 1>에서 제작한 동물모델을 이용하여 트리메토벤자미드 화합물의 통증 억제 효과를 확인하였다.The pain inhibitory effect of the trimethobenzamide compound was confirmed using the animal model produced in <Example 1>.
구체적으로, 트리메토벤자미드를 생리식염수에 녹여 10, 20, 40 및 80 mg/kg의 농도로 제조하였으며, 신경병증 모델 마우스에 경구투여한 후 1, 2, 3, 4 및 5시간 후에 Von Frey 필라멘트 자극 시험을 수행하여 신경병증의 억제 효과를 확인하였다.Specifically, trimethobenzamide was dissolved in physiological saline and prepared at concentrations of 10, 20, 40 and 80 mg / kg, and
그 결과, 도 1에 나타낸 바와 같이 트리메토벤자미드를 단독으로 투여한 경우 농도 의존적으로 신경병증 억제에 유의적으로 효과가 있음을 확인하였다(도 1).As a result, as shown in FIG. 1, when trimethobenzamide was administered alone, it was confirmed that there was a significant effect on neuropathy inhibition in a concentration-dependent manner (FIG. 1).
<< 시험예Test Example 2> 2> 트리메토벤자미드의Of trimethobenzamide 병용투여에 의한 신경병증 억제 확인 Confirmation of neuropathy suppression by combined administration
상기 <실시예 1>에서 제작한 동물모델을 이용하여 트리메토벤자미드를 트라마돌과 병용투여 하였을 때, 통증억제 효과를 확인하였다.When the trimethobenzamide was co-administered with tramadol using the animal model produced in Example 1, the pain inhibitory effect was confirmed.
구체적으로, 트리메토벤자미드 또는 트라마돌을 생리식염수에 녹여 트리메토벤자미드 60 mg/kg 또는 트라마돌 20 mg/kg의 농도로 제조하였고, 트라마돌 20 mg/kg에 트리메토벤자미드를 20, 40 또는 60 mg/kg를 섞어 투여한 후 병용투여의 효과를 확인하였다. 상기 투여는 신경병증 모델 마우스에 경구투여하였으며, 투여 1, 2, 3, 4 및 5시간 후 Von Frey 필라멘트 자극 시험을 수행하여 신경병증의 억제 효과를 확인하였다.Specifically, trimethobenzamide or tramadol was dissolved in physiological saline and prepared at a concentration of 60 mg / kg of trimethobenzamide or 20 mg / kg of tramadol, and 20, 40 or 60 of trimethobenzamide at 20 mg / kg of tramadol. After mixing and administering mg / kg, the effect of the combined administration was confirmed. The administration was orally administered to neuropathy model mice, Von Frey filament stimulation test was performed 1, 2, 3, 4 and 5 hours after administration to confirm the inhibitory effect of neuropathy.
그 결과, 도 2 및 3에 나타난 바와 같이 트리메토벤자미드 또는 트라마돌을 단독으로 투여한 경우에 비해서 트리메토벤자미드와 트라마돌을 병용투여 하였을 때 통증 억제 효과가 유의적으로 증가하였다(도 2). 아울러, 병용투여에 있어서 트리메토벤자미드의 농도가 증가할수록 통증 억제 효과 또한 증가하는 것을 확인하였다(도 3).As a result, as shown in FIGS. 2 and 3, the pain inhibitory effect was significantly increased when trimethobenzamide and tramadol were administered in combination as compared with the administration of trimethobenzamide or tramadol alone (FIG. 2). In addition, it was confirmed that the pain inhibitory effect also increased as the concentration of trimethobenzamide increased in combination administration (FIG. 3).
Claims (8)
상기 신경병증은 당뇨병성 신경병증(Diabetic neuropathy), 대상포진후 신경병증, 삼차 신경병증(trigeminal neuropathy), 다발성 말초 신경병증(Peripheral Neuropathies), 단발성 말초 신경병증, 다발성 홑신경염(Mononeuritis multiplex), 자율신경병증, 염증성 신경병증(inflammatory neuropathy), 대사 또는 내분비이상에 의한 신경병증(metabolic or endocrine neuropathy), 중독 또는 약물에 의한 신경병증(toxic or drug-induced neuropathy), 영양신경병증(nutritional neuropathy), 혈관염증신경병증(vasculitic neuropathy), 종양관련신경병증(paraneoplastic neuropathy), 외상신경병증(traumatic neuropathy), 유전신경병증(hereditary neuropathy) 및 특발성 신경병증(idiopathic neuropathy)으로 구성된 군으로부터 선택되는 어느 하나 이상의 신경병증인, 신경병증의 예방 또는 치료용 약학적 조성물.
In the pharmaceutical composition for the prevention or treatment of neuropathy containing trimethobenzamide or a pharmaceutically acceptable salt thereof as an active ingredient,
The neuropathy may include diabetic neuropathy, post shingles neuropathy, trigeminal neuropathy, multiple peripheral neuropathies, single peripheral neuropathy, multiple mononeuritis multiplex, autonomic Neuropathy, inflammatory neuropathy, metabolic or endocrine neuropathy, toxic or drug-induced neuropathy, nutritional neuropathy, At least one selected from the group consisting of vasculitic neuropathy, tumor-related neuropathy, traumatic neuropathy, hereditary neuropathy, and idiopathic neuropathy. Neuropathy, pharmaceutical composition for the prevention or treatment of neuropathy.
[화학식 1]
The pharmaceutical composition for preventing or treating neuropathy of claim 1, wherein the trimethobenzamide is a compound represented by the following Chemical Formula 1:
[Formula 1]
The pharmaceutical composition for preventing or treating neuropathy of claim 1, further comprising tramadol or a pharmaceutically acceptable salt thereof.
[화학식 2]
The pharmaceutical composition for preventing or treating neuropathy of claim 3, wherein the tramadol is a compound represented by Formula 2 below:
[Formula 2]
A first component containing a pharmaceutically treatable amount of trimethobenzamide or a pharmaceutically acceptable salt thereof as an active ingredient; And a second component containing a pharmaceutically treatable amount of tramadol or a pharmaceutically acceptable salt thereof as an active ingredient.
The pharmaceutical kit for preventing or treating neuropathy according to claim 6, wherein the first component and the second component are administered sequentially or simultaneously.
7. The method of claim 6, wherein the neuropathy is diabetic neuropathy, post shingles neuropathy, trigeminal neuropathy, multiple peripheral neuropathies, single peripheral neuropathy, multiple mononeuritis (Mononeuritis multiplex), autonomic neuropathy, inflammatory neuropathy, metabolic or endocrine neuropathy, toxic or drug-induced neuropathy, nutritional nerve Group consisting of nutritional neuropathy, vasculitic neuropathy, tumor-associated neuropathy, traumatic neuropathy, hereditary neuropathy and idiopathic neuropathy Pharmaceutical kit for the prevention or treatment of neuropathy, which is at least one neuropathy selected from.
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