KR20230127957A - Pharmaceutical composition for the prevention and the treatment of respiratory deseases - Google Patents
Pharmaceutical composition for the prevention and the treatment of respiratory deseases Download PDFInfo
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- KR20230127957A KR20230127957A KR1020230110534A KR20230110534A KR20230127957A KR 20230127957 A KR20230127957 A KR 20230127957A KR 1020230110534 A KR1020230110534 A KR 1020230110534A KR 20230110534 A KR20230110534 A KR 20230110534A KR 20230127957 A KR20230127957 A KR 20230127957A
- Authority
- KR
- South Korea
- Prior art keywords
- pharmaceutical composition
- pelargonium sidoides
- respiratory diseases
- extract
- pharmaceutically acceptable
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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Abstract
본 발명은 펠라고니움 시도이데스 추출물과 하기의 4종의 약리학적 활성물질로 이루어지는 호흡기 질환 치료용 약학 조성물을 유효성분으로 포함하는 호흡기 질환 치료용 약학 조성물이 개시된다.
(1) 코데인 또는 이의 약학적으로 허용되는 유도체 또는 염;
(2) 에페드린 또는 이의 약학적으로 허용되는 유도체 또는 염;
(3) 페니라민 또는 이의 약학적으로 허용되는 유도체 또는 염
(4) 염화암모늄Disclosed is a pharmaceutical composition for treating respiratory diseases comprising a pharmaceutical composition for treating respiratory diseases consisting of a Pelargonium sidoides extract and the following four pharmacologically active substances as an active ingredient.
(1) codeine or a pharmaceutically acceptable derivative or salt thereof;
(2) ephedrine or a pharmaceutically acceptable derivative or salt thereof;
(3) pheniramine or a pharmaceutically acceptable derivative or salt thereof
(4) Ammonium chloride
Description
본 발명은 호흡기 질환의 예방 및 치료용 약학 조성물에 관한 것이다. 구체적으로는, 코데인 또는 이의 약학적으로 허용되는 유도체 또는 염; 에페드린 또는 이의 약학적으로 허용되는 유도체 또는 염; 페니라민 또는 이의 약학적으로 허용되는 유도체 또는 염; 및 염화암모늄 4종의 약리학적 활성물질로 구성되는 호흡기 질환의 예방 및 치료용 약학 조성물에 펠라고니움 시도이데스 추출물을 추가로 포함시킨 약학 조성물에 관한 것이다. 이러한 약학 조성물은 진해작용, 거담작용 및 소염작용을 통해 효과적인 호흡기 질환 치료 결과를 나타냄으로써 호흡기 질환의 예방 및 치료에 유용하게 이용된다. 보다 특별하게는, 상기 4종의 약리학적 활성물질로 구성되는 호흡기 질환의 예방 및 치료용 약학 조성물에 펠라고니움 시도이데스 추출물을 포함시켜, 상기 4종의 약리학적 활성물질로 구성되는 약학 조성물의 거담효과를 현저히 증가시킬 수 있는 약학 조성물에 관한 것이다. 추가적으로 본 발명은, 상기 4종의 약리학적 활성물질의 세포투과도가 펠라고니움 시도이데스 추출물에 의하여 증가된 것을 특징으로 하는 약학 조성물에 관한 것이다. The present invention relates to a pharmaceutical composition for preventing and treating respiratory diseases. Specifically, codeine or a pharmaceutically acceptable derivative or salt thereof; Ephedrine or a pharmaceutically acceptable derivative or salt thereof; pheniramine or a pharmaceutically acceptable derivative or salt thereof; And it relates to a pharmaceutical composition further comprising a Pelargonium sidoides extract in a pharmaceutical composition for preventing and treating respiratory diseases consisting of four kinds of pharmacologically active substances of ammonium chloride. These pharmaceutical compositions are useful for the prevention and treatment of respiratory diseases by showing effective respiratory disease treatment results through antitussive, expectorant and anti-inflammatory actions. More specifically, by including Pelargonium sidoides extract in a pharmaceutical composition for preventing and treating respiratory diseases consisting of the above four kinds of pharmacologically active substances, the pharmaceutical composition consisting of the above four kinds of pharmacologically active substances It relates to a pharmaceutical composition capable of significantly increasing the expectorant effect. Additionally, the present invention relates to a pharmaceutical composition characterized in that the cell permeability of the above four pharmacologically active substances is increased by the Pelargonium sidoides extract.
기침은 감기 및 천식, 기관지염, 폐렴 등과 같은 염증성 중증 호흡기 질환, 후비루 등에 흔히 수반되는 증상으로, 먼지나 미생물, 자극을 주는 유해물질 등이 기도 안으로 들어오는 것을 방지하고, 기관지와 폐로 들어온 외래 유해물질을 제거하는 신체방어를 위한 불수의적 반사행동이다. 이러한 기침이 너무 심할 경우 일상생활에 큰 불편이 될 수 있으며 호흡곤란, 흉통, 구토, 현기증 등의 증상을 겪게 되기도 한다. 또한, 심할 경우 잦은 기침으로 인해 인후두 점막에 상처가 생기게 되는 경우도 있다. 일반 감기의 경우라 하더라도 적절한 시기에 증상완화를 위한 적절한 치료를 하지 않으면 상기도 감염, 기관지염, 폐렴 등과 같은 감염성 및 염증성 질환으로 발전할 가능성이 크기 때문에 효과적인 증상 경감 및 원인 치료를 위한 약제의 사용이 중요하다.Cough is a common symptom accompanying severe inflammatory respiratory diseases such as colds, asthma, bronchitis, and pneumonia, and postnasal drip. It is an involuntary reflex action for body defense to eliminate. If this cough is too severe, it can be a great inconvenience in daily life, and symptoms such as shortness of breath, chest pain, vomiting, and dizziness may be experienced. In addition, in severe cases, frequent coughing may cause scarring on the mucous membrane of the pharynx. Even in the case of a common cold, there is a high possibility of developing infectious and inflammatory diseases such as upper respiratory tract infection, bronchitis, and pneumonia if appropriate treatment is not given to relieve symptoms in a timely manner. It is important.
한편, 타액과 함께 기관지 근육운동을 통해 외래 유해물질을 밖으로 배출하고자 하는 작용을 객담(가래)라고 일컫는데, 기관지 또는 폐에 염증 반응이 있을 경우 화농성 객담이 생기거나 기도 점막에 염증이 생기게 된다. 기도 점막에 염증이 생기면 자위적 생리현상으로 분비물이 증가하게 되고, 이 분비물의 객출을 용이하게 하는 것이 거담제이다.On the other hand, the action of expelling foreign harmful substances through bronchial muscle movement along with saliva is called sputum (sputum). When the airway mucosa is inflamed, the secretion increases due to self-induced physiological phenomenon, and expectorants facilitate the excretion of this secretion.
종래 사용되는 진해제로서는, 아편류 알칼로이드, 덱트스로메트로판, 페노바비탈류와 같은 중추성 진해제 및 교감신경 흥분제나 크산틴 화합물(아미노필린, 테오필린)과 같은 말초성 진해제가 있으며, 거담제로서는 아모포르핀, 사포닌류 등의 최토성 거담제와 바라다제, 키모트립신과 같은 단백분해 효소제 등이 있다.Conventionally used antitussives include central antitussives such as opioid alkaloids, dextromethorphan, and phenobarbital, and peripheral antitussives such as sympathomimetics and xanthine compounds (aminophylline and theophylline), and expectorants such as amorphorphine and saponins These include antiemetic expectorants such as varadase and proteolytic enzymes such as chymotrypsin.
그러나, 염증성 호흡기 질환은 각종 백혈구 세포와 다양한 싸이토카인 및 염증 매개인자들이 관여하므로, 진해제 또는 거담제 단일성분만으로는 효과적인 치료효과를 가져오기 어려울 수 있기 때문에 다양한 약리기전을 가지는 성분들이 혼합된 천연물 추출물과 병용투여 하는 것이 더욱 효과적일 수 있다.However, since various white blood cells, various cytokines, and inflammatory mediators are involved in inflammatory respiratory diseases, it may be difficult to obtain an effective treatment effect with only a single component of an antitussive or expectorant. Doing so may be more effective.
또한, 임상에서 감기 등 급성 호흡기 질환 환자에게 있어 단지 감염의 예방만을 목적으로 하거나 상세 불명의 박테리아 감염증 치료를 위해 항생제를 과잉처방하는 비율이 높은데, 부적절한 항생제의 사용은 환자에게 있어 감기 치료효과보다는 내성발현 등 부정적인 결과를 가져오게 할 수도 있다. 이러한 이유로 천연물 의약품 등 비항생제적 치료 약제에 대한 수요가 있는 실정이다.In addition, there is a high rate of overprescribing antibiotics for the purpose of preventing infection or for the treatment of an unknown bacterial infection in patients with acute respiratory diseases such as colds in clinical practice. It can also lead to negative consequences such as manifestations. For this reason, there is a demand for non-antibiotic treatment drugs such as natural medicines.
본 발명은 호흡기 질환의 예방 및 치료용 약학 조성물을 제공하는 것을 해결과제로 하며, 펠라고니움 시도이데스와 4종의 약리학적 활성물질로 이루어지는 호흡기 질환 치료용 약학 조성물을 복합제로 만들어 소염 및 진해, 거담작용을 나타내는 천연물 의약품을 첨가한 조성물을 제공하는 것을 구체적인 해결과제로 한다. 나아가, 우수한 소염효과 및 향상된 거담효과를 나타낼 수 있는 조성비를 제공하여 효과적인 호흡기 질환 예방 및 치료제를 제공하는 것이 본 발명의 특별한 해결과제이다. An object of the present invention is to provide a pharmaceutical composition for the prevention and treatment of respiratory diseases, and a pharmaceutical composition for the treatment of respiratory diseases consisting of Pelargonium sidoides and four types of pharmacologically active substances is made into a complex, anti-inflammatory and antitussive, A specific problem is to provide a composition to which a natural drug having an expectorant effect is added. Furthermore, it is a special problem of the present invention to provide an effective respiratory disease preventive and therapeutic agent by providing a composition ratio capable of exhibiting excellent anti-inflammatory and improved expectorant effects.
상기 과제를 해결하기 위해서, 본 발명에서는 하기와 같은 수단을 개시한다.In order to solve the above problems, the present invention discloses the following means.
하기 (1) 내지 (4)의 성분 및 펠라고니움 시도이데스 추출물을 활성성분으로 함유하는 기침, 가래 및 그에 수반하는 호흡기 질환 치료용 약학 조성물을 개시한다. Disclosed is a pharmaceutical composition for treating cough, phlegm and accompanying respiratory diseases, containing the following ingredients (1) to (4) and Pelargonium sidoides extract as active ingredients.
(1) 코데인 또는 이의 약학적으로 허용되는 유도체 또는 염;(1) codeine or a pharmaceutically acceptable derivative or salt thereof;
(2) 에페드린 또는 이의 약학적으로 허용되는 유도체 또는 염;(2) ephedrine or a pharmaceutically acceptable derivative or salt thereof;
(3) 페니라민 또는 이의 약학적으로 허용되는 유도체 또는 염;(3) pheniramine or a pharmaceutically acceptable derivative or salt thereof;
(4) 염화암모늄(4) Ammonium chloride
상기 약학 조성물에 있어서, 펠라고니움 시도이데스 추출물에 대한 4종의 약리학적 활성물질로 이루어지는 호흡기 질환 치료용 약학 조성물의 중량비(유리염기의 형태로서)가 펠라고니움 시도이데스 추출물 : 코데인: 에페드린 : 페니라민 : 염화암모늄이 600~1300 : 4~10 : 17~27 : 0.5~5 : 100~400인 약학 조성물을 개시한다.In the above pharmaceutical composition, the weight ratio (in the form of a free base) of the pharmaceutical composition for the treatment of respiratory diseases consisting of four types of pharmacologically active substances to the Pelargonium sidoides extract is Pelargonium sidoides extract: codeine: ephedrine: Disclosed is a pharmaceutical composition in which pheniramine: ammonium chloride is 600-1300: 4-10: 17-27: 0.5-5: 100-400.
상기 약학 조성물에 있어서, 펠라고니움 시도이데스 추출물, 디히드로코데인주석산염, dl-메틸에페드린염산염, 클로르페니라민말레산염 및 염화암모늄을 각각 1235.52 mg, 10.00 mg, 26.25 mg, 3.00 mg 및 200.00 mg을 포함하는 것을 특징으로 하는 약학 조성물이 개시된다.In the pharmaceutical composition, 1235.52 mg, 10.00 mg, 26.25 mg, 3.00 mg and 200.00 mg of Pelargonium sidoides extract, dihydrocodeine tartrate, dl-methylephedrine hydrochloride, chlorpheniramine maleate and ammonium chloride, respectively, were included. A pharmaceutical composition characterized in that is disclosed.
본 발명에 따른 약학 조성물은 소염 및 진해, 거담작용을 달성하는 효과를 나타낸다. 보다 특별하게는, 케미칼 의약품 조합인 4종의 약리학적 활성물질로 구성되는 호흡기 질환 치료용 약학 조성물 또는 펠라고니움 시도이데스 추출물을 단독으로 각각 사용했을 때 보다, 본 발명에 따른 약학 조성물의 소염작용을 통해 호흡기 질환의 치료효과를 현저히 상승시키는 효과가 있다. 또한, 본 발명에 따른 약학 조성물은 거담효과를 향상시키는 효과가 있다. 이러한 효과로 인해 하나의 약물만 복용하여도 원하는 치료 효과를 달성할 수 있어 환자의 복약순응도를 높이는 장점이 있다. The pharmaceutical composition according to the present invention exhibits effects of achieving anti-inflammatory and antitussive and expectorant actions. More specifically, the anti-inflammatory action of the pharmaceutical composition according to the present invention is greater than when the pharmaceutical composition for treating respiratory diseases or Pelargonium sidoides extract, which is composed of four types of pharmacologically active substances, which is a combination of chemical drugs, is used alone. It has the effect of significantly increasing the treatment effect of respiratory diseases. In addition, the pharmaceutical composition according to the present invention has an effect of improving the expectorant effect. Due to this effect, it is possible to achieve a desired therapeutic effect even if only one drug is taken, thereby increasing the patient's medication compliance.
호흡기 질환 치료에 사용 될 수 있는 천연물 의약품 중 특히 펠라고니움 시도이데스(Pelagonium sidoides)는 남아프리카 자생의 생약으로, 뿌리 추출물은 급성 호흡기 질환의 치료에 널리 사용되어 온 약재이다. 최근에 들어서는 펠라고니움 시도이데스 추출물을 천연물 의약품으로서 제제화하여 상용화가 이루어졌으며, 그 대표적인 제품으로는 펠라고니움 시도이데스 11% 에탄올 추출물(1→8~10)ㆍ글리세린 혼합액(8:2) 17.16%w/v을 함유하는 시럽제인 움카민®(한화제약, 한국)이 있다. Matthys(Phytomedicine 10 (2003) 7-17)에 의해 보고된 바에 따르면 펠라고니움 시도이데스 추출물은 현저한 기관지염 완화와 항균작용을 나타내었다. 또한, 아직까지 상기 추출물과 타 약제를 병용투여 하였을 때 부정적인 상호작용이 발생한다는 어떠한 보고도 없다.Among natural medicines that can be used for the treatment of respiratory diseases, Pelagonium sidoides, in particular, is a herbal medicine native to South Africa, and its root extract has been widely used for the treatment of acute respiratory diseases. Recently, Pelargonium sidoides extract has been formulated and commercialized as a natural medicine, and its representative product is Pelargonium sidoides 11% ethanol extract (1→8~10)ㆍglycerin mixture (8:2) 17.16 There is Umcarmin ® (Hanwha Pharmaceutical, Korea), which is a syrup containing %w/v. According to a report by Matthys (Phytomedicine 10 (2003) 7-17), Pelargonium sidoides extract showed remarkable bronchitis relief and antibacterial activity. In addition, there is no report that negative interactions occur when the extract and other drugs are co-administered.
본 발명은, 펠라고니움 시도이데스 추출물과 4종의 약리학적 활성물질로 이루어지는 호흡기 질환 치료용 약학 조성물을 함께 투여하는 경우, 펠라고니움 시도이데스 추출물로 인하여 4종의 약리학적 활성물질의 세포투과도가 향상하고, 이로 인하여 4종의 약리학적 활성물질의 호흡기 질환 치료효과, 특히, 단독 성분의 함량 증가만으로는 달성될 수 없는 수준의 우수한 소염효과를 나타낸다는 것에 기초하여 이루어진 것이다.The present invention, when the pharmaceutical composition for the treatment of respiratory diseases consisting of the Pelargonium sidoides extract and the four pharmacologically active substances is administered together, the cell permeability of the four pharmacologically active substances due to the Pelargonium sidoides extract It is made based on the fact that it shows an excellent anti-inflammatory effect at a level that cannot be achieved by improving the respiratory disease treatment effect of the four pharmacologically active substances, in particular, by increasing the content of a single component alone.
본 발명에 따라, 펠라고니움 시도이데스 추출물에 의해 호흡기 치료효과가 증강되는 4종의 약리학적 활성물질로 이루어지는 호흡기 질환 치료용 약학 조성물은 코데인 또는 이의 약학적으로 허용되는 유도체 또는 이의 약학적으로 허용되는 염; 에페드린 또는 이의 약학적으로 허용되는 유도체 또는 이의 약학적으로 허용되는 염; 페니라민 또는 이의 약학적으로 허용되는 유도체 또는 이의 약학적으로 허용되는 염; 및 염화암모늄을 포함한다.According to the present invention, a pharmaceutical composition for the treatment of respiratory diseases consisting of four pharmacologically active substances whose respiratory therapeutic effect is enhanced by a Pelargonium sidoides extract is codeine or a pharmaceutically acceptable derivative thereof or a pharmaceutically acceptable derivative thereof. salt; ephedrine or a pharmaceutically acceptable derivative thereof or a pharmaceutically acceptable salt thereof; pheniramine or a pharmaceutically acceptable derivative thereof or a pharmaceutically acceptable salt thereof; and ammonium chloride.
코데인 또는 이의 약학적으로 허용되는 유도체 또는 염에는, 코데인, 코데인 메틸 브로마이드, 코데인 N-옥시드, 코데인 포스페이트, 코데인 술페이트, 디히드로코데인 등을 들 수 있으며, 제약분야에서 통상적으로 사용가능한 염, 예를 들면, 디히드로코데인 주석산염 등이 모두 포함된다. Codeine or its pharmaceutically acceptable derivatives or salts include codeine, codeine methyl bromide, codeine N-oxide, codeine phosphate, codeine sulfate, dihydrocodeine and the like, salts commonly used in the pharmaceutical field; For example, dihydrocodeine tartrate and the like are all included.
에페드린 또는 이의 약학적으로 허용되는 유도체 또는 염에는 에페드린, 슈도에페드린 또는 dl-메틸에페드린 등을 들 수 있으며, 제약분야에서 통상적으로 사용가능한 염, 예를 들면, dl-메틸에페드린 염산염 등이 모두 포함된다.Ephedrine or a pharmaceutically acceptable derivative or salt thereof includes ephedrine, pseudoephedrine, dl-methylephedrine, and the like, and salts commonly used in the pharmaceutical field, such as dl-methylephedrine hydrochloride, etc. are all included.
페니라민 또는 이의 약학적으로 허용되는 유도체 또는 염에는 브롬페니라민, 클로르페니라민, 페니라민 등이 있고, 제약분야에서 통상적으로 사용가능한 염, 예를 들면, 클로르페니라민 말레산염 등이 모두 포함된다.Pheniramine or its pharmaceutically acceptable derivatives or salts include brompheniramine, chlorpheniramine, pheniramine, and the like, and include salts commonly used in the pharmaceutical field, such as chlorpheniramine maleate.
본 발명에 따르면, 위 4종의 약리학적 활성물질이 펠라고니움 시도이데스 추출물과 조합되어 함께 투여되는 경우, 호흡기 질환의 예방 및 치료효과가 현저히 증가된다. According to the present invention, when the above four pharmacologically active substances are combined with Pelargonium sidoides extract and administered together, the preventive and therapeutic effects of respiratory diseases are significantly increased.
펠라고니움 시도이데스 추출물에 대한 4종의 약리학적 활성물질로 이루어지는 호흡기 질환 치료용 약학 조성물의 중량비(유리염기로서)는 펠라고니움 시도이데스 : 코데인 : 에페드린 : 페니라민 : 염화암모늄이 600~1300 : 4~10 : 17~27 : 0.5~5 : 100~400이 될 수 있다.The weight ratio (as a free base) of the pharmaceutical composition for the treatment of respiratory diseases consisting of four types of pharmacologically active substances to the Pelargonium sidoides extract is Pelargonium sidoides: codeine: ephedrine: pheniramine: ammonium chloride is 600 to 1300: It can be 4-10: 17-27: 0.5-5: 100-400.
본 발명은 약학 조성물의 제조에 통상적으로 사용하는 적절한 담체, 부형제 및 희석제를 포함할 수 있다. 본 발명에 따른 약학 조성물은 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽 등의 경구형 제형으로 제제화 될 수 있다. 본 발명에 포함될 수 있는 담체, 부형제, 희석제 및 첨가제에는, 유당, 무수 유당, 유당 수화물, 옥수수 전분, 덱스트로스, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유가 포함된다. 본 발명의 약학 조성물은 제약분야에서 통상적으로 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 제제화 된다. 경구투여를 위한 고형제제로서, 정제, 과립제, 캡슐제가 특히 바람직한데, 이러한 고형제제는 상기 혼합 추출물에 적어도 하나 이상의 부형제 예를 들면, 유당, 전분, 옥수수 전분, 카르복시메틸셀룰로오스칼슘, 칼슘카보네이트, 수크로스 또는 락토오스, 젤라틴 등을 사용해서 통상적인 과립제, 정제, 캡슐제의 제조방법에 따라 제조될 수 있다. 또한, 마그네슘 스테아레이트, 탈크 같은 활택제, 크로스카멜로스나트륨, 전분 글리골레이트와 같은 붕해제를 포함할 수 있다. 본 발명은 경구투여를 위한 액상제제로 제제화 될 수 있으며, 여기에는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 정제수 등과 같은 용매에 다양한 부형제 및 첨가제, 예를 들면, 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. The present invention may include suitable carriers, excipients and diluents commonly used in the preparation of pharmaceutical compositions. The pharmaceutical composition according to the present invention may be formulated into oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, and syrups according to conventional methods. Carriers, excipients, diluents and additives that may be included in the present invention include lactose, anhydrous lactose, lactose hydrate, corn starch, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin , calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. The pharmaceutical composition of the present invention is formulated using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants commonly used in the pharmaceutical field. As solid preparations for oral administration, tablets, granules, and capsules are particularly preferred, and such solid preparations include at least one excipient, for example, lactose, starch, corn starch, carboxymethylcellulose calcium, calcium carbonate, and water in the mixed extract. It can be prepared according to conventional manufacturing methods for granules, tablets, and capsules using cross, lactose, gelatin, and the like. In addition, a lubricant such as magnesium stearate and talc, and a disintegrant such as croscarmellose sodium and starch glycolate may be included. The present invention can be formulated as a liquid formulation for oral administration, which includes suspensions, internal solutions, emulsions, syrups, and the like. Various excipients and additives such as wetting agents, sweeteners, aromatics, Preservatives and the like may be included.
본 발명의 혼합 추출물의 바람직한 투여량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 기간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다. 그러나, 바람직한 효과를 위해서, 본 발명의 약학 조성물은 1일 50 내지 2000 mg으로 투여할 수 있다. 투여는 하루에 한번 투여할 수도 있고, 수회 나누어 투여할 수도 있다. 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다.A preferred dose of the mixed extract of the present invention varies depending on the condition and body weight of the patient, the severity of the disease, the type of drug, the route and duration of administration, but can be appropriately selected by those skilled in the art. However, for desirable effects, the pharmaceutical composition of the present invention may be administered in an amount of 50 to 2000 mg per day. Administration may be administered once a day, or may be administered in several divided doses. The dosage is not intended to limit the scope of the present invention in any way.
이하, 본 발명을 실시예에 의해 상세히 설명한다. 단, 하기 실시예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 실시예에 한정되는 것은 아니다.Hereinafter, the present invention will be described in detail by examples. However, the following examples are only to illustrate the present invention, and the content of the present invention is not limited to the following examples.
제조예 1. 과립제의 제조Preparation Example 1. Preparation of granules
디히드로코데인 주석산염 5 mg, dl-메틸에페드린 염산염 13.13 mg, 클로르페니라민말레산염 1.5 mg, 염화암모늄 100 mg, 펠라고니움 시도이데스 에탄올 추출물(1→8~10) 617.76 mg, 유당수화물 146 mg, 옥수수 전분 44 mg, 젤라틴 5 mg과 정제수 적량을 사용하여 통상적인 과립제의 제조방법을 이용하여 제조한다.Dihydrocodeine tartrate 5 mg, dl-methylephedrine hydrochloride 13.13 mg, chlorpheniramine maleate 1.5 mg, ammonium chloride 100 mg, Pelargonium sidoides ethanol extract (1→8~10) 617.76 mg, lactose hydrate 146 mg, It is prepared using a conventional method for preparing granules using 44 mg of corn starch, 5 mg of gelatin, and an appropriate amount of purified water.
제조예 2. 정제의 제조Preparation Example 2. Preparation of tablets
디히드로코데인 주석산염 5 mg, dl-메틸에페드린 염산염 13.13 mg, 클로르페니라민 말레산염 1.5 mg, 염화암모늄 100 mg, 펠라고니움 시도이데스 에탄올 추출물(1→8~10) 617.76 mg, 유당수화물 195 mg, 옥수수 전분 58 mg, 카르복시메틸셀룰로오스칼슘 12 mg, 젤라틴 7.5 mg, 스테아린산마그네슘 9 mg과 정제수 적량을 사용하여 통상적인 정제의 제조방법을 이용하여 제조한다.Dihydrocodeine tartrate 5 mg, dl-methylephedrine hydrochloride 13.13 mg, chlorpheniramine maleate 1.5 mg, ammonium chloride 100 mg, Pelargonium sidoides ethanol extract (1→8~10) 617.76 mg, lactose hydrate 195 mg, 58 mg of corn starch, 12 mg of carboxymethylcellulose calcium, 7.5 mg of gelatin, 9 mg of magnesium stearate, and an appropriate amount of purified water were prepared using a conventional tablet manufacturing method.
제조예 3. 내용액제의 제조Preparation Example 3. Preparation of internal solution
디히드로코데인 주석산염 5 mg, dl-메틸에페드린 염산염 13.13 mg, 클로르페니라민 말레산염 1.5 mg, 염화암모늄 100 mg, 펠라고니움 시도이데스 에탄올 추출물(1→8~10) 617.76 mg, D-소르비톨 62.5 mg, 크산탄고무 24 mg, 벤조산나트륨 6 mg을 정제수에 녹여 10 mL 용량이 되도록 통상적인 액제의 제조방법을 이용하여 제조한다. 적당한 양의 감미제, 착색제, 착향제가 추가 될 수 있다.Dihydrocodeine tartrate 5 mg, dl-methylephedrine hydrochloride 13.13 mg, chlorpheniramine maleate 1.5 mg, ammonium chloride 100 mg, Pelargonium sidoides ethanol extract (1→8~10) 617.76 mg, D-sorbitol 62.5 mg , 24 mg of xanthan gum, and 6 mg of sodium benzoate are dissolved in purified water to make a 10 mL volume, and it is prepared using a conventional liquid preparation method. Appropriate amounts of sweetening, coloring and flavoring agents may be added.
실험예 1. 카라기난 유발성 발 부종모델을 이용한 소염활성 실험Experimental Example 1. Anti-inflammatory activity test using carrageenan-induced foot edema model
디히드로코데인 주석산염, dl-메틸에페드린 염산염, 클로르페니라민 말레산염, 염화암모늄 혼합물에 펠라고니움 시도이데스 에탄올 추출물(1→8~10)을 혼합한 조성물을 제조하여 소염활성 측정실험을 진행하였다. 양성대조약물로는 인도메타신을 사용하였다. 투여용량에 따른 결과를 표 1에 나타내었다.A composition obtained by mixing Pelargonium sidoides ethanol extract (1→8-10) with a mixture of dihydrocodeine tartrate, dl-methylephedrine hydrochloride, chlorpheniramine maleate, and ammonium chloride was prepared, and an anti-inflammatory activity measurement experiment was conducted. Indomethacin was used as a positive control drug. The results according to the dosage are shown in Table 1.
실험동물로는 7주령의 수컷 Wistar 랫트를 사용하였으며, 각 시험물질을 경구투여하고 1시간 후, 카라기난 1 %w/v용액(멸균 증류수에 용해하여 제조)을 오른쪽 뒷발의 평평한 부위에 피하주사 하였다. 쥐의 발 두께를 버니어캘리퍼스로 시간대별(1, 2, 4시간)로 측정하고, 소염활성 정도를 퍼센트로 나타내었다.7-week-old male Wistar rats were used as experimental animals, and 1 hour after each test substance was orally administered, a 1% w/v solution of carrageenan (prepared by dissolving in sterilized distilled water) was subcutaneously injected into the flat part of the right hind paw. . The paw thickness of the rats was measured with vernier calipers for each time period (1, 2, 4 hours), and the degree of anti-inflammatory activity was expressed as a percentage.
(소염활성(%)=(1-D/C)×100, D=초기 두께와 실험군의 두께 차, C=초기 두께와 음성대조군의 두께 차)(Anti-inflammatory activity (%) = (1-D / C) × 100, D = difference between the initial thickness and the thickness of the experimental group, C = difference between the initial thickness and the thickness of the negative control group)
표 2에 시험물질과 대조군의 시간대별 소염활성을 나타내었다.Table 2 shows the anti-inflammatory activity of the test substance and the control group over time.
이상으로부터 알 수 있는 바와 같이, 펠라고니움 시도이데스 추출물 또는 4종의 약리학적 활성성분으로 구성되는 약학 조성물의 경우, 이를 단독으로 투여했을 때보다 양자를 병용투여 한 경우 소염제인 인도메타신과 동등한 수준의 소염 효과를 나타내는 것을 확인하였다. 특히, 펠라고니움 시도이데스 추출물 또는 4종의 약리학적 활성성분으로 구성되는 약학 조성물을 단독으로 투여했을 때에는 그 투여량을 증가시켜도 일정수준 이상으로 소염작용이 증가하지 않는다는 점에서, 위와 같은 결과는 펠라고니움 시도이데스 추출물과 4종의 약리학적 활성성분의 병용투여에 의해 상승효과가 발생했다는 것을 의미한다. 특히, 펠라고니움 시도이데스 추출물을 적은 용량으로 투여한 E3경우에도 병용과 유사한 효과를 나타낸다는 점에서 이와 같은 시너지효과가 발생함을 확인할 수 있었다. As can be seen from the above, in the case of the pharmaceutical composition consisting of Pelargonium sidoides extract or 4 kinds of pharmacologically active ingredients, the level is equivalent to that of indomethacin, an anti-inflammatory agent, when both are administered in combination than when administered alone. It was confirmed that the anti-inflammatory effect of In particular, when the Pelargonium sidoides extract or the pharmaceutical composition consisting of four pharmacologically active ingredients is administered alone, the anti-inflammatory action does not increase beyond a certain level even when the dosage is increased, the above results are It means that a synergistic effect occurred by the combined administration of Pelargonium sidoides extract and four kinds of pharmacologically active ingredients. In particular, it was confirmed that such a synergistic effect occurred in that E3, in which the Pelargonium sidoides extract was administered in a small dose, showed an effect similar to that of the combined use.
실험예 2. 페놀레드 배출법을 이용한 거담활성 실험Experimental Example 2. Expectorant activity test using phenol red discharge method
디히드로코데인 주석산염, dl-메틸에페드린 염산염, 클로르페니라민 말레산염, 염화암모늄 혼합물에 펠라고니움 시도이데스 에탄올 추출물(1→8~10)을 혼합한 조성물을 제조하여 거담활성 측정실험을 진행하였다. 양성대조약물로는 시네츄라을 사용하였다. 투여용량에 따른 결과를 표 3에 나타내었다.A composition obtained by mixing Pelargonium sidoides ethanol extract (1→8-10) in a mixture of dihydrocodeine tartrate, dl-methylephedrine hydrochloride, chlorpheniramine maleate, and ammonium chloride was prepared, and the expectorant activity was measured. Synatura was used as a positive control drug. The results according to the dosage are shown in Table 3.
실험동물로는 8주령 수컷 BALB/c 마우스를 사용하였으며, 각 시험물질을 경구투여 하고 30분 후, 페놀레드(생리 식염수에 10 %w/v용액으로 조제하여 500 mg/kg의 용량으로 투여 함)를 복강 주사하였다. 30분 후 이산화탄소 가스로 안락사 하여 기관(trachea) 전체를 절제하였다. 분리한 기관에 1 mL의 생리식염수를 가하여 세척하고, 10,000 rpm으로 5분 간 원심분리하여 얻어진 상층액을 취하여 1 N 수산화나트륨 용액을 0.1 mL 첨가한 뒤 교반한 것을 검체로 하였다. 각 검체를 마이크로플레이트 리더에 분주하여 자외선 흡광도측정기로 546 nm에서 흡광도를 측정하고, 농도별 페놀레드 표준액을 제조하여 얻은 검량선 식에 대입하여 배출된 페놀레드 양을 산출하고 객담배출능을 %로 계산하였다.8-week-old male BALB/c mice were used as experimental animals, and 30 minutes after each test substance was orally administered, phenol red (prepared as a 10% w/v solution in physiological saline and administered at a dose of 500 mg/kg) ) was injected intraperitoneally. After 30 minutes, they were euthanized with carbon dioxide gas and the entire trachea was resected. The separated organ was washed with 1 mL of physiological saline, centrifuged at 10,000 rpm for 5 minutes, and the obtained supernatant was taken, 0.1 mL of 1 N sodium hydroxide solution was added, and the sample was stirred. Each sample is dispensed into a microplate reader, the absorbance is measured at 546 nm with an ultraviolet absorbance meter, and the amount of phenol red discharged is calculated by substituting the standard solution of phenol red for each concentration into the calibration curve equation obtained, and the sputum discharge capacity is calculated as % did
(객담배출능(%)=(Ct-C0)/C0×100, (C0: 음성 대조군 Ct: 시험군)) 표 4에 시험물질과 양성대조군의 객담배출능을 나타내었다.(Sputum excretion capacity (%) = (C t -C 0 )/C 0 × 100, (C 0 : negative control C t : test group)) Table 4 shows the sputum excretion capacity of the test substance and the positive control group.
위 표에서 알 수 있는 바와 같이, 본 발명에 따른 약학 조성물은 거담효과가 매우 현저함을 알 수 있다. 구체적으로, 펠라고니움 시도이데스 추출물 단독, 또는 4종의 약리학적 활성물질 단독으로 투여한 경우보다 양자를 병용투여 하면 거담효과가 현저히 개선되었다. 또한, 단순히 펠라고니움 시도이데스 추출물이나 4종의 약리학적 활성물질의 단독 투여량을 올린다고 하여 거담효과가 상승하지 않음도 확인되었다.As can be seen from the above table, it can be seen that the pharmaceutical composition according to the present invention has a very remarkable expectorant effect. Specifically, the expectorant effect was significantly improved when both were administered in combination compared to the case of administering the Pelargonium sidoides extract alone or the four pharmacologically active substances alone. In addition, it was also confirmed that the expectorant effect did not increase simply by raising the single dose of the Pelargonium sidoides extract or the four pharmacologically active substances.
실험예 3. Caco-2 cell line을 이용한 in vitro cell permeability 시험Experimental Example 3. In vitro cell permeability test using Caco-2 cell line
Hubatcsch 등(Nature Protocols 2 (2007) 2111-2119)에 의해 기술된 바를 참고하여, 일반적으로 통용되는 Caco-2 monolayer를 이용한 약물투과도 시험방법에 따라 시험을 진행하였다. 세포주를 적당한 기간 동안 계대배양하고(passage number 20에서 40 사이의 세포를 사용), 12-well Transwell™ insert(폴리카보네이트 재질, pore size 0.4 μm)에 약 5×105 cell/cm2가 되도록 분주하여 14일 간 CO2 incubator(5 % CO2, 37 ℃)에서 배양하였다. 각 약물(디히드로코데인 주석산염, dl-메틸에페드린 염산염, 클로르페니라민 말레산염, 염화암모늄)을 0.05 M로 HBSS에 녹여 제조한 용액과 각 약물의 용액에 동일 중량으로 펠라고니움 시도이데스 추출물을 첨가하여 녹인 용액을 가지고 apical chamber에서 basolateral chamber, basolateral chamber에서 apical chamber의 두 방향 각각으로의 세포투과도 실험을 실시하였다. 샘플은 15, 30, 45, 60 90, 120, 180분의 시간대별로 채취하여 HPLC와 전위차적정법을 이용해 분석하여 약물농도를 구하고 P app 를 계산하였다. 디히드로코데인 주석산염, dl-메칠에페드린 염산염, 클로르페니라민 말레산염의 정량분석은 250 mm × 4.6 mm, 5 μm의 옥타데실실리카로 충진된 컬럼에 0.05 M 인산이수소칼륨용액 : 아세토니트릴 : 테트라히드로푸란 = 90 : 7 : 3 v/v/v 혼합액을 인산으로 pH 2.2로 조정한 것을 이동상으로 1.0 mL/분의 속도로 흘려주면서, 시액 10 μL을 주입하여 자외선 검출기로 파장 254 nm(dl-메틸에페드린 염산염, 클로르페니라민 말레산염) 및 280 nm(디히드로코데인 주석산염)에서 관찰하여 표준품과의 피크 면적비를 계산하는 방법으로 진행하였다. 염화암모늄의 경우, 영국약전 “염화암모늄 내용액제” 항의 함량시험법에 따라 시험, 검액을 100 mL 볼륨 플라스크에 담은 후 증류수로 표선하고, 이 용액을 0.1 M 질산은 시액과 전위차 적정하였다. 그 결과를 표 5에 나타내었다.Referring to the bar described by Hubatcsch et al. (Nature Protocols 2 (2007) 2111-2119), the test was conducted according to the drug permeability test method using a commonly used Caco-2 monolayer. Cell lines are subcultured for a suitable period of time (cells between passage number 20 and 40 are used), and the cell lines are dispensed so that they become about 5×10 5 cells/cm 2 in 12-well Transwell™ inserts (polycarbonate material, pore size 0.4 μm). and cultured in a CO 2 incubator (5% CO 2 , 37 °C) for 14 days. A solution prepared by dissolving each drug (dihydrocodeine tartrate, dl-methylephedrine hydrochloride, chlorpheniramine maleate, ammonium chloride) in HBSS at 0.05 M and an equal weight of Pelargonium sidoides extract were added to the solution of each drug. With the dissolved solution, cell permeability experiments were conducted in each of the two directions, from the apical chamber to the basolateral chamber and from the basolateral chamber to the apical chamber. Samples were taken at time points of 15, 30, 45, 60, 90, 120, and 180 minutes and analyzed using HPLC and potentiometric titration to determine the drug concentration and calculate P app . Quantitative analysis of dihydrocodeine tartrate, dl-methylephedrine hydrochloride, and chlorpheniramine maleate was performed on a 250 mm × 4.6 mm, 5 μm octadecyl silica column packed with 0.05 M potassium dihydrogen phosphate solution: acetonitrile: tetrahydro Furan = 90: 7: 3 v / v / v mixed solution adjusted to pH 2.2 with phosphoric acid, flowing as a mobile phase at a rate of 1.0 mL / min, injecting 10 μL of the sample solution and measuring the wavelength of 254 nm (dl-methyl Observation at 280 nm (ephedrine hydrochloride, chlorpheniramine maleate) and 280 nm (dihydrocodeine tartrate) was carried out by calculating the peak area ratio with the standard product. In the case of ammonium chloride, it was tested according to the content test method of “Ammonium chloride solution for internal use” in the British Pharmacopoeia, and the sample solution was put in a 100 mL volumetric flask, and then titrated with distilled water. The results are shown in Table 5.
(1→8~10)+ Pelargonium sidoides 11% ethanol diluted solution
(1→8~10)
(1→8~10)+ Pelargonium sidoides 11% ethanol diluted solution
(1→8~10)
(1→8~10)+ Pelargonium sidoides 11% ethanol diluted solution
(1→8~10)
(1→8~10)+ Pelargonium sidoides 11% ethanol diluted solution
(1→8~10)
이상으로부터 4종의 약리학적 활성물질의 세포투과도가 펠라고니움 시도이데스 에탄올 추출물(1→8~10)과의 병용투여에 의해서 증가됨이 확인되었다. 본 발명의 상승효과는 이와 같은 세포투과도의 증가에 따른 것으로 생각된다.From the above, it was confirmed that the cell permeability of the four pharmacologically active substances was increased by the combined administration of Pelargonium sidoides ethanol extract (1→8~10). The synergistic effect of the present invention is thought to be due to such an increase in cell permeability.
실험예 4. 임상 1상에서 Drug-Drug-Interaction (DDI) 확인시험Experimental Example 4. Drug-Drug-Interaction (DDI) confirmation test in clinical phase 1
펠라고니움 시도이데스 추출물과 4종의 약리학적 활성성분의 병용투여에 의한 인체 내 안전성을 확인하기 위하여 임상 1상 시험을 진행하였다. 시험방법은 Kotzan 등(J. Pharm. Sci. (1982) 71(8) 919-923), Rowell 등(Eur. J. Clin. Pharmacol. (1983) 25(3) 419-424), Huang 등(Eur. J. Clin. Pharmacol. (1982) 22(4) 359-365)에 의해 기술된 바를 참고하였으며, 공개, 무작위배정, 공복, 경구투여, 2군, 2기 교차시험의 형태로, 군당 15명씩 총 30명을 대상으로 수행하였다. 투약군별 펠라고니움 시도이데스 추출물과 4종의 약리학적 활성성분 및 함량은 표 6과 같다. A phase 1 clinical trial was conducted to confirm the safety in the human body by the combined administration of Pelargonium sidoides extract and 4 types of pharmacologically active ingredients. The test method is Kotzan et al. (J. Pharm. Sci. (1982) 71(8) 919-923), Rowell et al. (Eur. J. Clin. Pharmacol. (1983) 25(3) 419-424), Huang et al. Eur J. Clin Pharmacol. A total of 30 subjects were conducted for each subject. Table 6 shows Pelargonium sidoides extract and four pharmacologically active ingredients and contents for each administration group.
A군과 B군 간 약동학적 특징을 비교 및 평가하기 위해 투약예정일에 오전 8시부터 공복인 상태에서 임상시험용 의약품을 물과 함께 경구 투여한 후 72시간동안 채혈을 진행하였으며, 그 결과는 표 7과 같다. In order to compare and evaluate the pharmacokinetic characteristics between group A and group B, blood was collected for 72 hours after oral administration of the drug for clinical trials with water in an empty stomach from 8:00 am on the scheduled administration date, and the results are shown in Table 7. Same as
(Geometric mean ratio,
90% CI)geometric mean ratio
(Geometric mean ratio,
90% CI)
위 표에서 알 수 있는 바와 같이, 4종의 약리학적 활성성분을 투여한 A군과 이에 펠라고니움 시도이데스 추출물을 병용 투여한 B군 간의 디히드로코데인, dl-메틸에페드린, 클로르페니라민의 약동학적 동등성이 확인됨에 따라, 약물 상호작용이 없음을 알 수 있었다. 또한 본 임상시험에서 본 발명에 따른 의약품을 1회 이상 투약한 30명의 대상자 모두 활력징후, 12-lead 심전도, 이학적 검진 등에서 임상적으로 유의미한 소견이 관찰되지 않았는바, 펠라고니움 시도이데스 추출물과 4종의 약리학적 활성성분의 병용투여에 의한 인체 내 안전성이 확인되었다. As can be seen from the table above, the pharmacokinetics of dihydrocodeine, dl-methylephedrine, and chlorpheniramine between group A administered with four pharmacologically active ingredients and group B administered with Pelargonium sidoides extract in combination. As equivalence was confirmed, it was found that there were no drug interactions. In addition, in this clinical trial, no clinically significant findings were observed in vital signs, 12-lead electrocardiogram, physical examination, etc. of all 30 subjects who administered the drug according to the present invention at least once, and Pelargonium sidoides extract and 4 The safety in the human body was confirmed by the concomitant administration of the pharmacologically active ingredients of the species.
본 발명에 따른 약학 조성물은 소염 및 진해, 거담작용을 달성하는 효과를 나타내므로, 제약산업 및 의료현장에서 의약품으로서 이용 가능하다. Since the pharmaceutical composition according to the present invention exhibits effects of achieving anti-inflammatory, antitussive, and expectorant actions, it can be used as a medicine in the pharmaceutical industry and medical field.
Claims (4)
(1) 코데인 또는 이의 약학적으로 허용되는 유도체 또는 염;
(2) 에페드린 또는 이의 약학적으로 허용되는 유도체 또는 염;
(3) 페니라민 또는 이의 약학적으로 허용되는 유도체 또는 염;
(4) 염화암모늄A pharmaceutical composition for treating respiratory diseases comprising a pharmaceutical composition for treating respiratory diseases consisting of an extract of Pelargonium sidoides and the following four pharmacologically active substances as an active ingredient.
(1) codeine or a pharmaceutically acceptable derivative or salt thereof;
(2) ephedrine or a pharmaceutically acceptable derivative or salt thereof;
(3) pheniramine or a pharmaceutically acceptable derivative or salt thereof;
(4) Ammonium chloride
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