KR20240039252A - Azilsartan dicyclohexylamine as an angiotensin ⅱ antagonist, and pharmaceutical composition comprising the same as an active ingredient for preventing or treating cardiovascular disease - Google Patents
Azilsartan dicyclohexylamine as an angiotensin ⅱ antagonist, and pharmaceutical composition comprising the same as an active ingredient for preventing or treating cardiovascular disease Download PDFInfo
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- azilsartan
- dicyclohexylamine
- active ingredient
- cardiovascular disease
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- 239000005485 Azilsartan Substances 0.000 title claims abstract description 47
- 229960002731 azilsartan Drugs 0.000 title claims abstract description 47
- KGSXMPPBFPAXLY-UHFFFAOYSA-N azilsartan Chemical compound CCOC1=NC2=CC=CC(C(O)=O)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NOC(=O)N1 KGSXMPPBFPAXLY-UHFFFAOYSA-N 0.000 title claims abstract description 43
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 title claims abstract description 19
- 239000004480 active ingredient Substances 0.000 title claims abstract description 16
- 208000024172 Cardiovascular disease Diseases 0.000 title claims abstract description 14
- 239000002333 angiotensin II receptor antagonist Substances 0.000 title claims abstract description 9
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 9
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- OIQOAYVCKAHSEJ-UHFFFAOYSA-N 2-[2,3-bis(2-hydroxyethoxy)propoxy]ethanol;hexadecanoic acid;octadecanoic acid Chemical compound OCCOCC(OCCO)COCCO.CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O OIQOAYVCKAHSEJ-UHFFFAOYSA-N 0.000 claims description 3
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 2
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- 230000000694 effects Effects 0.000 abstract description 6
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4245—Oxadiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Abstract
본 발명은 안지오텐신 Ⅱ 길항제로서의 아질사르탄 디시클로헥실아민 및 이를 유효성분으로 하는 심혈관질환 치료 또는 예방용 약학적 조성물에 관한 것으로서, 보다 상세히는, 안지오텐신 Ⅱ 길항제로서의 하기 화학식 1로 표현되는 아질사르탄 디시클로헥실아민 화합물 및 이를 유효성분으로 포함하는 심혈관질환 치료 또는 예방용 약학적 조성물이다. 본 발명은 용해성, 안정성이 높고아 약제학적으로 우수한 물성적 특성을 가질 뿐만 아니라, 약동학적으로 아질사르탄 메독소밀 칼륨염과 동등하거나 그 이상의 효과를 나타내어, 심혈관계 질환의 예방 및/또는 치료에 유효성분으로서 유용하게 사용될 수 있다.
[화학식 1]
The present invention relates to azilsartan dicyclohexylamine as an angiotensin II antagonist and a pharmaceutical composition for treating or preventing cardiovascular disease using it as an active ingredient. More specifically, azilsartan represented by the following formula (1) as an angiotensin II antagonist: It is a dicyclohexylamine compound and a pharmaceutical composition for treating or preventing cardiovascular disease containing it as an active ingredient. The present invention not only has high solubility and stability and has excellent pharmaceutical physical properties, but also exhibits pharmacokinetic effects equal to or greater than azilsartan medoxomil potassium salt, so that it can be used for the prevention and/or treatment of cardiovascular diseases. It can be usefully used as an active ingredient.
[Formula 1]
Description
본 발명은 안지오텐신 Ⅱ 길항제로서의 아질사르탄 디시클로헥실아민 및 이를 유효성분으로 하는 심혈관질환 치료 또는 예방용 약학적 조성물에 관한 것이다.The present invention relates to azilsartan dicyclohexylamine as an angiotensin II antagonist and a pharmaceutical composition for treating or preventing cardiovascular disease using it as an active ingredient.
고혈압 치료제는 혈관 확장제와 교감 신경 억제제로 나뉘고, 혈관 확장제의 한 종류인 ARB 계열의 치료제가 전체 고혈압 치료제 처방액 중 70% 이상으로 압도적으로 시장을 점유하고 있는 추세인데, 이 중에서도, 아질사르탄 메독소밀은 동일 기전의 약물들에 비해 최저 효과/최대 효과비를 가지고 있어 24시간 혈압 조절에 유리하다는 장점을 가지고 있는 최근 주목을 받고 있다.Hypertension treatments are divided into vasodilators and sympathetic nervous system inhibitors, and ARB series treatments, a type of vasodilator, dominate the market, accounting for more than 70% of all prescriptions for hypertension treatments. Among these, azilsartan medoc. Somil has recently been attracting attention for its advantage in controlling blood pressure for 24 hours, as it has the lowest/maximum effect ratio compared to drugs with the same mechanism.
아질사르탄 메독소밀은 아래 도시한 것과 같은 구조의 칸데살탄의 화학구조를 변경한 물질로서, AT1 수용체에 강력하게 결합하고 천천히 해리하는 약리학적 특성을 가지는 물질이다.Azilsartan medoxomil is a substance that has changed the chemical structure of candesartan as shown below, and has the pharmacological property of strongly binding to AT1 receptors and slowly dissociating.
즉, 안지오텐신 Ⅱ와 AT1 수용체 간의 결합을 억제시킴으로써 혈관 수축을 일으키고, 알도스테론의 분비 작용을 억제하여 혈압을 낮추는 역할을 한다.In other words, it causes blood vessel constriction by inhibiting the binding between angiotensin II and AT1 receptors and lowers blood pressure by inhibiting the secretion of aldosterone.
아질사르탄 메독소밀은, 아질사르탄의 매우 낮은 용해도와 생체이용율 문제를 해결하기 위한 일종의 프로드럭(prodrug)으로서, 복용 후 체내에서 아질사르탄으로서 작용하고, 약리적 유효성분은 아질사르탄임은 알려져 있다(비특허문허 1 참조). Azilsartan medoxomil is a type of prodrug to solve the problems of very low solubility and bioavailability of azilsartan. It is known that after taking it, it acts as azilsartan in the body, and the pharmacologically active ingredient is azilsartan. There is (see non-patent document 1).
아질사르탄 메독소밀의 상업적으로 널리 활용되는 염의 형태는 칼륨염인 것이며, Takeda(일본)사 구로이타 다카노부 등에 의해 미국 특허등록 US 7157584 B2(특허문헌 1)에 그의 안지오텐신 II 수용체 길항제 활성이 개시되어 있다. 이것은 사람의 고혈압 치료제로서 20mg, 40mg, 및 80mg의 필름 코팅정으로 상품명 이달비정™으로 시판되고 있다.The commercially widely used salt form of azilsartan medoxomil is the potassium salt, and its angiotensin II receptor antagonist activity is disclosed in U.S. Patent Registration US 7157584 B2 (Patent Document 1) by Takanobu Kuroita et al. of Takeda (Japan). It is done. This is a treatment for high blood pressure in humans and is sold under the brand name Idalbee™ in 20mg, 40mg, and 80mg film-coated tablets.
한편, 아질사르탄 디시클로헥실아민에 대해서는 대한민국 특허등록 KR 10-2220011 B1(특허문헌 2)에서 아질사르탄 메독소밀을 합성하기 위한 중간체 화합물로서 공지된 바 있다. 대한민국 특허등록 KR 10-2220011 B1에서는, One-Pot 반응의 핵심 중간체로서 아질사탄 디사이클로헥실아민을 합성하고, 유기 용매 대신 친환경 용매로 이온성 액체와 공융용매를 사용하여 50℃ 미만에서도 반응이 가능하도록 반응성을 증가시켜 유연물질의 생성을 감소시키고, 고순도, 고수율 및 경쟁력 있는 아질사탄 메독소밀을 생산한다.Meanwhile, azilsartan dicyclohexylamine is known as an intermediate compound for synthesizing azilsartan medoxomil in Korean Patent Registration KR 10-2220011 B1 (Patent Document 2). In Korea Patent Registration KR 10-2220011 B1, azilsartan dicyclohexylamine is synthesized as a key intermediate for one-pot reaction, and the reaction is possible even under 50℃ by using ionic liquid and eutectic solvent as an eco-friendly solvent instead of organic solvent. It reduces the production of related substances by increasing reactivity and produces high purity, high yield, and competitive azilsartan medoxomil.
그러나, 대한민국 특허등록 KR 10-2220011 B1에서 밝히고 있는 것은 아질사르탄 메독소밀 합성에 과정에서 필요한 핵심 중간체 화합물로서의 아질사르탄 디시클로헥실아민일 뿐이고, 이것의 약리적 및 약동학적 유용성 등에 대해 알려진 바 없다.However, what is disclosed in the Korean patent registration KR 10-2220011 B1 is only azilsartan dicyclohexylamine as a key intermediate compound required in the process of synthesizing azilsartan medoxomil, and nothing is known about its pharmacological and pharmacokinetic usefulness. .
아울러, 비특허문헌 1, 및 특허문헌 1 내지 2 내용 전부는, 본 발명의 내용과 배치되지 않는 범위 내에서, 본 발명의 명세서의 내용으로서 인용·합체된다.In addition, the entire contents of Non-Patent Document 1 and Patent Documents 1 to 2 are cited and incorporated as the content of the specification of the present invention to the extent that they do not conflict with the content of the present invention.
약제학적 제제로부터 유효성분의 용해가 너무 느린 경우, 유효성분의 혈액농도는 효과적인 수준에 도달할 수 없으며, 기대되는 효과를 충분하게 나타낼 수 없으므로, 유효성분의 용해특성 극히 중요하다.If the dissolution of the active ingredient from the pharmaceutical preparation is too slow, the blood concentration of the active ingredient cannot reach an effective level and the expected effect cannot be sufficiently shown, so the dissolution characteristics of the active ingredient are extremely important.
또한, 유효성분이 시간경과에 따라 용이하게 분해하거나 변성되는 경우, 약제학적 제제는 효과 및 안정성에 문제가 발생하므로, 유효성분의 보관 안정성도 매우 중요하다.In addition, if the active ingredient is easily decomposed or denatured over time, problems may arise in the effectiveness and stability of the pharmaceutical preparation, so storage stability of the active ingredient is also very important.
이에 따라, 본 발명은, 용해성, 안정성 등 약제학적으로 우수한 물성적 특성을 가질 뿐만 아니라, 이와 동시에, 약동학적으로 아질사르탄 메독소밀 칼륨염과 동등하거나 그 이상의 효과를 갖는 신규한 아질사르탄염 화합물을 제공하고자 한다.Accordingly, the present invention provides a novel azilsartan salt compound that not only has excellent pharmaceutical physical properties such as solubility and stability, but at the same time has pharmacokinetic effects equivalent to or better than azilsartan medoxoyl potassium salt. We would like to provide.
본 발명은 상술한 종래기술의 문제점을 해결하기 위해 안출된 것으로서,The present invention was devised to solve the problems of the prior art described above,
안지오텐신 Ⅱ 길항제로서의 하기 화학식 1로 표현되는 아질사르탄 디시클로헥실아민 화합물을 제공한다:Provided is an azilsartan dicyclohexylamine compound represented by the following formula (1) as an angiotensin II antagonist:
[화학식 1][Formula 1]
또한, 본 발명의 화학식 1로 표시되는 아질사르탄 디시클로헥실아민을 유효성분으로 포함하는 심혈관질환 치료 또는 예방용 약학적 조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for treating or preventing cardiovascular disease containing azilsartan dicyclohexylamine represented by Formula 1 as an active ingredient.
본 발명은 용해성, 안정성이 높아 약제학적으로 우수한 물성적 특성을 가질 뿐만 아니라, 약동학적으로 아질사르탄 메독소밀 칼륨염과 동등하거나 그 이상의 효과를 나타내어, 심혈관계 질환의 예방 및/또는 치료에 유효성분으로서 유용하게 사용될 수 있다.The present invention not only has excellent pharmaceutical physical properties due to its high solubility and stability, but also exhibits pharmacokinetic effects equal to or greater than azilsartan medoxomil potassium salt, making it effective in preventing and/or treating cardiovascular diseases. It can be usefully used as an ingredient.
도 1은, 본 발명 렛트 약동학 시험결과를 나타낸 그래프이다.
도 2는, 본 발명 저장 안정성 시험 결과를 나타낸 그래프이다(X축은 시간으로 단위는 주(week)이고, Y축은 유연물질로 %단위이다).Figure 1 is a graph showing the results of a rat pharmacokinetic test of the present invention.
Figure 2 is a graph showing the results of the storage stability test of the present invention (the
이하, 본 발명에 대해서 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명의 일측면은,One aspect of the present invention is,
안지오텐신 Ⅱ 길항제로서의 하기 화학식 1로 표현되는 아질사르탄 디시클로헥실아민 화합물이다:Azilsartan dicyclohexylamine compound represented by the following formula (1) as an angiotensin II antagonist:
[화학식 1][Formula 1]
특허문헌 2(KR 10-2220011 B1)에 개시된 바와 같이, 아질사르탄 디시클로헥실아민은 아질사르탄 메독소밀을 합성하기 위한 핵심 중간체 화합물로서는 알려진 바 있지만, 안지오텐신 Ⅱ 길항제로서의 약리·약동학적 내용에 대해서 알려진 바 없다. 이에 본 발명자들은 아질사르탄 디시클로헥실아민이 중간체 화합물로서 유용할 뿐 아니라, 그 자체로 아질사르탄에 비해 안정성이 높으며, 약리적 효과가 우수함을 발견하고 본 발명을 완성하기에 이르렀다. 아질사르탄 디시클로헥실아민의 안정성 및 약리적 특성 등에 대해서는 후술할 실시예를 통해 이해할 수 있을 것이다.As disclosed in Patent Document 2 (KR 10-2220011 B1), azilsartan dicyclohexylamine is known as a key intermediate compound for synthesizing azilsartan medoxomil, but its pharmacology and pharmacokinetics as an angiotensin II antagonist are unknown. Nothing is known about it. Accordingly, the present inventors discovered that azilsartan dicyclohexylamine is not only useful as an intermediate compound, but also has higher stability and superior pharmacological effects than azilsartan, and completed the present invention. The stability and pharmacological properties of azilsartan dicyclohexylamine will be understood through examples to be described later.
또한, 특허문헌 2(KR 10-2220011 B1)에 개시된 바와 같이, 아질사르탄 디시클로헥실아민의 합성 및 제조방법은 알려져 있으므로, 이에 대한 구체적인 내용은 공지된 내용을 참조하여 이해할 수 있고, 이에 대한 설명은 생략한다.In addition, as disclosed in Patent Document 2 (KR 10-2220011 B1), the synthesis and production method of azilsartan dicyclohexylamine is known, and specific details thereof can be understood by referring to the known contents. The explanation is omitted.
또한, 본 발명의 다른 측면은, 상기 화학식 1로 표시되는 아질사르탄 디시클로헥실아민을 유효성분으로 포함하는 심혈관질환 치료 또는 예방용 약학적 조성물이다.In addition, another aspect of the present invention is a pharmaceutical composition for treating or preventing cardiovascular disease containing azilsartan dicyclohexylamine represented by Formula 1 above as an active ingredient.
본 발명의 조성물은 투여를 위해서 상기 유효성분 이외에 추가적으로 약제학적으로 허용 가능한 담체를 1종 이상 포함하여 제조할 수 있다.For administration, the composition of the present invention may be prepared by including one or more pharmaceutically acceptable carriers in addition to the above active ingredients.
약학적으로 허용 가능한 담체는 식염수, 멸균수, 링거액 완충 식염수, 덱스트로즈용액, 말토덱스트린용액, 글리세롤, 에탄올, 및 이들 성분 중 1 성분 이상을 혼합하여 사용할 수 있으며, 필요에 따라 항산화제, 완충제, 정균제, 등 다른 통상의 첨가제를 첨가할 수 있다. Pharmaceutically acceptable carriers may be saline solution, sterilized water, Ringer's buffered saline solution, dextrose solution, maltodextrin solution, glycerol, ethanol, and a mixture of one or more of these ingredients. Antioxidants and buffers may be added as needed. , bacteriostatic agents, etc., other common additives can be added.
또한 희석제, 분산제, 계면활성제, 결합제, 및 윤활제를 부가적으로 첨가하여 수용액 현탁액, 유탁액과 같은 주사용 제형, 환약, 캡슐제, 과립, 또는 정제로 제제화 할 수 있다.Additionally, diluents, dispersants, surfactants, binders, and lubricants can be additionally added to formulate injectable formulations such as aqueous suspensions and emulsions, pills, capsules, granules, or tablets.
본 발명의 조성물은 목적하는 방법에 따라 경구 투여하거나 비경구 투여(예를 들어 정맥 내, 피하, 복강 내 또는 국소에 적용) 할 수 있으며 투여량은 환자의 체중, 성별, 연령, 건강상태, 식이, 투여시간, 투여방법, 배설율 및 질환의 정도에 따라 그 범위가 다양하다. 경구 투여를 위한 액체복용형태들은 물과 같은 업계에서 일반적으로 사용되는 불활성 희석제를 포함하는 약물학적으로 수용가능한 에멀션, 용액, 현탁액, 시럽 및 엘릭시르를 포함할 수 있다. 그러한 조성물들은 습윤제, 에멀션 및 현탁제와 같은 보조약 및 감미료, 향료 및 이와 유사한 것들을 포함할 수 있다.The composition of the present invention can be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically) depending on the desired method, and the dosage depends on the patient's weight, gender, age, health condition, and diet. , the range varies depending on the administration time, administration method, excretion rate, and disease severity. Liquid dosage forms for oral administration can include pharmacologically acceptable emulsions, solutions, suspensions, syrups and elixirs, including inert diluents commonly used in the industry such as water. Such compositions may contain adjuvants such as wetting agents, emulsions and suspending agents, as well as sweeteners, flavors and the like.
본 발명의 아질사르탄 디시클로헥실아민 투여되어야만 하는 유효성분의 일일 투여량은 단일 투여량이 될 수 있거나 하루에 걸쳐 투여되는 몇 번의 더 작은 복용량으로 나뉜 효과적인 양이 될 수도 있다. 통상, 치료 또는 예방 목적의 전체 하루 복용량은 바람직하게는 0.5~500 mg이 될 수 있고, 바람직하게는 약 1mg~100mg, 더 바람직하게는 10mg~80mg, 보다 더 바람직하게는 20mg~80mg일 수 있고, 하루 일회 내지는 수 회에 분할 투여할 수 있다.Azilsartan dicyclohexylamine of the present invention The daily dosage of the active ingredient to be administered may be a single dose or the effective amount may be divided into several smaller doses administered over the course of the day. Typically, the total daily dose for therapeutic or prophylactic purposes may preferably be 0.5 to 500 mg, preferably about 1 mg to 100 mg, more preferably 10 mg to 80 mg, even more preferably 20 mg to 80 mg, , can be administered once a day or in divided doses.
또한, 본 발명의 조성물은 단독 또는 호르몬 치료, 다른 고혈압 약물 제제 치료, 당뇨병(예를 들면 DPP-IV, SGLT2 등 약물-A Glyflozines) 및 고지혈증 치료제(예를 들면 아토바스타틴, 로슈바스타틴, 피타바스타틴 등 스타틴류) 및 생물학적 반응 조절제를 사용하는 약제와 2제 내지는 3제 복합제로 만들어 사용할 수 있다.In addition, the composition of the present invention can be used alone or for hormonal treatment, treatment with other antihypertensive drugs, diabetes (e.g. DPP-IV, SGLT2, etc. Drug-A Glyflozines) and hyperlipidemia treatment (e.g. atorvastatin, rosuvastatin, pitta). It can be used as a combination of two or three drugs with drugs using statins (vastatin, etc.) and biological response regulators.
특히, 심혈관질환을 치료하기 위해 사용되는 화합물은, ACE 저해제, HMGCoA 환원저해제, 베타- 아드레날린 차단제, 칼슘채널차단제, 이뇨제, 아스피린과 같은 항혈전제, 니트로화 ACE 저해제, 니트로화 HMGCoA 환원저해제, 니트로화 베타- 아드레날린 차단제, 니트로화 아스피린 및 니트로화 이뇨제로 구성된 그룹으로 선택되는 1종 이상의 약물과 병용투여될 수도 있다:In particular, compounds used to treat cardiovascular diseases include ACE inhibitors, HMGCoA reduction inhibitors, beta-adrenergic blockers, calcium channel blockers, diuretics, antithrombotic agents such as aspirin, nitrated ACE inhibitors, nitrated HMGCoA reduction inhibitors, nitro It may also be administered in combination with one or more drugs selected from the group consisting of nitrated beta-adrenergic blockers, nitrated aspirin and nitrated diuretics:
상기 심혈관질환은, 심부전, 심근경색증, 허혈성 뇌졸중, 동맥경화증, 안구 및 폐고혈압증, 고혈압증, 당뇨병성 신병증, 말초혈관질환, 좌심실기능장애 및 비후, 간섬유증, 간문고혈압 등을 비제한적으로 예시할 수 있다.The above cardiovascular diseases include, but are not limited to, heart failure, myocardial infarction, ischemic stroke, arteriosclerosis, ocular and pulmonary hypertension, hypertension, diabetic nephropathy, peripheral vascular disease, left ventricular dysfunction and hypertrophy, liver fibrosis, and portal hypertension. You can.
이하, 본 발명에 대하여 실시예를 들어 보다 더 상세히 설명한다. 다만, 이하의 실시예는 발명의 상세한 설명을 위한 것일뿐 이에 의해 권리범위를 제한하려는 의도가 아님을 분명히 해둔다.Hereinafter, the present invention will be described in more detail through examples. However, it should be made clear that the following examples are only for detailed description of the invention and are not intended to limit the scope of rights.
실시예Example
1. 용해도 평가1. Solubility evaluation
아질사르탄 무염(azilsartan free base), 아질사르탄 메독소밀 칼륨염(azilsartan medoxomil potassium), 및 아질사르탄 디시클로헥실아민염(azilsartan dicyclohexylamine)의 3가지 주성분의 pH에 따른 용해도 평가를 진행하였다.Solubility evaluation was conducted according to pH of the three main components: azilsartan free base, azilsartan medoxomil potassium, and azilsartan dicyclohexylamine.
결과는 하기 표 1과 같았다.The results were as shown in Table 1 below.
(AZ)Azilsartan unsalted
(AZ)
(AZMk)Azilsartan medoxomil potassium salt
(AZMk)
디시클로헥실아민염
(AZD)Azilsartan
Dicyclohexylamine salt
(AZD)
시험결과 세 주성분의 pH에 따른 용해도는 산성조건인 pH1.2, pH4.0에서 AZ < AZD 순으로 높게 나왔고, pH6.8에선 AZMk < AZ < AZD, 물에선 AZ < AZMk < AZD 순으로 용해도 결과를 보였다.As a result of the test, the solubility of the three main components according to pH was high in the order of AZ < AZD under acidic conditions of pH 1.2 and pH 4.0, and at pH 6.8, AZMk < AZ < AZD, and in water, AZ < AZMk < AZD. showed.
아질사르탄 세가지 주성분은 pH가 용해도에 미치는 영향이 다른 가운데, 특히 높은 pH에서 아질사르탄 디시클로헥실아민염의 용해도가 높은 것으로 나타났다. While the three main components of azilsartan have different effects on solubility of pH, the solubility of azilsartan dicyclohexylamine salt was found to be particularly high at high pH.
2. 2. 렛트let 약동학 시험(Rat Pharmacokinetic test (Rat PharmacokineticsPharmacokinetics ))
(1) 시험방법(Pharmacokinetics-design)(1) Test method (Pharmacokinetics-design)
* 동물 : Rat (male, 8주령)* Animal: Rat (male, 8 weeks old)
-투여 : 경구투여 (투여 전 16시간 절식) -Dosage: Oral administration (fast for 16 hours before administration)
-채혈방법 : 경정맥 채혈-Blood collection method: Jugular vein blood collection
-채혈 포인트 : 0.082, 0.25, 0.5, 1, 2, 4, 8, 24 hr-Blood collection points: 0.082, 0.25, 0.5, 1, 2, 4, 8, 24 hr
(2) Pharmacokinetics 결과(2) Pharmacokinetics results
결과는 하기 표 3과 같았다.The results were as shown in Table 3 below.
상기 표 3에서 확인할 수 있는 바와 같이, Cmax 및 AUC는 각각 AZ < AZMk < AZD 순으로 높게 나왔으며, 이에 따라 생체이용률도 이와 같은 순으로 높게 나왔다. 참고로 AZ 대비한 상대 생체이용률은 AZMK가 약 1.3이고, AZD가 약 1.7로, AZD가 AZMK에 비해서도 대략 30% 정도 생체이용률이 높음을 확인되었다.As can be seen in Table 3, Cmax and AUC were high in the order AZ < AZMk < AZD, respectively, and bioavailability was also high in the same order. For reference, the relative bioavailability compared to AZ is about 1.3 for AZMK and about 1.7 for AZD, and it was confirmed that AZD has approximately 30% higher bioavailability than AZMK.
이에 따라, 아질사르탄의 생체이용률은 생체 투과정도 요인보다는 용해도에 따라 약물노출이 달라질 것으로 예상되며, 또한, 아질사르탄 자체가 약리적 효과가 나타나는 유효성분이라는 점을 고려할 때, 아질사르탄 생체이용률이 높은 AZD가 약리적 효과 역시도 우수함을 확인할 수 있다.Accordingly, the bioavailability of azilsartan is expected to vary depending on the drug exposure depending on the solubility rather than the biopermeability factor, and considering that azilsartan itself is an active ingredient that exhibits pharmacological effects, the bioavailability of azilsartan It can be seen that this high AZD also has excellent pharmacological effects.
아울러, 해당 전임상시험에서 특별히 독성이나 이상 징후는 관찰되지 않았다.In addition, no particular toxicity or abnormal signs were observed in the preclinical test.
3. 안정성 시험3. Stability test
실온(RT) 및 65℃(60%RH)에서, 아질사르탄(AZ) 및 아질사르탄 디시클로헥실아민(AZD)를 대상으로 2주 동안 저장안정성 시험을 시험을 시행하였다.Storage stability tests were conducted on azilsartan (AZ) and azilsartan dicyclohexylamine (AZD) for two weeks at room temperature (RT) and 65°C (60%RH).
결과는 도 2와 같았고, 도 2에서 확인할 수 있는 바와 같이, 아질사르탄 디시클로헥실아민(AZD)은 실온에서 아질사르탄에 비해 높은 안정성을 나타낼 뿐 아니라, 고온에서는 상대적으로 더 큰 안정성을 나타냈는 바, 매우 안정성이 높은 물질임을 확인할 수 있었다.The results were the same as in Figure 2, and as can be seen in Figure 2, azilsartan dicyclohexylamine (AZD) not only shows higher stability than azilsartan at room temperature, but also shows relatively greater stability at high temperatures. As a result, it was confirmed that it was a very stable material.
4. 부형제 배합적합성 시험4. Excipient compatibility test
(1) 시험방법(1) Test method
(2) 검체(2) Sample
(3) 시험결과(3) Test results
대표적으로 사용되는 가용화제의 배합적합성 시험결과 아질사르탄 free base는 폴리비닐피롤리돈, Eudragit®E PO, 라브라필을 제외한 부형제와 배합상태에서 적합한 결과를 보이며, 아질사르탄 디시클로헥실아민은 라우릴황산나트륨과 라브라필을 제외한 부형제와 배합상태에서 적합한 결과를 보이므로 제형설계 및 부형제 선정을 고려할 시 우선적으로 선택이 가능한 부형제를 선별할 수 있는 자료로 활용할 수 있다고 보여진다.As a result of testing the compatibility of commonly used solubilizers, azilsartan free base shows suitable results when mixed with excipients excluding polyvinylpyrrolidone, Eudragit®E PO, and Labrafil, and azilsartan dicyclohexylamine Since it shows suitable results when mixed with excipients except sodium lauryl sulfate and Labrafil, it can be used as data to select excipients that can be selected first when considering formulation design and excipient selection.
Claims (4)
[화학식 1]
Azilsartan dicyclohexylamine compound represented by the following formula (1) as an angiotensin II antagonist:
[Formula 1]
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| US7157584B2 (en) | 2004-02-25 | 2007-01-02 | Takeda Pharmaceutical Company Limited | Benzimidazole derivative and use thereof |
| KR102220011B1 (en) | 2020-05-15 | 2021-02-25 | 대봉엘에스 주식회사 | Method for preparing azilsartan with environment-friendly solvent, and key intermediate compounds thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7157584B2 (en) | 2004-02-25 | 2007-01-02 | Takeda Pharmaceutical Company Limited | Benzimidazole derivative and use thereof |
| KR102220011B1 (en) | 2020-05-15 | 2021-02-25 | 대봉엘에스 주식회사 | Method for preparing azilsartan with environment-friendly solvent, and key intermediate compounds thereof |
Non-Patent Citations (1)
| Title |
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| "Azilsartan: Current Evidence and Perspectives in Management of Hypertension", Hindawi International Journal of Hypertension Volume 2019, Article ID 1824621, 8pages. |
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