KR20050025274A - A pharmaceutical composition for hepatitis - Google Patents
A pharmaceutical composition for hepatitis Download PDFInfo
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- KR20050025274A KR20050025274A KR1020040066497A KR20040066497A KR20050025274A KR 20050025274 A KR20050025274 A KR 20050025274A KR 1020040066497 A KR1020040066497 A KR 1020040066497A KR 20040066497 A KR20040066497 A KR 20040066497A KR 20050025274 A KR20050025274 A KR 20050025274A
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- South Korea
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- pharmaceutical composition
- hepatitis
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 30
- 208000006454 hepatitis Diseases 0.000 title claims abstract description 29
- 231100000283 hepatitis Toxicity 0.000 title claims abstract description 24
- BKRIRZXWWALTPU-UHFFFAOYSA-N methyl 4-(4-methoxycarbonylphenyl)benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1C1=CC=C(C(=O)OC)C=C1 BKRIRZXWWALTPU-UHFFFAOYSA-N 0.000 claims abstract description 54
- RUDATBOHQWOJDD-UHFFFAOYSA-N (3beta,5beta,7alpha)-3,7-Dihydroxycholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 RUDATBOHQWOJDD-UHFFFAOYSA-N 0.000 claims abstract description 40
- RUDATBOHQWOJDD-UZVSRGJWSA-N ursodeoxycholic acid Chemical compound C([C@H]1C[C@@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-UZVSRGJWSA-N 0.000 claims abstract description 40
- 229960001661 ursodiol Drugs 0.000 claims abstract description 39
- 229960001280 amantadine hydrochloride Drugs 0.000 claims description 33
- WOLHOYHSEKDWQH-UHFFFAOYSA-N amantadine hydrochloride Chemical compound [Cl-].C1C(C2)CC3CC2CC1([NH3+])C3 WOLHOYHSEKDWQH-UHFFFAOYSA-N 0.000 claims description 33
- 239000000126 substance Substances 0.000 claims description 4
- 239000000203 mixture Substances 0.000 abstract description 10
- 230000000694 effects Effects 0.000 abstract description 9
- 210000004185 liver Anatomy 0.000 abstract description 8
- 206010008909 Chronic Hepatitis Diseases 0.000 abstract description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 abstract description 4
- 150000001875 compounds Chemical class 0.000 abstract 2
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 abstract 1
- 229960003805 amantadine Drugs 0.000 abstract 1
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- 230000001988 toxicity Effects 0.000 abstract 1
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 10
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- 238000002474 experimental method Methods 0.000 description 7
- 208000002672 hepatitis B Diseases 0.000 description 7
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- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 4
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- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
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- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
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- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
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- QAPSNMNOIOSXSQ-YNEHKIRRSA-N 1-[(2r,4s,5r)-4-[tert-butyl(dimethyl)silyl]oxy-5-(hydroxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O[Si](C)(C)C(C)(C)C)C1 QAPSNMNOIOSXSQ-YNEHKIRRSA-N 0.000 description 1
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 1
- LHEJDBBHZGISGW-UHFFFAOYSA-N 5-fluoro-3-(3-oxo-1h-2-benzofuran-1-yl)-1h-pyrimidine-2,4-dione Chemical compound O=C1C(F)=CNC(=O)N1C1C2=CC=CC=C2C(=O)O1 LHEJDBBHZGISGW-UHFFFAOYSA-N 0.000 description 1
- 229930195730 Aflatoxin Natural products 0.000 description 1
- XWIYFDMXXLINPU-UHFFFAOYSA-N Aflatoxin G Chemical compound O=C1OCCC2=C1C(=O)OC1=C2C(OC)=CC2=C1C1C=COC1O2 XWIYFDMXXLINPU-UHFFFAOYSA-N 0.000 description 1
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- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 1
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- HTBWBWWADZJXID-UHFFFAOYSA-N gamma-schisandrin Natural products COC1=C2C=3C(OC)=C4OCOC4=CC=3CC(C)C(C)CC2=CC2=C1OCO2 HTBWBWWADZJXID-UHFFFAOYSA-N 0.000 description 1
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- OHDXDNUPVVYWOV-UHFFFAOYSA-N n-methyl-1-(2-naphthalen-1-ylsulfanylphenyl)methanamine Chemical compound CNCC1=CC=CC=C1SC1=CC=CC2=CC=CC=C12 OHDXDNUPVVYWOV-UHFFFAOYSA-N 0.000 description 1
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- 229960000329 ribavirin Drugs 0.000 description 1
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 1
- 201000005404 rubella Diseases 0.000 description 1
- SEBFKMXJBCUCAI-HKTJVKLFSA-N silibinin Chemical compound C1=C(O)C(OC)=CC([C@@H]2[C@H](OC3=CC=C(C=C3O2)[C@@H]2[C@H](C(=O)C3=C(O)C=C(O)C=C3O2)O)CO)=C1 SEBFKMXJBCUCAI-HKTJVKLFSA-N 0.000 description 1
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Classifications
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
- A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
-
- 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
- A61K31/13—Amines
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/20—Elemental chlorine; Inorganic compounds releasing chlorine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2121/00—Preparations for use in therapy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Virology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Gastroenterology & Hepatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Inorganic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
본 발명은 간염 치료용 약제조성물에 관한 것으로, 더욱 상세하게는 비페닐 디메칠 디카르복실레이트(BDD)와 염산 아만타딘을 일정량 함유시켜 얻은 만성 B형 및 C형 간염 치료제로서 유용한 약제조성물에 관한 것이다.The present invention relates to a pharmaceutical composition for treating hepatitis, and more particularly, to a pharmaceutical composition useful as a therapeutic agent for chronic hepatitis B and C obtained by containing a certain amount of biphenyl dimethyl dicarboxylate (BDD) and amantadine hydrochloride. .
만성 B형 바이러스성 간염(HBV) 및 C형 바이러스성 간염(HCV)은 세계적으로 널리 퍼져있는 질환으로서 특히 아시아에서 만성 B형 간염 발생율이 세계 다른 지역에 비하여 훨씬 많다. 만성 B형 바이러스성 간염(HBV) 및 C형 바이러스성 간염(HCV)의 감염은 일부 환자의 경우 5 ∼ 20년의 감염과정 후 간경변증으로 진행될 수 있으며 또한 일차 간세포암의 병인과 연관성이 매우 깊다. 오늘날 많은 약제가 만성 HBV 및 HCV 감염의 치료에 사용되고 있더라도 간염치료제로서 만족스럽지 못하다. 현재까지 인터페론-2α가 단일요법제 또는 리바비린(ribavirin)과의 병용요법제로서 만성 HBV 및 HCV 감염의 치료에 유일하게 일반적으로 사용되는 약제이다. 그러나 인터페론-2α요법의 효과는 만성 HBV 환자에서 30% 이하이며 오히려 부작용이 높다.Chronic hepatitis B (HBV) and viral hepatitis C (HCV) are widespread in the world, and the incidence of chronic hepatitis B is particularly high in Asia, especially in other parts of the world. Chronic hepatitis B (HBV) and hepatitis C (HCV) infections can progress to cirrhosis after 5-20 years of infection in some patients and are highly associated with the pathogenesis of primary hepatocellular carcinoma. Although many drugs today are being used to treat chronic HBV and HCV infections, they are not satisfactory as hepatitis agents. To date, interferon-2α is the only commonly used agent for the treatment of chronic HBV and HCV infection as a monotherapy or combination therapy with ribavirin. However, the effectiveness of interferon-2α therapy is less than 30% in patients with chronic HBV and rather high side effects.
따라서, 최근에 효과가 높은 지속형 Peg-인터페론-2α가 개발되어 만성 HCV의 치료에 사용되었으나 아직 환자에게 비용부담이 매우 크다. 인터페론외에 라미부딘(lamivudine)과 같은 뉴클레오사이드 동족체가 개발되었으나 라미부딘의 사용 중단후 높은 리바운드작용으로 지속적 치료효과는 제한되어 있으며 더욱이 라미부딘은 야생형 B형 간염바이러스의 변이를 유발하여 약물저항성을 일으킨다. 이외에 글리시진 및 실리마린과 같은 몇가지 종류의 간보호제도 역시 HBV의 치료에 사용되었으나 이들 약물은 바이러스복제에 대한 억제효과가 없다. 그러므로 만성 HBV 및 HCV의 치료에 새로운 전략이 필요하다.Therefore, recently, high-efficiency long-acting Peg-interferon-2α has been developed and used for the treatment of chronic HCV, but the cost is still very high for the patient. Nucleoside homologues such as lamivudine have been developed in addition to interferon, but the continuous treatment effect is limited due to high rebound after discontinuation of lamivudine. Furthermore, lamivudine causes drug resistance by causing mutations in wild-type hepatitis B virus. In addition, several types of hepatoprotectants, such as glycidine and silymarin, have also been used to treat HBV, but these drugs have no inhibitory effect on viral replication. Therefore, new strategies are needed for the treatment of chronic HBV and HCV.
따라서 병용요법은 만성 HBV 및 HCV의 치료에 새로운 동향으로 대두되었다. Combination therapy has thus emerged as a new trend in the treatment of chronic HBV and HCV.
한편, 종래에 다음 화학식 1로 표시되는 비페닐 디메칠 디카르복실레이트(BDD)는 만성 간염치료제로서 잘 알려져 있다(미국특허 제4,868,207호).On the other hand, biphenyl dimethyl dicarboxylate (BDD) represented by the following general formula (1) is well known as a chronic hepatitis therapeutic agent (US Patent No. 4,868,207).
상기 비페닐 디메칠 디카르복실레이트(BDD)는 본래 중국 의학과학원 약물연구소의 과학자들에 의해 개발된 것으로 천연 생약재인 오미자로부터 단리된 Schizandrin C의 합성 동족체이다. 1979 이래 BDD는 HBV의 치료제로 사용되었으며 1983년부터는 중국에서 만성 HBV 및 약물유발성 간연의 치료에 널리 사용되었다. 한편, 1990년대부터는 에집트, 인도네시아, 베트남 및 한국에서 만성 HBV 및 HCV 환자의 치료에 응용되어 왔다. BDD의 임상효과는 부작용없이 혈청 GPT를 크게 저하시키는 것으로 표현될 수 있다. 최근에 BDD의 높은 용량은 환자에서 양성 HBeAg 및 HBV-DNA를 음성으로 전환시키는 것으로 지적된 바와같이 HBV복제를 억제할 수 있음이 보고되었다.The biphenyl dimethyl dicarboxylate (BDD), originally developed by scientists at the Institute of Drug Research, is a synthetic homologue of Schizandrin C isolated from the natural herb, Schisandra chinensis. Since 1979, BDD has been used as a treatment for HBV, and since 1983, it has been widely used in the treatment of chronic HBV and drug-induced edema. Meanwhile, since the 1990s, it has been applied to the treatment of chronic HBV and HCV patients in Egypt, Indonesia, Vietnam and Korea. The clinical effect of BDD can be expressed as significantly lowering serum GPT without side effects. It has recently been reported that high doses of BDD can inhibit HBV replication, as indicated by the conversion of positive HBeAg and HBV-DNA to negative in patients.
BDD의 약리작용은 (1) 세포막의 안정화를 통해서 B.C.G 플러스 리포폴리사카라이드(LPS)와 같은 간독소 및 생물학적 독소에 의한 손상에 대한 간세포보호, (2) 인체 HBV 게놈과 일치된 인체 간혈종인 2.2.15 cell line의 HBV 복제의 억제, (3) 간의 해독메카니즘에 중요한 역할을 하는 간 마이크로소말 시토콤(microsomal cytochome) P-450의 유발을 통해서 간의 해독능력의 증가, (4) 아플라톡신(aflatoxin) B1과 같은 화학적 발암원(carcinogens)의 돌연변이유도의 길항 등이다.The pharmacological action of BDD is: (1) hepatocellular protection against damage caused by hepatotoxic and biological toxins such as BCG plus lipopolysaccharide (LPS) through stabilization of the cell membrane, and (2) human hepatocellular carcinoma consistent with the human HBV genome. 2.2.15 inhibition of HBV replication in the cell line, (3) increased liver detoxification through the induction of liver microsomal cytochome P-450, which plays an important role in liver detoxification mechanisms, and (4) aflatoxin Antagonists of mutagenesis of chemical carcinogens such as B1.
또한, 다음 화학식 2로 표시되는 염산 아만타딘은 항바이러스제로서 알려져 있다.In addition, amantadine hydrochloride represented by the following formula (2) is known as an antiviral agent.
상기 염산 아만타딘은 본래 인플루엔자 바이러스의 치료 및 예방에 사용된 합성 항바이러스제로서 나중에 파킨슨병에도 사용되었으며 최근에 만성 HCV에 응용되었다. 즉, 염산 아만타딘은 인터페론과 병용요법으로 하여 만성 C형 간염의 치료목적으로 사용이 시도된 바 있으나, 지속적 반응을 나타내는 환자가 1/3에 불과하고 현저한 부작용 때문에 이러한 목적으로 그 사용이 실용화되지 못하였다.Amantadine hydrochloride is a synthetic antiviral agent originally used for the treatment and prevention of influenza virus, which was later used in Parkinson's disease and has recently been applied to chronic HCV. In other words, amantadine hydrochloride has been attempted to be used for the treatment of chronic hepatitis C in combination with interferon, but only one-third of patients with persistent reactions have not been put to practical use for this purpose. It was.
염산 아만타딘의 약리작용은 (1) 항바이러스제로서 특정한 믹소-바이러스(myxo-virus), 즉 인플루엔자(influenza), 루벨라(rubella) 및 일부 종양바이러스의 복제 억제, (2) 파킨슨병 치료제로서 약간의 항무스카린효과로 중추 신경절로부터 도파민의 방출을 일으키는 것 등이다.The pharmacological action of amantadine hydrochloride is (1) as an antiviral agent that inhibits the replication of certain myxo-viruses, namely influenza, rubella and some tumor viruses, and (2) as a therapeutic for Parkinson's disease. Its anti-muscarinic effect causes the release of dopamine from the central ganglion.
한편, 1990년대에 염산 아만타딘은 단독용법 또는 다른 약물과의 병용요법으로 여러 연구자들에 의해 만성 HCV의 치료에 응용이 시도되었으나 결과는 좋지 않았다. 인터페론으로 치료를 실패한 만성 HCV 환자에 염산 아마타딘의 효과 및 안전성은 염산 아만타딘으로 치료받은 환자의 27%는 6개월 후 ALT의 정상화를 보인 반면 18%는 염산 아만타딘의 투약을 중단하고 6개월 후 PCR에 의한 HCV RNA의 상실로 지속적 반응을 보인 것으로 보고되었다.On the other hand, in the 1990s, amantadine hydrochloride was used alone or in combination with other drugs, but several researchers tried to treat chronic HCV, but the results were not good. The efficacy and safety of amartadine hydrochloride in patients with chronic HCV who failed treatment with interferon showed normalization of ALT after 6 months in patients treated with amantadine hydrochloride, while 18% stopped amantadine hydrochloride in 6 months after PCR. It has been reported that there was a sustained response due to the loss of HCV RNA by.
그리고, 다음 화학식 3으로 표시되는 우르소데옥시콜린산(UDCA)은 이담제로서 알려져 있다. In addition, ursodeoxycholic acid (UDCA) represented by the following formula (3) is known as an antagonist.
상기와 같이 만성 HBV 및 HCV의 치료를 위해 단일요법 및 병용요법 등 많은 연구가 시도되어지고 있으나, 아직까지 만족스럽지 못한 실정이다.As described above, many studies, such as monotherapy and combination therapy, have been attempted for the treatment of chronic HBV and HCV, but are not satisfactory.
따라서, 본 발명은 종래에 만성 HBV 및 HCV의 치료에 사용된 약제가 대부분 만족스럽지 못한 점을 감안하여 이를 극복하기 위한 연구를 거듭한 결과 종래에 만성 간염 치료제로서 사용된 상기 화학식 1로 표시되는 비페닐 디메칠 디카르복실레이트(BDD)와 항바이러스제로서 사용된 상기 화학식 2로 표시되는 염산 아만타딘 및/또는 이담제로서 사용된 상기 화학식 3의 우르소데옥시콜린산(UDCA)을 배합한 새로운 약제조성물을 제조하여, 만성 B형 및 C형 간염바이러스 감염(HBV 및 HCV) 획기적인 임상개선을 보임을 확인하여 본 발명을 완성하였다. Therefore, the present invention has been repeated in order to overcome this in consideration of the fact that the conventionally used drugs for the treatment of chronic HBV and HCV are mostly unsatisfactory, the ratio represented by the formula (1) used as a conventional treatment for chronic hepatitis A new pharmaceutical composition combining phenyl dimethyl dicarboxylate (BDD) and amantadine hydrochloride represented by the formula (2) used as an antiviral agent and / or ursodeoxycholic acid (UDCA) of the formula (3) used as a diluent To prepare, chronic hepatitis B and C infection (HBV and HCV) confirmed a significant clinical improvement to complete the present invention.
따라서, 본 발명은 간염 치료에 유용한 약제조성물을 제공하는데 그 목적이 있다. Accordingly, an object of the present invention is to provide a pharmaceutical composition useful for treating hepatitis.
본 발명은 상기 화학식 1로 표시되는 비페닐 디메칠 디카르복실레이트(BDD) 7.5 ∼ 200 중량부와 상기 화학식 2로 표시되는 염산 아만타딘 50 ∼ 200 중량부가 함유된 간염 치료용 약제조성물을 그 특징으로 한다.The present invention is characterized in that the pharmaceutical composition for treating hepatitis containing 7.5 to 200 parts by weight of biphenyl dimethyl dicarboxylate (BDD) represented by Formula 1 and 50 to 200 parts by weight of amantadine hydrochloride represented by Formula 2 do.
이와같은 본 발명을 더욱 상세히 설명하면 다음과 같다.Referring to the present invention in more detail as follows.
본 발명은 병용요법으로 만성 B형 및 C형 간염바이러스 등의 간염 치료에 유용한 약제조성물로서 상기 화학식 1의 비페닐 디메칠 디카르복실레이트(BDD)와 상기 화학식 2의 염산 아만타딘 및/또는 상기 화학식 3의 우르소데옥시콜린산(UDCA)를 일정량 함유시켜 제조한다.The present invention is a combination of the therapy as a pharmaceutical composition useful in the treatment of hepatitis, such as chronic hepatitis B virus and hepatitis C virus, biphenyl dimethyl dicarboxylate (BDD) of Formula 1 and Amantadine hydrochloride of Formula 2 and / or It is prepared by containing a predetermined amount of ursodeoxycholic acid (UDCA) of 3.
상기와 같은 본 발명의 약제조성물의 구성성분을 더욱 상세히 살펴보면 다음과 같다.Looking at the components of the pharmaceutical composition of the present invention as described above in more detail.
먼저, 본 발명의 약제조성물에는 만성 간염 치료제로서 사용된 상기 화학식 1로 표시되는 비페닐 디메칠 디카르복실레이트(BDD)를 7.5 ∼ 200 중량부 함유하며, 만일 그 함유량이 7.5 중량부 미만이면 약효가 미흡한 문제가 있고, 200 중량부를 초과하면 안전성에 문제가 있다.First, the pharmaceutical composition of the present invention contains 7.5 to 200 parts by weight of biphenyl dimethyl dicarboxylate (BDD) represented by Chemical Formula 1 used as a therapeutic agent for chronic hepatitis, and if the content is less than 7.5 parts by weight There is a poor problem, and if it exceeds 200 parts by weight, there is a safety problem.
또한, 본 발명의 약제조성물에는 항바이러스제로서 사용된 상기 화학식 2로 표시되는 염산 아마타딘을 50 ∼ 200 중량부 함유하며, 만일 그 함유량이 50 중량부 미만이면 약효가 미흡한 문제가 있고, 200 중량부를 초과하면 안전성에 문제가 있다.In addition, the pharmaceutical composition of the present invention contains 50 to 200 parts by weight of amaradiate hydrochloride represented by the formula (2) used as an antiviral agent, and if the content is less than 50 parts by weight, there is a problem of insufficient efficacy, 200 parts by weight If exceeded, there is a safety problem.
그리고, 본 발명의 약제조성물에는 이담제로서 사용된 상기 화학식 3으로 표시되는 우르소데옥시콜린산(UDCA)를 추가적으로 50 ∼ 100 중량부 함유할 수 있으며, 만일 그 함유량이 50 중량부 미만이면 약효가 미흡한 문제가 있고, 100 중량부를 초과하면 안전성에 문제가 있다.In addition, the pharmaceutical composition of the present invention may further contain 50 to 100 parts by weight of ursodeoxycholic acid (UDCA) represented by Formula 3 used as an antagonist, if the content is less than 50 parts by weight There is an inadequate problem, and if it exceeds 100 parts by weight, there is a problem in safety.
그리고, 본 발명에 따른 약제조성물은 상기 성분 이외에 통상의 당업자라면 용이하게 선택 취합할 수 있는 유당, 전분, 스테아린산마그네슘, 카르복시메칠셀룰로오스 등의 약제학적으로 허용되는 부형제를 함유시킬 수 있다.In addition to the above components, the pharmaceutical composition according to the present invention may contain pharmaceutically acceptable excipients such as lactose, starch, magnesium stearate, and carboxymethyl cellulose which can be easily selected by those skilled in the art.
특히, 본 발명의 약제조성물의 바람직한 일례는 상기 화학식 1로 표시되는 비페닐 디메칠 디카르복실레이트(BDD) 50 중량부, 상기 화학식 2로 표시되는 염산 아만타딘 50 중량부 및 약제학적으로 허용되는 부형제를 함유한 약제조성물이다.In particular, a preferred example of the pharmaceutical composition of the present invention is 50 parts by weight of biphenyl dimethyl dicarboxylate (BDD) represented by Formula 1, 50 parts by weight of amantadine hydrochloride represented by Formula 2 and a pharmaceutically acceptable excipient It is a pharmaceutical composition containing.
또 다른 본 발명의 약제조성물의 바람직한 일례는 상기 화학식 1로 표시되는 비페닐 디메칠 디카르복실레이트(BDD) 15 중량부, 상기 화학식 2로 표시되는 염산 아만타딘 50 중량부, 상기 화학식 3으로 표시되는 우르소데옥시콜린산(UDCA) 50 중량부 및 약제학적으로 허용되는 부형제를 함유한 약제조성물이다.Another preferred example of the pharmaceutical composition of the present invention is 15 parts by weight of biphenyl dimethyl dicarboxylate (BDD) represented by Formula 1, 50 parts by weight of amantadine hydrochloride represented by Formula 2, represented by Formula 3 A pharmaceutical composition containing 50 parts by weight of ursodeoxycholic acid (UDCA) and a pharmaceutically acceptable excipient.
상기와 같은 본 발명에서 유효성분으로 사용한 비페닐 디메칠 디카르복실레이트(BDD), 염산 아만타딘, 우르소데옥시콜린산(UDCA)은 이미 시판되고 있는 약제로서 그 안정성이 널리 입증되어 있는 바, 본 발명에 의한 약제조성물의 안정성도 역시 매우 높다.Biphenyl dimethyl dicarboxylate (BDD), amantadine hydrochloride, and ursodeoxycholic acid (UDCA) used as an active ingredient in the present invention as described above are already commercially available drugs, and the stability thereof has been widely demonstrated. The stability of the pharmaceutical composition according to the invention is also very high.
이와 같이, 본 발명의 약제조성물은 비페닐 디메칠 디카르복실레이트(BDD)와 염산 아만타딘 및/또는 우르소데옥시콜린산(UDCA)을 유효성분으로 하고 약제학적으로 허용되는 부형제를 적정량 병용하여 제조함으로써 상기 성분들의 상승효과에 의해 간독성에 대해 강력한 보호작용을 나타내어 간염 치료제로서 매우 유용하게 사용할 수 있다.As described above, the pharmaceutical composition of the present invention is prepared by using biphenyl dimethyl dicarboxylate (BDD), amantadine hydrochloride and / or ursodeoxycholic acid (UDCA) as an active ingredient, and an appropriate amount of a pharmaceutically acceptable excipient in combination. As a result, a synergistic effect of the above components shows strong protection against hepatotoxicity, which makes it very useful as a hepatitis therapeutic agent.
이러한 본 발명에 따른 약제조성물은 통상의 방법으로 캅셀제 또는 정제의 형태로 제제화할 수 있다. Such pharmaceutical compositions according to the invention can be formulated in the form of capsules or tablets by conventional methods.
또한, 상기 본 발명에 따른 약제조성물의 유효투입량은 환자의 나이, 신체적 조건, 몸무게 등에 의해 다양화될 수 있지만, 일반적으로 1 내지 100 ㎎/㎏(몸무게)/1일 범위 내에서 투여된다. 그리고, 1일 유효투입량 범위 내에서 하루에 한번 또는 하루에 여러 번 나누어 투입한다.In addition, the effective dosage of the pharmaceutical composition according to the present invention can be varied depending on the age, physical condition, weight, etc. of the patient, it is generally administered within the range of 1 to 100 mg / kg (weight) / day. In addition, within a daily effective dosage range is divided into once a day or several times a day.
이하, 본 발명을 다음의 실시예에 의거하여 더욱 상세하게 설명하겠는바, 본 발명이 실시예에 의해 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail based on the following examples, but the present invention is not limited by the examples.
실시예 1. 경질캅셀제의 제조Example 1 Preparation of Hard Capsule
비페닐 디메칠 디카르복실레이트(BDD) 15 mg, 우르소데옥시콜린산(UDCA) 50 mg 및 염산 아만타딘 50 mg의 혼합물에 아래의 부형제를 첨가하여 균질로 혼합한 후 통상의 경질캅셀제의 제조방법에 따라 제조하였다.The following excipients were added to a mixture of 15 mg of biphenyl dimethyl dicarboxylate (BDD), 50 mg of ursodeoxycholic acid (UDCA), and 50 mg of amantadine hydrochloride, followed by homogeneous mixing to prepare a conventional hard capsule. It was prepared according to.
실시예 2. 경질캅셀제의 제조Example 2 Preparation of Hard Capsule
비페닐 디메칠 디카르복실레이트(BDD) 50 mg 및 염산 아만타딘 50 mg의 혼합물에 아래의 부형제를 첨가하여 균질로 혼합한 후 통상의 경질캅셀제의 제조방법에 따라 제조하였다.The following excipients were added to a mixture of 50 mg of biphenyl dimethyl dicarboxylate (BDD) and 50 mg of amantadine hydrochloride, mixed homogeneously, and prepared according to a conventional hard capsule preparation method.
실시예 3. 정제의 제조Example 3. Preparation of Tablets
비페닐 디메칠 디카르복실레이트(BDD) 50 mg 및 염산 아만타딘 50 mg의 혼합물에 아래의 부형제를 첨가하여 균질로 혼합한 후 통상의 정제의 제조방법에 따라 제조하였다.To the mixture of 50 mg of biphenyl dimethyl dicarboxylate (BDD) and 50 mg of amantadine hydrochloride, the following excipients were added, mixed homogeneously, and prepared according to a conventional method for preparing a tablet.
실시예 4. 정제의 제조Example 4. Preparation of Tablets
비페닐 디메칠 디카르복실레이트(BDD) 15 mg, 우르소데옥시콜린산(UDCA) 50 mg 및 염산 아만타딘 50 mg의 혼합물에 아래의 부형제를 첨가하여 균질로 혼합한 후 통상의 정제의 제조방법에 따라 제조하였다.To a mixture of 15 mg of biphenyl dimethyl dicarboxylate (BDD), 50 mg of ursodeoxycholic acid (UDCA), and 50 mg of amantadine hydrochloride, the following excipients were added and mixed homogeneously, followed by a method for preparing a conventional tablet. Prepared accordingly.
시험예 1 Test Example 1
상기 실시예 1 ∼ 4의 제제가 만선 B형 및 C형 간염바이러스 감염(HBV 및 HCV)에 대한 항바이러스 효과 및 간장보호 효과를 규명하기 위하여 사람의 전격성 바이러스 간염의 동물 모델로 알려진 마우스간염바이러스(MHV-2주)를 이용하여 테스트를 실시하였다.Mouse hepatitis virus known as an animal model of human epidemic hepatitis in order to characterize the antiviral and hepatoprotective effects of the formulations of Examples 1 to 4 against chronic hepatitis B and C infection (HBV and HCV) (MHV-2 week) was used to test.
실험에 사용된 마우스는 생후 6 주령 SPF ICR 마우스(샘타코사)(체중 25 ㅁ 2 g)을 이용하였다. 시험군으로는 마우스간염바이러스(Mouse hepatitis virus-2 strain)를 감염시켜서 전격성 바이러스간염을 유발하는 것으로, 다음과 같이 8개 로 구분하고 각 군당 13 마리씩 배치하였다.The mice used in the experiment were 6-week-old SPF ICR mice (Samta Co., Ltd.) (weight 25 W 2 g). The test group was to induce acute viral hepatitis by infecting mouse hepatitis virus-2 strain, it was divided into eight as follows and placed 13 dogs in each group.
(1) MHV-2 + 증류수 투여군(1) MHV-2 + distilled water administration group
(2) MHV-2 + 제픽스™(상품명, 영국의 글락소웰컴사)(100 mg/kg) 투여군(2) MHV-2 + Gepix ™ (trade name, Glaxowelcome, UK) (100 mg / kg) group
(3) MHV-2 + UDCA(40 mg/kg) 투여군(3) MHV-2 + UDCA (40 mg / kg) administration group
(4) MHV-2 + BDD(40 mg/kg) 투여군(4) MHV-2 + BDD (40 mg / kg) administration group
(5) MHV-2 + AH(40 mg/kg) 투여군(5) MHV-2 + AH (40 mg / kg) administration group
(6) MHV-2 + AD(80 mg/kg) 투여군(6) MHV-2 + AD (80 mg / kg) administration group
(7) MHV-2 + ADU(100 mg/kg) 투여군(7) MHV-2 + ADU (100 mg / kg) administration group
(8) 증류수 단독 투여군(8) distilled water alone administration group
상기 모든 시험군에 MHV-2주를 마우스 당 1 × 103 PFU/0.2 ㎖의 농도로 복강접종하고 1일 후부터 상기 각 약물을 매일 경구투여하고, 바이러스 접종 3일째에 미정맥으로 부터 혈액을 채취한 다음, 사망시 까지 생존 여부를 관찰하고 최종부검은 10일째에 실시하였으며, 바이러스 역가 측정, 병리조직학적 검사 및 면역조직화학적 관찰을 다음과 같은 방법으로 수행하여 그 결과를 다음 표 5, 표 6 및 표 7에 나타내었다.MHV-2 weeks were intraperitoneally inoculated to all the test groups at a concentration of 1 × 10 3 PFU / 0.2 ml per mouse, and each day was orally dosed with the above-mentioned drugs daily, and blood was collected from the vein on the third day of virus inoculation. Survival was observed until death and final autopsy was performed on day 10. The virus titer, histopathological examination, and immunohistochemical observation were performed in the following manner. Table 7 shows.
[측정방법][How to measure]
1. 바이러스 역가 측정 : 혈액내의 바이러스 역가는 원심분리하여 분리한 각 혈장을 SR-CDF1-DBT(DBT) 세포에 접종하여 plaque assay법에 의하여 바이러스 역가를 측정하였다.1. Virus titer: Virus titer in blood was inoculated into SR-CDF1-DBT (DBT) cells by centrifugation to measure plasma titer by plaque assay.
2. 병리조직학적 검사 : 사망 또는 도살부검시 혈액을 채취하고 방혈한 후에, 간장을 일반적인 파라핀 포매과정을 거쳐 5 ㎛ 두께의 조직 절편을 제작한 다음 Hematoxylin-Eosin(H & E) 염색을 하여 광학현미경으로 관찰하였다.2. Histopathological examination: After blood collection and bleeding at the time of death or slaughter, the liver was subjected to normal paraffin embedding to prepare 5 μm thick tissue sections, and then stained with Hematoxylin-Eosin (H & E) for optical analysis. It was observed under a microscope.
3. 면역조직화학적 관찰 : 실험기간 중에 폐사하거나 접종 10일에 부검한 마우스로부터 간장을 적출하여 육안적인 소견을 관찰하고, Bouin 용액에 고정시킨 후 통상적인 방법에 따라서 파라핀으로 포매하여 슬라이드를 만들어 hematoxylin과 eosin 염색과 anti-MHV serum을 이용한 면역조직화학 염색을 실시하여 간장조직내의 바이러스의 광학현미경으로 관찰하였다.3. Immunohistochemical observation: Hepatic livers were removed from the mice that died during the experiment or autopsied at 10 days of inoculation, followed by visual observation. After immobilization in Bouin solution, the cells were embedded in paraffin according to a conventional method to make slides. Eosin staining and immunohistochemical staining with anti-MHV serum were performed to observe the optical microscopy of virus in liver tissue.
상기 표 5에 나타낸 바와 같이, 바이러스 접종 후 UDCA 투여군, BDD 투여군에서는 전부 사망하였으나, 제픽스 투여군과 AH 투여군에서는 약간의 생존율을 보이고, AD 투여군과 ADU 투여군에서는 현저히 증가된 생존율을 확인할 수 있었다.As shown in Table 5, all of the UDCA-administered group and the BDD-administered group died after the virus inoculation, but showed little survival in the Gepix-administered group and the AH-administered group.
상기 표 6에 나타낸 바와 같이, 본 발명에 따른 AD와 ADU 투여군이 다른 약물 투여군에 비하여 평균사망에 이르는 일수가 긴 것을 확인할 수 있었다.As shown in Table 6, it was confirmed that the AD and ADU-administered group according to the present invention has a longer number of days leading to an average death than other drug-administered groups.
상기 바이러스 접종 3일째 각 마우스내의 바이러스 역가를 나타낸 표 7로, AD와 ADU 투여군이 다른 약물 투여군에 비하여 바이러스의 혈중농도가 낮은 것이 관찰되어 바이러스 증식을 약간 억제하는 것을 확인할 수 있었다.In Table 7 showing virus titers in each mouse on day 3 of the virus inoculation, AD and ADU-administered groups were observed to have lower blood plasma concentrations than other drug-administered groups, indicating a slight inhibition of virus proliferation.
또한, 마우스간염바이러스에 의해 유발된 전격성바이러스간염에 대한 각 약물의 효과를 살펴본 결과, 대부분의 약물이 간전체에 걸쳐 간세포의 붕괴와 융해로 인한 호산성의 융합된 괴사소를 보이는 심한 세포괴사가 관찰되어 정상적인 간세포는 거의 관찰되지 않았다. 그러나, AH, AD 및 ADU를 투여한 군에서는 간전체에 걸친 괴사소견이 다소 미약하게 관찰되고 일부에는 정상적인 간조직도 관찰되었으며, 특히 ADU 투여군에서 뚜렷이 나타나고 있다. 더욱이 생존한 마우스군에서 간전체 세포에 걸쳐 핵분열상 및 이핵이 다수 관찰되어 간세포가 재생상이 현저하게 관찰되었다.In addition, as a result of examining the effects of each drug on the hepatitis virus induced by mouse hepatitis virus, most of the drugs showed severe cell necrosis showing eosinophilic fused necrosis due to disruption and fusion of liver cells throughout the liver. Normal hepatocytes were rarely observed. However, in the group administered with AH, AD, and ADU, necrosis over the liver was slightly weakened, and some normal liver tissues were observed, especially in the group treated with ADU. Furthermore, in the surviving mouse group, many nuclear fission and dinuclei were observed throughout the whole liver cells, and regeneration of hepatocytes was remarkably observed.
이상의 결과를 종합해 볼 때, 본 발명에 따른 AD 및 ADU는 마우스간염바이러스에 의해 유발된 전격성 바이러스간염에 대하여 기존의 약물보다 우수한 효과를 나타내는 것을 확인할 수 있었다.In summary, the AD and ADU according to the present invention was confirmed to show an excellent effect than the conventional drug against the hepatitis virus caused by mouse hepatitis virus.
시험예 2 : 생체외 세포실험(In vitro cellline assay)를 이용한 HBV 저해활성.Test Example 2: HBV inhibitory activity using an in vitro cellline assay.
인간 B형 간염 바이러스를 생산하는 세포주인 HepG2-2.2.15 세포를 T25 플라스크에서 10% FBS(Fetal Bovine Serum) 1% ABAM(GIBCO BRL. #15240-013), 최종농도 200 mg/ml이 되는 G418을 포함하는 DMEM배지에서 6일간 배양한 후 24 Well 마이크로 플레이트에 1.0 ∼ 1.2 ×105 cell/ml/well 되게 희석, 분주하여 5% CO2 배양기에서 3시간 정도 배양하였다. 세포가 플레이트 바닥에 잘 붙은 것을 확인한 다음 각 시료를 최종농도 10 μM에서 1 nM로 1/10씩 희석하여 처리하였다.HepG2-2.2.15 cells, a cell line producing human hepatitis B virus, were prepared in a T25 flask with 10% FeBS (Fetal Bovine Serum), 1% ABAM (GIBCO BRL. # 15240-013), and G418 at a final concentration of 200 mg / ml. After 6 days of incubation in a DMEM medium containing a dilution and aliquot to 1.0 ~ 1.2 × 10 5 cell / ml / well in a 24 well microplate and incubated for about 3 hours in a 5% CO 2 incubator. After confirming that the cells adhered well to the bottom of the plate, each sample was treated by diluting 1/10 by 1 nM at a final concentration of 10 μM.
이때 대조군은 적정 최고용량으로서 인터페론알파 (1000IU), lamivudine (10μg/ml) 농도로 처리하였다. At this time, the control group was treated with the concentration of interferon alpha (1000 IU) and lamivudine (10 μg / ml) as the appropriate maximum dose.
상기 HepG2-2.2.15 세포를 이용하여, RT-PCR, 웨스턴 블랏(Western Blot), LDH 세포독성(cytotoxicity) 및 NO assay을 다음의 방법으로 실험하였다. Using the HepG2-2.2.15 cells, RT-PCR, Western blot, LDH cytotoxicity and NO assay were tested by the following method.
(1) RT-PCR : PCR kit - Taq Core Kit 10, Q-Bio gene, USA (1) RT-PCR: PCR kit-Taq Core Kit 10, Q-Bio gene, USA
(2) Western Blot (2) Western Blot
20 μg의 단백질 샘플을 SDS 로딩 버퍼(SDS loading buffer)에서 90 ℃, 5분간 끓인 후 12% SDS-폴리아크릴아마이드 미니-겔(SDS-polyacrylamide mini-gels)에 로딩하였다. 전기영동 종료 후 PVDF 멤브레인(membrane)에 옮겨 TBS-T 버퍼(buffer)로 세척 후 5% 스킴 밀크(skim milk)로 1시간 동안 블록킹(blocking) 하였다. 15-5-5분간 세척 후 1차 항체로 1시간 동안 프로빙(probing) 하였고, 15-5-5분간 세척 후 2차 항체 (HRP-conjugated)를 붙여 ECL 시스템 (Santa Cruz)하에서 X-ray 필름에 노출하여 감광하였다. 20 μg of protein samples were boiled in SDS loading buffer at 90 ° C. for 5 minutes and loaded onto 12% SDS-polyacrylamide mini-gels. After the end of electrophoresis was transferred to a PVDF membrane (membrane) and washed with TBS-T buffer (buffer) and then blocked (blocking) for 1 hour with 5% skim milk (skim milk). After washing for 15-5-5 minutes, the probe was probed with primary antibody for 1 hour. After washing for 15-5-5 minutes, a secondary antibody (HRP-conjugated) was attached to the X-ray film under ECL system (Santa Cruz). It was exposed to light and exposed.
(3) LDH cytotoxicity (3) LDH cytotoxicity
본 실험을 위해 Promega사의 Cytotox 96 Asaay kit (Cat.# G1781)을 사용하였으며 이를 통해 안정한 세포질 효소인 LDH의 양을 관찰하여 약물에 의한 세포독성을 알아보았다. 실험방법은 제조사에서 제공한 방법을 적용하였으며 결과는 490 nm에서 측정되었다. For this experiment, Promega Cytotox 96 Asaay kit (Cat. # G1781) was used, and the cytotoxicity of the drug was examined by observing the amount of LDH, a stable cellular enzyme. The experimental method was applied to the method provided by the manufacturer and the result was measured at 490 nm.
(4) NO assay (4) NO assay
본 실험을 위해 Promega사의 Griess reagent system kit(Cat.# G2930) 을 사용하였으며 이를 통해 세포로부터 생성되어 분비되는 nitric oxide를 관찰하여 약물에 의한 세포의 반응을 알아보았다. 실험방법은 제조사에서 제공한 방법을 적용하였으며 결과는 540 nm에서 측정되었다. For this experiment, Promega's Griess reagent system kit (Cat. # G2930) was used, and the reaction of the cells by the drug was observed by observing nitric oxide produced and secreted from the cells. The experimental method was applied to the method provided by the manufacturer and the result was measured at 540 nm.
도 1, 2 및 3에 나타낸 바와 같이, In vitro 실험의 결과는 약 72시간이 경과한 후에, 그 효과가 확연히 드러남을 확인할 수 있으며, 본 발명에 따른 비페닐 디메칠 디카르복실레이트(BDD)와 염산 아만타딘(AMANTADIN) 및/또는 우르소데옥시콜린산(UDCA)이 복합적으로 사용되는 경우 효과적인 결과를 보였으며, STAT1-alpha protein 및 6-6 gene의 활성도로부터 항바이러스 효과가 있는 것을 확인하였다. As shown in Figures 1, 2 and 3, the results of in vitro experiments can be seen that after about 72 hours, the effect is obvious, biphenyl dimethyl dicarboxylate (BDD) according to the present invention When the combination of and amantadine hydrochloride (AMANTADIN) and / or ursodeoxycholic acid (UDCA) showed an effective result, it was confirmed that there is an antiviral effect from the activity of STAT1-alpha protein and 6-6 gene.
또한, 염산 아만타딘(AMANTADIN)와 우르소데옥시콜린산(UDCA) 투여시 IFN-alpha와 유사한 수준의 IL-1beta를 발현함이 관찰되어 두 약물의 복합 투여시 항바이러스의 시너지 효과를 기대할 수 있다. 도 1와 도 2에 나타낸 바와 같이, 직접적인 종말점(endpoint)로 부터 HBsAg의 발현이 명 3종 복합 투여시 억제됨이 나타났으며, HBcAg 또한 이러한 결과를 보였다.In addition, the expression of IL-1beta similar to IFN-alpha was observed when Amantadine hydrochloride (AMANTADIN) and ursodeoxycholic acid (UDCA) were administered. As shown in Figure 1 and 2, it was shown that the expression of HBsAg from the direct endpoint (endpoint) is inhibited in the combination of three people, HBcAg also showed this result.
도 4에서는 LDH의 변화를 보여주는 결과이며, 이 결과로부터, 기존의 약물에 비해 본 연구약물에 의한 세포독성은 발견되지 않아 안전한 약물로 판단되었으며, 도 5에서는 HBV 바이러스 증식과 관련이 있는 것으로 알려진 nitric oxide(NO)의 생성도를 보여주는 실험으로서 UDCA가 포함된 군에서 NO의 양적 변화가 기대되므로 UDCA에 의한 HBV 바이러스 증식에 추가적인 시너지 효과를 기대할 수 있다. 4 is a result showing the change in LDH, from this result, it was determined that the cytotoxicity by the study drug compared to the conventional drug was found to be a safe drug, in Figure 5 nitric known to be associated with HBV virus proliferation As an experiment showing the production of oxide (NO), the quantitative change of NO is expected in the group containing UDCA, so additional synergistic effect can be expected in HBV virus proliferation by UDCA.
즉, 염산 아만타딘(AMANTADIN) 단독제제로서는 HBV의 발현 억제를 기대하기 어려우나, 비페닐 디메칠 디카르복실레이트(BDD) 및 우르소데옥시콜린산(UDCA)와의 복합 투여시 장단기적인 효과를 예측될 수 있음을 확인하였다.In other words, it is difficult to expect the inhibition of HBV expression as an agent of amantadine hydrochloride (AMANTADIN) alone, but the long-term and long-term effects may be predicted when combined with biphenyl dimethyl dicarboxylate (BDD) and ursodeoxycholic acid (UDCA). It was confirmed that there is.
상술한 바와 같이, 본 발명에 따른 약제조성물은 비페닐 디메칠 디카르복실레이트(BDD)와 염산 아만타딘 및/또는 우르소데옥시콜린산(UDCA)을 유효성분으로 하고 약제학적으로 허용되는 부형제를 적정량 병용하여 제조함으로써 상기 성분들의 상승효과에 의해 간독성에 대해 강력한 보호작용을 나타내어 간염 치료제로서 매우 유용하게 사용할 수 있다.As described above, the pharmaceutical composition according to the present invention contains biphenyl dimethyl dicarboxylate (BDD), amantadine hydrochloride and / or ursodeoxycholic acid (UDCA) as an active ingredient, and an appropriate amount of a pharmaceutically acceptable excipient. By using in combination, it shows strong protection against hepatotoxicity due to the synergistic effect of the above components and can be very useful as a therapeutic agent for hepatitis.
도 1은 본 발명에 따른 실시예 및 종래 사용된 간염치료용 약제의 시간 변화(1일, 3일 및 5일)에 따른 HBsAg gene 발현억제능을 나타낸 것이다.Figure 1 shows the inhibitory ability of HBsAg gene expression according to the time change (1 day, 3 days and 5 days) of the agent according to the present invention and conventionally used hepatitis treatment.
도 2는 본 발명에 따른 실시예 및 종래 사용된 간염치료용 약제의 HBcAg gene 발현억제능을 나타낸 것이다.Figure 2 shows the inhibitory ability of HBcAg gene expression of the agent for treating hepatitis and the examples according to the present invention.
도 3은 본 발명에 따른 실시예 및 종래 사용된 간염치료용 약제의 시간 변화(1일, 3일 및 5일)에 따른 6-16 gene 발현활성을 나타낸 것이다.Figure 3 shows the expression activity of 6-16 gene according to the time change (1 day, 3 days and 5 days) of the agent according to the present invention and conventionally used for hepatitis treatment.
도 4는 본 발명에 따른 실시예 및 종래 사용된 간염치료용 약제의 LDH assay를 나타낸 것이다.Figure 4 shows the LDH assay of the agent for treating hepatitis and the examples according to the present invention used conventionally.
도 5는 본 발명에 따른 실시예 및 종래 사용된 간염치료용 약제의 시간 변화(1일, 3일 및 5일)에 따른 NO assay을 나타낸 것이다.Figure 5 shows the NO assay according to the time changes (1 day, 3 days and 5 days) of the agent according to the present invention and conventionally used for hepatitis treatment.
<110> SUN, Jong Keon <120> A pharmaceutical composition for hepatitis <150> KR10-2003-00569641 <151> 2003-08-27 <160> 6 <170> KopatentIn 1.71 <210> 1 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> 5'-primer of HBsA <400> 1 gaagcaccca agtgtcctg 19 <210> 2 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> 3'-primer of HBsA <400> 2 aaacggactg aggcccact 19 <210> 3 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> 5'-primer of HBcAg <400> 3 tccgtgatct gctcgacac 19 <210> 4 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> 3'-primer of HBcAg <400> 4 accttcgtct gcgaggcga 19 <210> 5 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> 5'-primer of 6-16 <400> 5 caagcttaac cgtttactcg ctgctgt 27 <210> 6 <211> 28 <212> DNA <213> Artificial Sequence <220> <223> 3'-primer of 6-16 <400> 6 tgcggccgct gctggctact cctcacct 28<110> SUN, Jong Keon <120> A pharmaceutical composition for hepatitis <150> KR10-2003-00569641 <151> 2003-08-27 <160> 6 <170> KopatentIn 1.71 <210> 1 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> 5'-primer of HBsA <400> 1 gaagcaccca agtgtcctg 19 <210> 2 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> 3'-primer of HBsA <400> 2 aaacggactg aggcccact 19 <210> 3 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> 5'-primer of HBcAg <400> 3 tccgtgatct gctcgacac 19 <210> 4 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> 3'-primer of HBcAg <400> 4 accttcgtct gcgaggcga 19 <210> 5 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> 5'-primer of 6-16 <400> 5 caagcttaac cgtttactcg ctgctgt 27 <210> 6 <211> 28 <212> DNA <213> Artificial Sequence <220> <223> 3'-primer of 6-16 <400> 6 tgcggccgct gctggctact cctcacct 28
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