KR19990015251A - Liquid formulation containing biphenyldimethyldicarboxylate, a poorly soluble chemical agent, as a main component, and preparation method thereof - Google Patents
Liquid formulation containing biphenyldimethyldicarboxylate, a poorly soluble chemical agent, as a main component, and preparation method thereof Download PDFInfo
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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Abstract
본 발명은 물에 난용성인 DDB를 디에틸렌글리콜 모노메틸에테르, 디에틸렌글리콜 모노에틸에테르, 에틸렌글리콜 모노메틸에테르, 에틸렌글리콜 모노에틸에테르와 같은 에테르계열 및 폴리에틸렌 옥사이드-폴리프로필렌 옥사이드 다이블록형태(플루론익: 상품명)에서 선택된 1종 이상의 유기용매 및 물 또는 주사용증류수에 용해시켜서 제조된 안정한 신규의 액제 또는 주사제를 제공하는 것이며, 본 발명에 의하여 DDB의 안정한 액제 및 주사제가 개발되었다.DDB which is poorly soluble in water can be prepared in the form of ethers such as diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, and polyethylene oxide-polypropylene oxide diblock. Lonick: Provides a stable novel liquid or injection prepared by dissolving in one or more organic solvents selected from (trade name) and water or distilled water for injection, the stable solution and injection of DDB was developed by the present invention.
Description
본 발명은 난용성 약물인 비페닐디메틸디카르복실레이트를 주성분으로 함유하는 액제 및 그 제조방법에 관한 것이다.The present invention relates to a liquid formulation containing biphenyldimethyldicarboxylate, which is a poorly water-soluble drug, as a main component, and a method for producing the same.
비페닐디메틸디카르복실레이트(이하 DDB라 한다.)는 예로부터 한방에서 강장제 등으로 사용된 오미자에서 단리된 유효성분의 하나인 쉬잔드린(Schizandrin) C의 합성동족체로서 간염치료 뿐만 아니라, 간보호 작용도 있어, 현재 국내에서 널리 사용되고 있다. 그러나 DDB는 물에 난용성이며, 경구투여시 위장관에서의 분해는 매우 적지만 흡수가 매우 저조하여 약 5∼30% 만이 흡수되며 나머지는 배변으로 배출된다.Biphenyldimethyldicarboxylate (hereinafter referred to as DDB) is a synthetic homologue of Shizandrin C, one of the active ingredients isolated from Schizandra chinensis used as a tonic in traditional Chinese medicine, as well as hepatitis treatment. It is also used and is widely used in Korea. However, DDB is poorly soluble in water, and during oral administration, the digestion in the gastrointestinal tract is very small, but absorption is very low, so only about 5-30% is absorbed and the rest is excreted in the bowel movement.
본 발명자들은 이러한 문제점을 해결하기 위하여 오랜 연구를 행한 결과, 현재 시판되는 DDB를 이용한 제제 즉, 정제, 캡슐제, 환제들에 비해 그 유효 함량만 투여하여도 될 뿐만 아니라, 응급시에 사용될 수 있고, 노약자가 경구 투여하기 어려울 때에 주사제로도 사용될 수 있는 놀라운 사실을 발견하여 본 발명을 완성하였다.The present inventors have conducted a long study to solve this problem, and as a result, it is not only necessary to administer the effective amount of the preparation using the commercially available DDB, that is, tablets, capsules, pills, but also can be used in an emergency The present invention was completed by discovering the surprising fact that the elderly can be used as an injection when it is difficult to orally administer.
지금까지 DDB의 통상적인 가용화방법은 폴리에틸렌글리콜과 글리세린의 혼합계, 또는 폴리소르베이트(트윈류) 등을 사용하여 제조하였으나, 이들은 주사제나 액제로 적용하기에는 점도상의 문제점과 적당량의 물을 가했을 때 DDB가 석출되는 관계로 이에 적용이 불가능하였다.Until now, the conventional solubilization method of DDB has been prepared using a mixed system of polyethylene glycol and glycerin, or polysorbate (twins), but these have problems in viscosity and proper amount of water for injection or liquid application. Because of the precipitation, it could not be applied.
본 발명자들은 적당량이 물을 첨가하여도 침전이 석출되지 않아 주사제나 액제로의 적용이 가능하게 하여 약효가 신속하게 나타나는 DDB의 제제를 개발하여 본 발명을 완성하였다.The present inventors have completed the present invention by developing a formulation of DDB which does not precipitate even when an appropriate amount of water is added, so that it can be applied as an injection or a liquid, so that the drug is rapidly exhibited.
본 발명자들은 디에틸렌글리콜 모노메틸에테르, 디에틸렌글리콜 모노에틸에테르, 에틸렌글리콜 모노메틸에테르, 에틸렌글리콜 모노에틸에테르와 같은 에테르계열 및 폴리에틸렌 옥사이드-폴리프로필렌옥사이드의 다이블록형태(프루로닉(상품명))에서 선택된 1종 이상의 용매에 DDB를 용해시키고 여기에 필요하면 결정 안정화제로 폴리에틸렌글리콜을 첨가하고 물을 가하여 용해시키면 DDB가 매우 잘 용해될 뿐만 아니라 장기간 저장하여도 결정이 석출되지 않는 놀라운 사실을 발견하여 본 발명을 완성하였다.The inventors of the present invention are diblock forms of ether series and polyethylene oxide-polypropylene oxide such as diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, ethylene glycol monomethyl ether, and ethylene glycol monoethyl ether (Pluronic (trade name) Dissolve DDB in one or more solvents selected from), and if necessary, add polyethylene glycol as a crystal stabilizer and add water to dissolve the DDB, which not only dissolves very well but also does not precipitate crystals even after long-term storage. The present invention was completed.
상기의 용제에 용해시에는 필요하면 아세톤을 소량 첨가하고 용해시킨 후 아세톤을 증발시켜서 제조할 수도 있다.When dissolving in the above solvent, if necessary, a small amount of acetone may be added, dissolved, and then prepared by evaporating acetone.
유기용매에 DDB를 용해시에는 필요하면 가온함이 바람직하다. 가온은 20-80℃까지가 바람직하다.When dissolving DDB in an organic solvent, it is preferable to warm if necessary. Heating is preferably up to 20-80 ° C.
DDB의 액제 및 주사제는 다음과 같은 조건을 만족하여야 한다.Solution and injection of DDB should satisfy the following conditions.
첫째: 적당량의 물이 첨가되어도 DDB가 용액상태로 안정하여야 한다.First: DDB should be stable in solution even if the proper amount of water is added.
둘째: 액제의 경우 체내에서 신속히 약물을 방출하여야 하고 약물의 흡수가 잘 되어야 한다.Secondly, in the case of liquids, the drug must be released quickly and absorbed well.
셋째: 주사제의 경우 사용하기에 편리한 적정의 점도를 유지하여야 한다.Third, in the case of injections, the viscosity of the titration should be convenient.
본 발명의 액제 및 주사제는 상기의 조건을 모두 만족시킨다.The solution and injection of the present invention satisfy all of the above conditions.
본 발명에서는 DDB의 양은 0.1 내지 20중량%를 사용하는 것이 바람직하다.In the present invention, the amount of DDB is preferably used 0.1 to 20% by weight.
본 발명에서는 유기용제는 10 내지 99.9%를 사용함이 바람직하다.In the present invention, the organic solvent is preferably used 10 to 99.9%.
본 발명에서는 정제수 또는 주사용정제수나 증류수는 1 내지 50중량%를 사용하는 것이 바람직하다.In the present invention, it is preferable to use 1 to 50% by weight of purified water, injectable purified water or distilled water.
다음의 실시예로써 본 발명을 상세히 설명하나, 본 실시예들이 본 발명이 범위를 한정하는 것은 아니다.The present invention will be described in detail with reference to the following examples, which are not intended to limit the scope of the invention.
[실시예 1]Example 1
디에틸렌글리콜 모노에틸에테르 500㎎에 DDB 7.5㎎을 녹인 후 물 300㎎과 디에틸렌글리콜 모노에틸에테르 200㎎을 가하여 교반하여 맑은 용액을 제조하였다.After dissolving 7.5 mg of DDB in 500 mg of diethylene glycol monoethyl ether, 300 mg of water and 200 mg of diethylene glycol monoethyl ether were added thereto, followed by stirring to prepare a clear solution.
[실시예 2]Example 2
에틸렌글리콜 모노에틸에테르 500㎎에 DDB 7.5㎎을 녹인 후 물 100㎎과 에틸렌글리콜 모노에틸에테르 400㎎을 가하여 교반하여 맑은 용액을 제조하였다.7.5 mg of DDB was dissolved in 500 mg of ethylene glycol monoethyl ether, and 100 mg of water and 400 mg of ethylene glycol monoethyl ether were added thereto, followed by stirring to prepare a clear solution.
[실시예 3]Example 3
디에틸렌글리콜 모노메틸에테르 500㎎에 DDB 7.5㎎을 녹인 후 물 300㎎과 디에틸렌글리콜 모노메틸에테르 200㎎을 가하여 교반하여 맑은 용액을 제조하였다.After dissolving 7.5 mg of DDB in 500 mg of diethylene glycol monomethyl ether, 300 mg of water and 200 mg of diethylene glycol monomethyl ether were added thereto, followed by stirring to prepare a clear solution.
[실시예 4]Example 4
디에틸렌글리콜 모노에틸에테르 500㎎에 DDB 7.5㎎을 녹인 후 물 200㎎과 에틸렌글리콜 모노에틸에테르 300㎎을 가하여 교반하여 맑은 용액을 제조하였다.After dissolving 7.5 mg of DDB in 500 mg of diethylene glycol monoethyl ether, 200 mg of water and 300 mg of ethylene glycol monoethyl ether were added thereto, followed by stirring to prepare a clear solution.
[실시예 5]Example 5
디에틸렌글리콜 모노에틸에테르 500㎎에 DDB 7.5㎎을 녹인 후 폴리에틸렌글리콜 #300을 200㎎과 혼합하고 물 200㎎을 가하고 다시 디에틸렌글리콜 모노메틸에테르를 100㎎을 가하여 교반하여 맑은 용액상태로 제조하였다.After dissolving 7.5 mg of DDB in 500 mg of diethylene glycol monoethyl ether, polyethylene glycol # 300 was mixed with 200 mg, 200 mg of water was added thereto, and 100 mg of diethylene glycol monomethyl ether was further stirred to prepare a clear solution. .
[실시예 6]Example 6
디에틸렌글리콜 모노메틸에테르 500㎎에 DDB 7.5㎎을 녹인 후 폴리에틸렌글리콜 #300을 200㎎을 가하고, 여기에 물 200㎎을 가하고 다시 디에틸렌글리콜 모노메틸에테르 100㎎을 가하여 교반하여 맑은 용액상태를 제조하였다.After dissolving 7.5 mg of DDB in 500 mg of diethylene glycol monomethyl ether, 200 mg of polyethylene glycol # 300 was added thereto, 200 mg of water was added thereto, and 100 mg of diethylene glycol monomethyl ether was added thereto, followed by stirring to prepare a clear solution. It was.
[실시예 7]Example 7
디에틸렌글리콜 모노에틸에테르 500㎎ DDB 7.5㎎을 녹인 후 주사용 증류수 300㎎과 디에틸렌글리콜 모노에틸에테르 200㎎을 가하여 교반한 다음 1ml용량의 앰플에 충진하고 멸균시켜서 주사제를 제조하였다.Diethylene glycol monoethyl ether 500 mg DDB 7.5 mg was dissolved, and 300 mg of distilled water for injection and 200 mg of diethylene glycol monoethyl ether were added thereto, followed by stirring and filling into a 1 ml ampoule and sterilization.
[실시예 8]Example 8
에틸렌글리콜 모노에틸에테르 500㎎에 DDB 7.5㎎을 녹인 후 주사용증류수 100㎎과 에틸렌글리콜 모노에틸에테르 400㎎을 가하여 교반한 다음 1ml용량의 앰플에 충진하고 멸균시켜서 주사제를 제조하였다.After dissolving 7.5 mg of DDB in 500 mg of ethylene glycol monoethyl ether, 100 mg of distilled water for injection and 400 mg of ethylene glycol monoethyl ether were added and stirred, followed by filling into a 1 ml ampoule and sterilizing to prepare an injection.
[실시예 9]Example 9
디에틸렌글리콜 모노메틸에테르 500㎎에 DDB 7.5㎎을 녹인 후 주사용증류수 300㎎과 디에틸렌글리콜 모노메틸에테르 200㎎을 가하여 교반한 다음 1ml용량의 앰플에 충진하고 멸균시켜서 주사제를 제조하였다.After dissolving 7.5 mg of DDB in 500 mg of diethylene glycol monomethyl ether, 300 mg of distilled water for injection and 200 mg of diethylene glycol monomethyl ether were added thereto, followed by stirring and filling into a 1 ml ampoule and sterilization.
[실시예 10]Example 10
디에틸렌글리콜 모노메틸에테르 500㎎에 DDB 7.5㎎을 녹인 후 주사용증류수 200㎎과 에틸렌글리콜 모노에틸에테르 300㎎을 가하여 교반한 다음 1ml용량의 앰플에 충진하고 멸균시켜서 주사제를 제조하였다.After dissolving 7.5 mg of DDB in 500 mg of diethylene glycol monomethyl ether, 200 mg of distilled water for injection and 300 mg of ethylene glycol monoethyl ether were added and stirred, followed by filling into a 1 ml ampoule and sterilizing to prepare an injection.
[실시예 11]Example 11
디에틸렌글리콜 모노에틸에테르 500㎎에 DDB 7.5㎎을 녹인 후 폴리에틸렌글리콜 #300 200㎎, 주사용 증류수 200㎎ 및 디에틸렌글리콜 모노에틸에테르 200㎎을 가하여 교반한 다음 1ml용량의 앰플에 충진하고 멸균시켜서 주사제를 제조하였다.After dissolving 7.5 mg of DDB in 500 mg of diethylene glycol monoethyl ether, 200 mg of polyethylene glycol # 300, 200 mg of distilled water for injection, and 200 mg of diethylene glycol monoethyl ether were added to the mixture, followed by stirring. Injections were prepared.
[실시예 12]Example 12
디에틸렌글리콜 모노에틸에테르 500㎎에 DDB 7.5㎎을 녹인 후 폴리에틸렌글리콜 #300 200㎎, 주사용 증류수 200㎎ 및 디에틸렌글리콜 모노메틸에테르 100㎎을 가하여 교반한 후 1ml용량의 앰플에 충진하고 멸균시켜서 주사제를 제조하였다.After dissolving 7.5 mg of DDB in 500 mg of diethylene glycol monoethyl ether, 200 mg of polyethylene glycol # 300, 200 mg of distilled water for injection, and 100 mg of diethylene glycol monomethyl ether were added to the mixture, followed by stirring. Injections were prepared.
[실험예 1]Experimental Example 1
효능실험 : 사염화 탄소로 유도된 간 장애에 대한 복강투여효과Efficacy test: intraperitoneal effect on carbon tetrachloride-induced liver disorders
(1) 실험동물(1) experimental animals
체중 120∼150g 전후의 S.D계 웅성 랫트 7 마리씩 9군을 실험 시작 10시간 전부터 물만 주어 사육하였다.Nine groups of seven S.D male rats at around 120-150 g body weight were fed with water only 10 hours before the experiment.
(2) 실험방법(2) Experimental method
실험 동물은 7 마리씩 9 군으로 나누었다.Experimental animals were divided into 9 groups of 7 animals each.
제 1군은 대조군으로 아무 처리 없이 사육하였다.The first group was raised without any treatment as a control.
제 2군은 사염화탄소의 중독여부를 알기 위하여 사염화탄소를 콩기름에 용해하여 농도는 6.25% (v/v)로 만든 액으로 체중 ㎏당 1.25mL 씩을 복강 주사하였다.The second group was intraperitoneally injected with carbon tetrachloride in soybean oil to determine the poisoning of carbon tetrachloride in a concentration of 6.25% (v / v) with 1.25 mL per kg body weight.
제 3, 4, 5, 6, 7, 8군은 양성대조군으로 6.25 % 사염화탄소를 ㎏당 1.25 mL 씩을 복강 주사하고 30분 경과한 후 실시예 1, 2, 3, 4, 5 및 6을 DDB로서 37.5 ㎎ 해당량을 취하여 복강 주사하였다. 마찬가지로, 제 9군도 사염화탄소를 ㎏당 1.25 mL 씩을 복강 주사한 후 30분 경과 후 DDB 37.5 ㎎을 콩기름에 현탁하여 복강주사하였다. 18 시간 경과 후 혈액을 취하여 s-GPT 와 s-GOT 를 측정하였다.The third, fourth, fifth, sixth, seventh, and eighth groups were positive control groups, which were intraperitoneally injected with 6.25% carbon tetrachloride at 1.25 mL per kg, and 30 minutes later, Examples 1, 2, 3, 4, 5, and 6 were treated as DDB. A 37.5 mg equivalent was taken and intraperitoneally injected. Similarly, Group 9 was also intraperitoneally injected with 37.5 mg of DDB in soybean oil 30 minutes after intraperitoneally injecting 1.25 mL of carbon tetrachloride per kg. After 18 hours, blood was taken to measure s-GPT and s-GOT.
그 결과는 [표. 1]와 같았다.The results are shown in [Table. 1].
[표. 1] 사염화 탄소 투여 후 화합물의 s-GPT 및 s-GOT에 대한 영향[table. 1] Effect of compounds on s-GPT and s-GOT after carbon tetrachloride
A : 대조군A: control group
B : 사염화 탄소 6.25 %, 1.25 mLB: carbon tetrachloride 6.25%, 1.25 mL
C : 사염화 탄소 6.25 %, 1.25 mL/㎏ + 실시예 1C: carbon tetrachloride 6.25%, 1.25 mL / kg + Example 1
D : 사염화 탄소 6.25 %, 1.25 mL/㎏ + 실시예 2D: 6.25% carbon tetrachloride, 1.25 mL / kg + Example 2
E : 사염화 탄소 6.25 %, 1.25 mL/㎏ + 실시예 3E: carbon tetrachloride 6.25%, 1.25 mL / kg + Example 3
F : 사염화 탄소 6.25 %, 1.25 mL/Kg + 실시예 4F: 6.25% carbon tetrachloride, 1.25 mL / Kg + Example 4
G : 사염화 탄소 6.25 %, 1.25 mL/Kg + 실시예 5G: carbon tetrachloride 6.25%, 1.25 mL / Kg + Example 5
H : 사염화 탄소 6.25 %, 1.25 ml/Kg + DDBH: carbon tetrachloride 6.25%, 1.25 ml / Kg + DDB
[실험예 2]Experimental Example 2
안정성에 대한 실험Experiment on stability
실시예 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 및 12의 액제 및 주사제를 실온에서 30일동안 방치하여 상태를 관찰하였으나, 침전이 생성된 것은 없었다.The solution and injection of Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 were left at room temperature for 30 days to observe the condition, but no precipitate was formed.
따라서, 본 발명의 액제는 매우 안정한 제제임이 확인된다.Therefore, it is confirmed that the liquid formulation of the present invention is a very stable formulation.
Claims (3)
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| KR1019970037233A KR100228752B1 (en) | 1997-08-04 | 1997-08-04 | Liquid preparation containing insoluble biphenyldimethyldicarboxylate as active ingredient |
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