KR100358934B1 - Injectable Pharmaceutical Compositions with Taxol - Google Patents
Injectable Pharmaceutical Compositions with Taxol Download PDFInfo
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- KR100358934B1 KR100358934B1 KR1019960039723A KR19960039723A KR100358934B1 KR 100358934 B1 KR100358934 B1 KR 100358934B1 KR 1019960039723 A KR1019960039723 A KR 1019960039723A KR 19960039723 A KR19960039723 A KR 19960039723A KR 100358934 B1 KR100358934 B1 KR 100358934B1
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- 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
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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Abstract
Description
본 발명은 종래의 탁솔(TAXOLR) 주사제에 비하여 용해성이 우수하고 제형이 안정하며 환자들에게 투여시 부작용이 적은, 탁솔을 함유한 주사용 약제 조성물에 관한 것이다.The present invention relates to a pharmaceutical composition for injection containing Taxol, which has better solubility, stable formulation, and fewer side effects when administered to patients compared to conventional TAXOL R injections.
주목나무(Taxus spp.)로부터 얻어지는 탁솔(TAXOLR: paclitaxel)은 20개 이상의 비대칭 중심을 갖는 극히 복잡한 디테르펜(diterpene)계 탁산(taxane) 화합물로, 특히 난소암, 유방암 등에 탁월한 치료 효과를 갖는 것으로 알려진 항암 물질이다. 탁솔에 관한 연구는 1960년대 미국 국립 암연구소가 35,000 종의 식물을 대상으로 실시한 항암 활성 물질의 대규모 스크리닝 프로그램에서 시작되어, 태평양 주목(Taxus brevifolia) 껍질의 추출물이 백혈병과 폐암을 포함하는 여러가지 종양에 대하여 강한 활성을 나타내는 것으로 보고된 후, 1969년에는 월(Wall) 등에 의해 활성 물질이 분리되었고, 1971년에는 활성물질의 본체로서 탁솔의 구조가 밝혀지게 되었다(Eric K. Rowinsky, Lorraine A. Cazenave, Ross C. Dondhower, J.National Cancer Inst., 82: 11247 (1990)).Taxol (TAXOL R : paclitaxel) from Taxus spp. It is known to be an anticancer substance. Taxol research began in the 1960s with a large-scale screening program of anticancer actives conducted by the National Cancer Institute of the United States on 35,000 species of plants, and extracts from the Pacificus ( Texus brevifolia ) bark on various tumors, including After being reported to have a strong activity against, the active material was separated by Wall et al. In 1969 and the structure of Taxol as the body of the active material was revealed in 1971 (Eric K. Rowinsky, Lorraine A. Cazenave , Ross C. Dondhower, J. National Cancer Inst., 82 : 11247 (1990)).
기존의 항암제인 콜키신(Colchicine)이나 빈카 알칼로이드(Vinca alkaloid)가 미세관(microtubule)을 분해하여 항암작용을 나타내는 것과는 달리, 탁솔은 미세관의 중합(microtubule assembly)을 촉진하고 그 다음 단계인 분해과정을 억제하는 특이한 작용기작을 나타낸다는 것이 쉬프(Schiff) 등에 의하여 알려지면서(Schiff, P. B., J. Fant and S. B. Horwitz,Nature, 277: 665 (1979)), 탁솔에 대한 연구가 활발히 이루어져 현재는 난소암과 유방암의 치료에 주로 이용되고 있다. 현재 미국 NCI 의 임상시험 결과를 보면, 탁솔은 기존의 항암제로 치료가 불가능한 말기 암환자중 특히 난소암 30 %, 유방암 50 %, 그리고 폐암 20 % 정도의 치료율을 보이는 것으로 알려져 있다(David G. I., Samaranayake, and C. A. Ivey, J,Nat. Prod., 53: 1, (1990)).Unlike conventional anticancer drugs, Colchicine or Vinca alkaloid, which decompose microtubules and show anticancer activity, Taxol promotes microtubule assembly and the next step, the decomposition process. Schiff et al. (Schiff, PB, J. Fant and SB Horwitz, Nature, 277 : 665 (1979)) indicate that they have a specific mechanism of action that inhibits ovaries. It is mainly used for the treatment of cancer and breast cancer. According to the current clinical trials of NCI, Taxol is known to treat 30% of ovarian cancer, 50% breast cancer, and 20% lung cancer among terminal cancer patients who cannot be treated with conventional anticancer drugs (David GI, Samaranayake). , and CA Ivey, J, Nat. Prod., 53 : 1, (1990)).
이처럼 항암제로서 크게 기대되고 있음에도 불구하고 탁솔에 대한 연구는 매우 느린 속도로 진전되고 있는데, 그 주된 원인은 탁솔의 공급이 매우 부족하고 대규모 추출 분리 및 조제가 어렵기 때문이다.Despite such anticipated anticancer drugs, studies on Taxol are progressing at a very slow rate, mainly due to the lack of Taxol supply and the difficulty of large-scale extraction and preparation.
또한, 탁솔은 비수용성이기 때문에 주사제로 제조하는 데에도 어려움이 따르고 있어, 이 문제를 해결하기 위한 연구도 활발히 진행되고 있다. 예를 들어, 미합중국 특허 제5,478,860호에서는 탁솔을 올리브 오일 또는 해바라기 오일 등의 오일과 폴리에틸렌글리콜-결합된 지질(PEG-linked lipids) 등을 혼합하여 미세유상액(micro-emulsion)으로 제조하는 방법을 개시하고 있으며, 유럽 특허출원 제639,577호에서는 탁솔에 포스포노옥시메틸(POM) 또는 메틸티오메틸(MTM) 등의 새로운 치환체를 도입하여 물에 대한 용해도를 향상시킨 탁솔 유도체를 제조하는 방법을, 그리고 PCT출원 국제공개 WO-9318757호에서는 새로운 의약전달체계(drug delivery system: DDS)로서 리포좀으로 캡슐화한 탁솔(liposome-encapsulated Taxol)을 개발하여 탁솔의 용해도 문제를 해결하고 안정성을 향상시킨 제조방법을 개시하고 있다.In addition, since Taxol is insoluble in water, it is difficult to prepare it as an injection, and studies to solve this problem have been actively conducted. For example, U.S. Patent No. 5,478,860 discloses a method of preparing a taxol in a micro-emulsion by mixing oils such as olive oil or sunflower oil with polyethylene glycol-linked lipids. European Patent Application No. 639,577 discloses a method for preparing Taxol derivatives having improved solubility in water by introducing new substituents such as phosphonooxymethyl (POM) or methylthiomethyl (MTM) to Taxol, and PCT Application International Publication No. WO-9318757 discloses a new drug delivery system (DDS) that develops a liposome-encapsulated taxo (liposome-encapsulated Taxol) to solve the problem of solubility and improve the stability of Taxol. Doing.
현재 탁솔 주사제의 제조방법으로서 가장 실용화되어 있는 방법은 탁솔의 용해제로서 무수에탄올과 폴리에톡실레이티드 캐스터 오일(Cremophor ELTM: BASF사 제품)을 사용하는 방법이다. 그러나, 이 방법에 의해 제조된 탁솔 주사제의 경우에도 제형의 안정성이 떨어져, 장기 보관시에는 탁솔이 분해되어 역가가 떨어질 뿐 아니라 부작용을 증대시키는 요인으로 작용하기도 한다는 문제가 있다.Currently, the most practical method for preparing Taxol injection is to use ethanol anhydride and polyethoxylated castor oil (Cremophor EL ™ : manufactured by BASF) as a solvent for Taxol. However, in the case of Taxol injection prepared by this method, there is a problem that the formulation is inferior in stability, and in the case of long-term storage, the Taxol is decomposed to lower the titer and also act as a factor of increasing side effects.
본 발명에서는 탁솔을 함유하는 주사제에 있어서 상기와 같은 문제점을 고려하여 특정의 첨가제를 사용함으로써 제제의 안정성을 개선하고 탁솔의 부작용을 경감시킨 주사용 조성물을 제공하는 것을 목적으로 한다.It is an object of the present invention to provide an injectable composition which improves the stability of a preparation and reduces the side effects of Taxol by using a specific additive in consideration of the above problems in an injection containing Taxol.
상기 목적을 달성하기 위하여 본 발명에서는 탁솔, 무수에탄올 및 폴리에틸렌글리콜(PEG)을 포함하는 것을 특징으로 하는 탁솔을 함유하는 주사용 조성물을 제공한다.In order to achieve the above object, the present invention provides a taxol-containing injectable composition comprising Taxol, anhydrous ethanol and polyethylene glycol (PEG).
본 발명에서는 탁솔 용해제로서 무수 에탄올과 PEG 만을 사용한 간단한 조성에 의해서 제제의 안정성을 개선하고 탁솔의 부작용을 경감시킬 수 있다는 것을 특징으로 하는데, 여기에서 PEG는 수평균 분자량 200 내지 400 범위의 것을 사용하는 것이 바람직하고, 전체 조성물 부피의 40 내지 60 % 의 비율로 포함되는 것이 또한 바람직하다. 가장 바람직한 본 발명의 주사용 조성물은 조성물 1 ml 당 탁솔 6 mg이 포함되고 PEG 가 전체 조성물 부피의 50 % 인 것이다.In the present invention, a simple composition using only anhydrous ethanol and PEG as the Taxol dissolving agent can improve the stability of the formulation and reduce the side effects of Taxol, wherein PEG has a number average molecular weight in the range of 200 to 400. It is preferred that it is also included in a proportion of 40 to 60% of the total composition volume. Most preferred injectable compositions of the invention comprise 6 mg of Taxol per ml of composition and PEG is 50% of the total composition volume.
본 발명의 탁솔을 함유하는 주사용 조성물을 제조하는 방법은, 먼저 무수에탄올에 탁솔을 가하고 교반하여 용해시킨 용액에 일정량의 PEG 를 가하고 교반 혼화하여 최종적으로 주사용 조성물을 제조하는 것으로 이루어진다.The method for preparing the injectable composition containing Taxol of the present invention consists of first adding Taxol to anhydrous ethanol, adding a certain amount of PEG to a solution dissolved by stirring, and stirring and mixing to finally prepare the composition for injection.
이하 하기 실시예를 통하여 본 발명을 더욱 상세히 설명한다. 단, 하기의 실시예는 본 발명을 예시한 것일 뿐, 본 발명이 이들 만으로 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are merely illustrative of the present invention, the present invention is not limited to these.
실시예 1Example 1
무수에탄올 30 ml에 탁솔 300 mg을 가하여 10 분 동안 교반하여 용해시켰다. 이 용액에 PEG 200을 첨가하여 전체 용량이 50 ml 가 되도록 조정한 후 10 분 동안 교반하여 최종액을 제조하였다.300 mg of Taxol was added to 30 ml of anhydrous ethanol, followed by stirring for 10 minutes to dissolve. PEG 200 was added to the solution to adjust the total volume to 50 ml, followed by stirring for 10 minutes to prepare a final solution.
실시예 2Example 2
무수에탄올 25 ml에 탁솔 300 mg을 가하여 10 분 동안 교반하여 용해시켰다. 이 용액에 PEG 400 을 첨가하여 전체 용량이 50 ml 가 되도록 조정한 후 10 분 동안 교반하여 최종액을 제조하였다.300 mg of Taxol was added to 25 ml of anhydrous ethanol, followed by stirring for 10 minutes to dissolve. PEG 400 was added to the solution to adjust the total volume to 50 ml, followed by stirring for 10 minutes to prepare a final solution.
실시예 3Example 3
무수에탄올 20 ml에 탁솔 300 mg을 가하여 10 분 동안 교반하여 용해시켰다. 이 용액에 PEG 200 을 첨가하여 전체 용량이 50 ml 가 되도록 조정한 후 10 분 동안 교반하여 최종액을 제조하였다.300 mg of Taxol was added to 20 ml of anhydrous ethanol, followed by stirring for 10 minutes to dissolve. PEG 200 was added to the solution to adjust the total volume to 50 ml, followed by stirring for 10 minutes to prepare a final solution.
탁솔 주사제에 용해제로서 무수에탄올과 폴리에틸렌글리콜을 사용한 본 발명의 주사용 조성물은, 제형의 안정성이 개선되고 탁솔의 부작용이 경감되는 효과를 나타내므로 항암제로서 임상에서 유용하게 사용될 수 있을 것으로 기대된다.The injectable composition of the present invention using anhydrous ethanol and polyethylene glycol as a dissolving agent in Taxol injectables is expected to be useful in clinical use as an anticancer agent because of the effect of improving the stability of the formulation and reducing the side effects of Taxol.
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
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WO1994012198A1 (en) * | 1992-11-27 | 1994-06-09 | F.H. Faulding & Co. Limited | Injectable taxol composition |
US5403858A (en) * | 1991-07-08 | 1995-04-04 | Rhone-Poulenc Rorer, S.A. | New compositions containing taxane derivatives |
US5438072A (en) * | 1992-12-02 | 1995-08-01 | Rhone-Poulenc Rorer S.A. | Taxoid-based compositions |
US5504102A (en) * | 1993-09-29 | 1996-04-02 | Bristol-Myers Squibb Company | Stabilized pharmaceutical composition and stabilizing solvent |
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1996
- 1996-09-13 KR KR1019960039723A patent/KR100358934B1/en not_active Expired - Lifetime
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Publication number | Priority date | Publication date | Assignee | Title |
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US5403858A (en) * | 1991-07-08 | 1995-04-04 | Rhone-Poulenc Rorer, S.A. | New compositions containing taxane derivatives |
WO1994012198A1 (en) * | 1992-11-27 | 1994-06-09 | F.H. Faulding & Co. Limited | Injectable taxol composition |
US5438072A (en) * | 1992-12-02 | 1995-08-01 | Rhone-Poulenc Rorer S.A. | Taxoid-based compositions |
US5504102A (en) * | 1993-09-29 | 1996-04-02 | Bristol-Myers Squibb Company | Stabilized pharmaceutical composition and stabilizing solvent |
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