KR101889121B1 - Pharmaceutical preparation - Google Patents
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- KR101889121B1 KR101889121B1 KR1020137023297A KR20137023297A KR101889121B1 KR 101889121 B1 KR101889121 B1 KR 101889121B1 KR 1020137023297 A KR1020137023297 A KR 1020137023297A KR 20137023297 A KR20137023297 A KR 20137023297A KR 101889121 B1 KR101889121 B1 KR 101889121B1
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- propofol
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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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
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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
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
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- 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
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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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2121/00—Preparations for use in therapy
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- 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
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- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
본 발명은 프로포폴 염과 시클로덱스트린의 복합체를 포함하는 제약 제제에 관한 것이다. 본 발명은 저장될 수 있으며 문제없이 정맥내 투여될 수 있는 제제로 프로포폴을 제공하는 것을 가능하게 만든다.The present invention relates to a pharmaceutical formulation comprising a complex of a propofol salt and a cyclodextrin. The present invention makes it possible to provide a propol with a formulation that can be stored and administered intravenously without problems.
Description
본 발명은 프로포폴을 포함하는 제약 제제에 관한 것이다.The present invention relates to pharmaceutical formulations comprising propofol.
약학에서, 적용의 특정 유형을 통해, 의도한 작용 부위에서 바람직한 농도로 및 가능한 한 효과적으로 투여되도록 제약 활성 성분을 제제화하는 것은 흔한 과제이다. 따라서, 혈중 전신 농도가 완전히 달성될 수 있기 위하여 정맥내 적용으로 의도된 활성 성분은 어느 정도로 물에 가용성이어야 한다. 반면에, 필요시, 일반적으로 특정 친유성을 적절하게 가져서 의도된 작용 부위에서 세포막을 침투할 수 있어야 한다. 정맥내 적용 이후에 단지 쉽게 수용성 활성 성분은 예를 들어, 높은 혈중 전신 농도를 얻을 수 있지만, 예를 들어 지나치게 낮은 친유성의 경우에, 이는 의도된 작용 부위에서 세포막을 통한 이동이 아마 부적합할 것이기 때문에 낮은 생체이용율을 가질 것이다.In pharmacy, it is a common practice to formulate pharmaceutical active ingredients to be administered at the desired concentration, and as effectively as possible, at the intended site of action, through a particular type of application. Thus, the active ingredient intended for intravenous application should be water soluble to some extent so that the systemic blood plasma concentration can be fully achieved. On the other hand, if necessary, it is generally necessary to have a certain lipophilic property to penetrate the cell membrane at the intended site of action. It is only readily possible for the water-soluble active ingredient to achieve a high blood systemic concentration, for example, after intravenous application, but in the case of an excessively low lipophilic property, for example, it is likely that migration through the cell membrane at the intended site of action And therefore will have low bioavailability.
프로포폴은 1977년에 처음으로 임상 시험된 정맥내 마취제이다. 프로포폴은 정맥내 투여가 용이하도록 만들어져야하는 수난용성 마취제 활성 성분이다.Propol was the first intravenous anesthetic tested in 1977. Propofol is a water-soluble anesthetic active ingredient that should be made easy to administer intravenously.
지방 에멀전 중의 마취제의 용액 (상품명 디프리반(Diprivan)®)은 정맥내(i.v.) 투여에서 종종 관찰되는 정맥 통증을 감소시킬 수 있었고, 따라서 프로포폴이 1989 년에 임상에 도입되었다.A solution of anesthetics during the fat emulsion (trade name Diprivan®) could reduce the vein pain often observed in intravenous (i.v.) administration, and so propol was introduced into the clinic in 1989.
이 프로포폴 지질 에멀전은 콩기름, 글리세롤 및 난(egg) 포스파티드를 포함한다. 주사시의 정맥 통증은 종종 계속해서 발생하는 과제이다. 게다가, 심각한 과민반응을 야기할 수 있다. 지방 에멀전으로서 제제는 미생물 성장에 유리하기 때문에, 에멀전의 오염은, 심지어 짧은 저장 시간 후에도, 투여 후에 패혈증을 야기할 수 있다.This propol lipid emulsion contains soybean oil, glycerol and egg phosphates. Vein pain at the time of injection is often an ongoing problem. In addition, it can cause serious hypersensitivity reactions. Since the formulation as a fat emulsion is beneficial to microbial growth, contamination of the emulsion may cause sepsis after administration, even after a short storage time.
본 발명의 목적은 문제가 없는 정맥내 투여를 가능하게 하고 명시된 단점을, 있다 하더라도, 보다 적게 가지는, 처음에 언급된 유형의 제약 제제를 제공하는 것이다.It is an object of the present invention to provide a pharmaceutical formulation of the type mentioned at the outset, which enables a problem-free intravenous administration and has, if any, the stated drawbacks.
이 목적은 염으로서의 프로포폴과 시클로덱스트린을 복합체로 형성하여 달성된다. 프로포폴은 알칼리성 매질에서 염으로 전환될 수 있다. 프로포폴 음이온은 시클로덱스트린에 의해 복합체로 형성될 수 있다. 본 발명의 내용 내에서, 용어 프로포폴 염은 시클로덱스트린에 의해 복합체로 형성될 수 있는 프로포폴의 음이온 (페놀레이트)을 지칭한다. 본 발명에 따른 복합체에서, 따라서 프로포폴은 음이온으로서 복합체 형태로 존재한다.This object is achieved by forming a complex of propofol and cyclodextrin as a salt. The propol may be converted to a salt in an alkaline medium. The propofol anion can be formed into a complex by cyclodextrin. Within the context of the present invention, the term propofol refers to the anion of the propofol (phenolate), which can be formed into a complex by cyclodextrin. In the complex according to the invention, the propol is thus present in complex form as an anion.
놀랍게도, 고 프로포폴 농도를 가지는 안정한, 주사가능한 제약 제제가 이러한 방법으로 제조될 수 있다는 것이 발견되었다. 본 발명에 따른 제약 제제는 주사에 적합한 수용액으로 제공될 수 있다. 다르게는, 복합체를 제조한 이후에, 용매를 제거하고 저장가능한 고체로 복합체를 제공하는 것이 가능하다. 투여 이전에, 이 고체는 다시 수용액으로 전환된다.Surprisingly, it has been found that stable, injectable pharmaceutical preparations having a high propofol concentration can be prepared in this way. The pharmaceutical preparations according to the invention may be provided in an aqueous solution suitable for injection. Alternatively, after preparing the complex, it is possible to remove the solvent and provide the complex with a storable solid. Prior to administration, the solid is again converted to an aqueous solution.
복합체의 수용액의 pH는 바람직하게는 7 초과, 더욱 바람직하게는 8 초과, 더욱 바람직하게는 9 초과이다. pH의 바람직한 상한선은 11 또는 10이다. 8-11, 더욱 바람직하게는 9-11, 더욱 바람직하게는 9-10의 pH 범위가 특히 선호된다. 만일 복합체가 저장가능한 고체로 제공된다면, 정해진 범위에서의 pH는 수중 재용해화 이후에 바람직하게는 달성된다.The pH of the aqueous solution of the complex is preferably more than 7, more preferably more than 8, more preferably more than 9. The preferred upper limit of pH is 11 or 10. A pH range of 8-11, more preferably 9-11, and more preferably 9-10 is particularly preferred. If the complex is provided as a storable solid, the pH in the defined range is preferably achieved after the in-water redissolution.
본 발명에 따라서, 프로포폴의 복합체 형성에 사용되는 시클로덱스트린은 특히 바람직하게는 2-히드록시프로필-베타-시클로덱스트린 (HPBCD)이다. 사용되는 프로포폴 염은 바람직하게는 알칼리 금속 염, 특히 바람직하게는 나트륨 염이다.According to the present invention, the cyclodextrin used for forming the complex of propol is particularly preferably 2-hydroxypropyl-beta-cyclodextrin (HPBCD). The propofol salt used is preferably an alkali metal salt, particularly preferably a sodium salt.
프로포폴 염과 시클로덱스트린의 서로에 대한 몰비는 바람직하게는 1:2 내지 1:6, 더욱 바람직하게는 1:2 내지 1:4, 더욱 바람직하게는 약 1:2이다. 복합체의 프로포폴 염 함량은 바람직하게는 약 4 내지 9 중량%이다.The molar ratio of the propofol salt to the cyclodextrin to each other is preferably 1: 2 to 1: 6, more preferably 1: 2 to 1: 4, more preferably about 1: 2. The propofol salt content of the complex is preferably about 4 to 9% by weight.
본 발명은 또한 본 발명에 따른 제약 제제를 제조하는 방법을 제공한다. 본 발명에 따라서, 먼저 시클로덱스트린의 알칼리성 수용액을 제조한다. 프로포폴을 알칼리성 용액에 첨가하고, 바람직하게는 저으면서, 용해 및 복합체 형성을 달성할 정도로 혼합한다. 이는 바람직하게는 비활성 기체 대기하에서 일어난다. 본 발명에 따라, 프로포폴이 시클로덱스트린에 첨가된 이후에 비로소 알칼리성 조건을 달성하는 것이 마찬가지로 가능하다.The present invention also provides a method for preparing a pharmaceutical preparation according to the present invention. According to the present invention, an alkaline aqueous solution of cyclodextrin is first prepared. The propol is added to the alkaline solution and mixed, preferably with stirring, to such an extent that dissolution and complex formation are achieved. This preferably takes place under an inert gas atmosphere. According to the present invention, it is likewise possible to achieve an alkaline condition only after the propofol is added to the cyclodextrin.
프로포폴의 용해 및 복합체 형성은 바람직하게는 2 내지 10 시간, 더욱 바람직하게는 3 내지 5 시간, 더욱 바람직하게는 약 4 시간의 기간에 걸쳐서 이루어진다. 본 발명에 따른 용해 및 복합체 형성 방법은, 프로포폴의 페놀 형태의 복합체 형성의 경우보다 본질적으로 더 빠르게 일어난다. 또한, 복합체 중의 프로포폴의 현저하게 더 높은 농도가 달성될 수 있다.The dissolution and complex formation of the propol is preferably carried out over a period of 2 to 10 hours, more preferably 3 to 5 hours, and more preferably about 4 hours. The dissolution and complexation methods according to the present invention occur essentially faster than in the case of complex formation of the phenol form of propol. In addition, a significantly higher concentration of propol in the complex can be achieved.
추가의 단계에서, 본 발명에 따라 얻어진 용액은 예를 들어 여과되어, 잔류 고체 부분이 없을 수 있다. 예를 들어, 0.45 ㎛의 공극 크기를 가지는 공극 필터를 통한 여과가 적합하다.In a further step, the solution obtained according to the invention may be filtered, for example, and there may be no residual solid portion. For example, filtration through a pore filter having a pore size of 0.45 mu m is suitable.
예컨대 동결 건조와 같은 공지된 적합한 방법에 의하여, 본 발명에 따라 제조된 용액으로부터 용매가 제거될 수 있다. 복합체는 이러한 방법으로 저장가능하고 재용해가능한 고체로 제공된다.The solvent may be removed from the solution prepared according to the present invention by known suitable methods such as, for example, freeze-drying. The complex is provided in this way as a storable and re-usable solid.
본 발명의 일 실시예를 아래에 설명하였다.One embodiment of the present invention has been described below.
사용된 모든 물질의 규격은 유럽 약전 (Ph. Eur.)에 부합한다. 다음의 공급 물질들을 사용하였다:The specifications of all the substances used conform to the European Pharmacopoeia (Ph. Eur.). The following feed materials were used:
- 프로포폴- Propol
- NaOH- NaOH
- HPBCD- HPBCD
- 주사용수- Injection water
NaOH를 60 ml의 물을 사용하여 제조하여 0.01 N NaOH 용액을 얻었다. 12 g의 HPBCD를 여기에 첨가했고 저으면서 용해시켰다. 그 다음, 0.817 g의 프로포폴을 첨가했고, 변화하는(evolving) 프로포폴 염이 용해되고 복합체로 형성될 때까지 혼합물을 40-80 min-1에서 4 h 동안 더 저었다. 생성된 용액은 9-10의 pH를 가진다.NaOH was prepared using 60 ml of water to obtain a 0.01 N NaOH solution. 12 g of HPBCD was added thereto and dissolved gently. Then 0.817 g of propol was added and the mixture was further stirred at 40-80 min < -1 > for 4 h until the evolving propofol salt dissolved and complexed. The resulting solution has a pH of 9-10.
0.45 ㎛의 공극 크기를 가지는 공극 필터를 통해 얻어진 용액을 여과하였다. 여과 후에, 용액을 동결 건조하였다. 백색 분말을 얻었다. 얻어진 복합체는 다음과 같이 특성화될 수 있다:A solution obtained through a pore filter having a pore size of 0.45 mu m was filtered. After filtration, the solution was lyophilized. A white powder was obtained. The resulting complexes can be characterized as follows:
물속에서 복합체의 재용해화는 46 mg/ml의 활성 프로포폴 함량을 가지는 수용액을 제공한다.The redissolution of the complex in water provides an aqueous solution having an active propofol content of 46 mg / ml.
Claims (17)
b) 프로포폴을 알칼리성 수용액에 용해하는 단계
를 특징으로 하는, 제1항 내지 제11항 중 어느 한 항에 기재된 제제의 제조 방법.a) preparing an alkaline aqueous solution of cyclodextrin,
b) dissolving the propol in an alkaline aqueous solution
12. The method for producing a preparation according to any one of claims 1 to 11,
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IB2012/000391 WO2012104730A1 (en) | 2011-02-04 | 2012-03-01 | Pharmaceutical preparation |
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| Publication Number | Publication Date |
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| KR20140120254A KR20140120254A (en) | 2014-10-13 |
| KR101889121B1 true KR101889121B1 (en) | 2018-09-20 |
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| KR1020137023297A KR101889121B1 (en) | 2012-03-01 | 2012-03-01 | Pharmaceutical preparation |
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| KR (1) | KR101889121B1 (en) |
| CA (1) | CA2826513C (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002074200A1 (en) * | 2001-03-20 | 2002-09-26 | Cydex, Inc. | Formulations containing propofol and a sulfoalkyl ether cyclodextrin |
| WO2003080079A1 (en) | 2002-03-19 | 2003-10-02 | Cydex, Inc. | Use of sulfoalkyl ether cyclodextrin as a preservative |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20040091004A (en) * | 2002-02-01 | 2004-10-27 | 쉬모다 바이오테크(피티와이) 리미티드 | Pharmaceutical Composition |
-
2012
- 2012-03-01 KR KR1020137023297A patent/KR101889121B1/en active IP Right Grant
- 2012-03-01 CA CA2826513A patent/CA2826513C/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002074200A1 (en) * | 2001-03-20 | 2002-09-26 | Cydex, Inc. | Formulations containing propofol and a sulfoalkyl ether cyclodextrin |
| WO2003080079A1 (en) | 2002-03-19 | 2003-10-02 | Cydex, Inc. | Use of sulfoalkyl ether cyclodextrin as a preservative |
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| Publication number | Publication date |
|---|---|
| CA2826513A1 (en) | 2012-08-09 |
| KR20140120254A (en) | 2014-10-13 |
| CA2826513C (en) | 2019-02-05 |
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