Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2001-12-21
2004-06-01
Azpuru, Carlos A. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C514S772300
Reexamination Certificate
active
06743436
ABSTRACT:
TECHNICAL FIELD
The present invention relates to an anesthetic composition for intravenous injection comprising 2,6-diisopropylphenol (hereinafter, referred to as “propofol”). More specifically, the present invention relates to an anesthetic composition for intravenous injection, characterized in that it contains propofol and a poloxamer as the surfactant.
BACKGROUND ART
Propofol is highly lipid-soluble and has a characteristic property that it can readily permeate biomembranes such as blood brain barrier (BBB). Therefore, it has been used as a useful anesthetic agent.
In general, anesthetic agents are eliminated through their metabolism and excretion in living body. When an anesthetic agent having a long half-life is repeatedly administered in a large amount, it may be greatly accumulated into storage tissues such as skeletal muscles, adipose tissues, etc., so that the recovery may be delayed. Thus, if such anesthetic agent is administered for a long period, since it may be diffused from storage tissues into the blood to increase its plasma concentration, the recovery rate of patients may be delayed and the psychomotor function may also be damaged over long period.
Contrary to this, an alkylphenol derivative, propofol, has a short half-life and thus, has some clinical characteristic features that it can be rapidly migrated into the brain to show a rapid onset of anesthetic effect and further, rapidly re-distributed into other tissues and then metabolized so that the patients can be rapidly recovered from the anesthetic state. In addition, propofol may cause less side effects such as headache, nausea, vomiting, etc., than other anesthetic agents in patients and its accumulation into human body can be minimized in spite of its administration for a long period. Therefore, it has been known that propofol is the most ideal anesthetic agent for intravenous injection.
Further, while many anesthetic agents commonly used in the clinical field are in a gaseous state, propofol is useful for intravenous injection and therefore, can be very effectively used as a local analgesic adjuvant due to its hypnotic and sedative activities, an anesthetic agent for patients for whom pulmonary respiration should be cared, an anesthetic agent used under conscious state, etc., or for patients under medical treatment in intensive care unit (ICU) or patients in serious state, etc.
In spite of such clinical advantages of propofol, the development of its injectable formulations is very difficult since propofol exists in the non-ionized state (pKa=10.4) in blood and has physico-chemical properties including a unique high lipid solubility (octanol water partition coefficient 4.33).
Thus, since water may substantially be an essential solvent in preparing all pharmaceutical formulations including anesthetic agents, it is very difficult to formulate lipid-soluble drugs such as propofol into pharmaceutical preparations using water as the solvent. In order to solve such problem, lipid-soluble drugs which are generally poorly soluble in water have been developed into such forms as emulsions, microemulsions, micelles, etc., using a surfactant. However, it also possesses a limitation.
In the prior art, Zeneca Inc. has prepared and sold the formulation wherein 1% propofol is dissolved in 16% CREMAPHOR EL (Polyoxyl 35 castor oil) as a non-ionic surfactant. However, this formulation causes some side effects such as anaphylactoid reaction as an allergic reaction in some patients, which is believed to be caused by CREMAPHOR EL (Polyoxyl 35 castor oil) contained therein in an excessive amount. Therefore, in order to overcome such side effects caused by the surfactant Zeneca Inc. has developed the injectable formulation (trade name: Diprivan) in the form of a novel fat emulsion, wherein 1% propofol is dissolved in 10% soybean oil and then stabilized with 1.25% egg phosphatide.
However, it has been indicated that the emulsions for intravenous injection containing lipid materials have many side effects and problems, which can be generally and roughly summarized as the following five issues:
First, the emulsion is thermodynamically unstable and therefore, is fused in the course of time to make the formulation unstable.
Second, there is a possibility of causing embolism due to particles in size of 1 &mgr;m or more which may possibly be present in heterogeneous emulsions.
Third, the active ingredient and lipid components may cause a pain when the formulation is injected.
Fourth, since the lipid component may serve as a cause of the acceleration of microorganism growth in the absence of any preservative, strict aseptic techniques must be maintained when handling these formulation.
Finally, the administration of lipid components as the main ingredient may result in hyperlipidemia.
Thus, in the field of anesthesiology, the development of novel formulation which can solve the above-mentioned problems has been on the rise as the forefront subject. In th□Åis regard, Zeneca Inc. has developed the formulation comprising a novel composition having an antiseptic activity by addition of a preservative (EDTA) in order to inhibit the microorganism growth due to lipid components amongst the above-mentioned problems (U.S. Pat. No. 5,714,520). However, this formulation still has the unsolved problems including physical unstability, pain at injection site, embolism, hyperlipidemia, Further, in order to improve such problems, the formulations have recently been studied using inclusion complexation of propofol with biodegradable surfactants or cyclodextrin (Giuseppe Trapani et al.,
J. Pharm. Sci
., 1998, 87, 514-518), the concept of prodrugs (Sagara Y.,
J. Neurochem
., 1999, 73, 2524-2530), etc. In addition, the study to reduce the pain during injection by administration in combination with such neuroblocking agents as lidocain has been actively and extensively practiced from all parts of the world (Parmar A. K.,
Anaesthesia
, 1998, 53, 79-83). However, such study has not been verified for their effect as yet and thus, not been actually completed. Therefore, the need an anesthetic composition for intravenous injection, which is capable of providing the efficient formulation and minimized side effects, has been very gradually increased.
Thus, the technical subject of the present invention is to provide a useful anesthetic composition for intravenous injection which can be efficiently converted into the desired formulation and further, can minimize the side effects, with overcoming the above-mentioned problems involved in the prior art.
DISCLOSURE OF THE INVENTION
The technical subject of the present invention is to provide a useful anesthetic composition for intravenous injection which can be efficiently converted into the desired formulation and further, can minimize the side effects, with overcoming the above-mentioned problems involved in the prior art.
In order to achieve said technical subject, the present invention provides an anesthetic composition for intravenous injection, which comprises propofol and a poloxamer as the surfactant.
According to the present invention, it is preferred that propofol is contained in an amount of 1 to 2% by weight of the total composition.
Further, the composition of the present invention may additionally contain at least one co-surfactant selected from the group consisting of SOLUTOL HS 15 (Macrogol-15 Hydroxystearate), egg lecithin, LABRASOL (Polyoxy capryllic glyceride), polyoxy 10 oleyl ether, TWEEN (polyoxyethylene sorbitan fatty acid esters), ethanol and polyethylene glycol, in addition to a Poloxamer POLOXAMER (Polyoxyethylene-polyoxypropylene copolymer) as the surfactant.
In the present invention, it is particularly preferred to use POLOXAMER 407 (Polyoxyethylene-polyoxypropylene copolymer) as the POLOXAMER (Polyoxyethylene-polyoxypropylene copolymer). It is desirable to have POLOXAMER 407 (Polyoxyethylene-polyoxypropylene copolymer) in an amount of 0.1 to 5% by weight of the total composition.
In addition, the composition of the present invention is preferably present in the fo
Cho Hoon
Jin Ji-Young
Lee Hyuk-Koo
Azpuru Carlos A.
Birch & Stewart Kolasch & Birch, LLP
Kuhnil Pharm. Co., Ltd.
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