Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-02-19
2003-10-28
Cook, Rebecca (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S415000, C514S816000, C514S817000, C514S818000
Reexamination Certificate
active
06638966
ABSTRACT:
BACKGROUND OF THE INVENTION
In the medical field there is a continuing need for new compounds having demonstrated use for inducing anesthesia. It is not only important to induce beneficial anesthesia, but it must be done in a manner that limits toxicity to patients, and as well, minimizes what is known as “anesthesia hangover”.
The pineal hormone melatonin (N-acetyl-5-c) has several putative functions, including regulation of circadian rhythms, regulation of the reproductive axis and antioxidant activity. Autoradiographic studies and receptor assays have demonstrated the presence of melatonin receptors in various regions of the central nervous system and in other tissues in humans.
Exogenous administration of melatonin has been found by several investigators to facilitate sleep onset and improve quality of sleep. Available data suggest that the sleep-inducing properties of melatonin may differ from those of benzodiazepines. Benzodiazepines decrease duration of REM sleep after single administration of a high dose or long-term administration of low dose. Benzodiazepines also reduce slow-wave sleep, thus negatively influencing sleep quality. In contrast, a single low dose of melatonin produced no suppression of REM sleep. Furthermore, unlike benzodiazepines, melatonin does not induce “hangover” effects.
In a previous publication of one of the inventors,
British Journal of Anesthesia
82(6):875-80(1999), low-level dosing of oral melatonin in a sublingual fashion was demonstrated as an effective pre-medication, prior to administering a general anesthetic. Patients who were administered such low-level doses sublingually had a significant decrease in anxiety levels and an increase in levels of sedation before operation. However, as pointed out in that article, the use of melatonin in anesthesia had as of then never been evaluated properly, and to the inventor's present knowledge it has never been used as a general anesthetic prior to this series of applications.
The invention of Ser. No. 09/927,687 had as its primary objective the development of pineal hormone melatonin (N-acetyl-5-methoxytryptamine) or its biologically active analogues as a general anesthetic which can be used without any significant anesthetic hangover. The continuing need in the art for meeting that objective was readily apparent.
With reference to the continuing need referred to above, applicants have continued to work with melatonin and its analogues to derive improved compounds which may be used for anesthetic effect generally and in small doses for hypnotic effect sedation or even sleep inducement. This continuing work has evolved into the discovery that 2-trihalo methyl melatonins and in particular the 2-trifluoromethylmelatonin are substantially more active in anesthetic effect than melatonin itself. The result of this increased activity means that the compounds may be used in larger doses for general anesthesia, but in smaller doses for hypnotic effect and sedation and sleep effect.
Further discoveries since the filing of the original application have revealed a particularly effective pharmaceutical carrier for melatonin, melatonin analogues and the improved derivatives of the present invention. The carrier allows dissolving and high concentrations of melatonin or its analogues. The preferred carrier is comprised of one volume of 1-methyl-2-pyrrolidinone, one volume of propylene glycol and two volumes of water. It goes without saying that the volumetric ratios of these carrier solvents may be varied somewhat, depending upon the circumstances.
SUMMARY OF THE INVENTION
Anesthetic compositions are prepared using a pharmaceutically-acceptable carrier, preferably a preferred carrier comprising a mixture of one volume of 1-methyl-2-pyrrolidinone, one volume of propylene glycol and two volumes of water and an anesthetic-inducing effective amount of melatonin or biologically active analogues of melatonin such as 2-trifluoromethylmelatonin. The invention also relates to the method of administration using the described compositions.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
N-acetyl-5-methoxytryptamine (melatonin) is synthesized mainly by the pineal gland, and to a lesser extent by extra pineal tissues such as the retina, harderian gland, and gastrointestinal tract. Melatonin has the following structure:
As seen, the chemical formula for melatonin is N-acetyl-5-methoxytryptamine. From time to time in the specification applicant uses the term “N-acetyl-5-methoxytryptamine (melatonin), or its biologically active analogues”. As used herein, this phrase refers to the precise compound itself and other compounds having the same general structure, but only differing in minor moieties, and therefore still having the same biological activity of anesthetic-inducing effectiveness. The biologically active compound of the present invention, such as melatonin, may be derived or extracted from the pineal gland, or it can be synthesized from 5-Methoxyindol as a starting material by known routes, Szmuszkovicz et al.,
J. Org. Chem.
25, 857 (1960). Biochemical role of melatonin:
Chem. & Eng. News
45, 40 (May 1, 1967).
The analogue of the present invention that has been found to be more active than melatonin itself, and therefore can be used in smaller dosage levels and even at such small dosage levels to effectively induce hypnotic state, sedation or sleep, is 2-trifluoromethylmelatonin. As can be seen from a comparison with the formula for melatonin it contains a carbon trifluoromethyl moiety at the 2-position, replacing a hydrogen moiety from melatonin. While 2-trifluoromethyl-melatonin is the most effective so far found to date, it may be that other 2-position moieties such as 2-trihalo moieties in general can be used. Therefore, within the term 2-trihalo we intend to encompass chloride, fluoride, bromide and iodide.
The anesthetic active, i.e., the N-acetyl-5-methoxytryptamine (melatonin), or its biologically active analogues, can be administered with traditionally acceptable pharmaceutical carriers as described in the patent applications. Examples include Intralipid®, Cyclodextrin, and others, some of which are briefly hereinafter described. However, there is no need for detailed description of suitable anesthetic carriers because they are so well known in the industry. Here, however, the present applicants have discovered a preferred pharmaceutical carrier system.
Melatonin has previously been administered to animals in organic solvents that have central nervous system (CNS) effects. Such organic solvents frequently consist of ethanol in water. An administration vehicle not having CNS effects is desired for the administration of melatonin to achieve pure melatonin effects.
It was discovered that melatonin could be dissolved in high concentrations in a solvent comprised of 1 volume 1-methyl-2-pyrrolidinone, 1 volume propylene glycol and 2 volumes of water. Melatonin can be dissolved up to a concentration of 300 mg/ml in this solvent. The volume ratios here expressed are preferred but generally can be within the range of 25% or less by volume of 1-methyl-2-pyrrolidinone.
Intravenous administration of melatonin in this solvent system results in a rapid increase in blood melatonin concentrations in rats that are suitable to cause an unexpected anesthetic effect without causing toxic side effects.
Formulations containing melatonin analogues that consist of melatonin or its analogues and 1-methyl-2-pyrrolidinone in water can be used or formulations containing melatonin analogues and 1-methyl-2-pyrrolidinone combined with water and other known inert solvents such as propylene glycol, polypropylglycol, polysorbitans and cyclodextrins can be used.
Derivatives or analogues of melatonin, such as 2-bromomelatonin and 2-phenylmelatonin may be administered in solvents described above containing 1-methyl-2-pyrrolidinone for delivery to mammals.
As earlier expressed, 1-methyl-2-pyrrolidinone may be present in the disclosed vehicles at concentrations less than 25% volume/volume. For example, concentrations of 1-methyl-pyrrolid
Attala Mohamed Naguib
Baker Max T.
Cook Rebecca
McKee,Voorhees & Sease, P.L.C.
University of Iowa Research Foundation
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