Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-08-10
2003-04-22
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...
C514S816000, C514S817000, C514S818000
Reexamination Certificate
active
06552064
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-methoxytryptamine) 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 the author,
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.
This invention has 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 such an objective is readily apparent.
SUMMARY OF THE INVENTION
Anesthetic compositions are prepared using a pharmaceutically-acceptable carrier and an anesthetic-inducing effective amount of melatonin or biologically active analogues of melatonin. 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-acety-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 anesthetic active, i.e., the N-acetyl-5-methoxytryptamine (melatonin), or its biologically active analogues, can be administered with traditionally acceptable pharmaceutical carriers. 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.
The composition may be administered by conventional administration methods for anesthetics, i.e., oral administration, nasal respiratory administration, bolus injection, intravenous administration by repeated doses or by continuous infusion, rectal, vaginal, sublingual, cutaneous and slow release routes. It may be, and often is preferred, that it be administered in two or more ways, such as by bolus injection followed by continuous intravenous administration.
The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin.
Preferred compositions for administration by injection include those comprising a melatonin biologically active analogue as the active ingredient, in association with a surface-active agent (or wetting agent or surfactant) or in the form of an emulsion (as a water-in-oil or oil-in-water emulsion).
Suitable surface-active agents include, in particular, nonionic agents, such as polyoxyethylenesorbitans (e.g. Tween™ 20, 40, 60, 80 or 85) and other sorbitans (e.g. Span™ 20, 40, 60, 80 or 85). Compositions with a surface-active agent will conveniently comprise between 0.05 and 5% surface-active agent, and preferably between 0.1 and 2.5%. It will be appreciated that other ingredients may be added, for example mannitol or other pharmaceutically acceptable vehicles, if necessary.
Suitable emulsions may be prepared using commercially available fat emulsions, such as Intralipid™, Liposyn™, Infonutrol™, Lipofundin™ and Lipiphysan™. The active ingredient may be either dissolved in a pre-mixed emulsion composition, or alternatively it may be dissolved in an oil (e.g. soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil or almond oil) and an emulsion formed upon mixing with a phospholipid (e.g. egg phospholipids, soybean phospholipids or soybean lecithin) and water. It will be appreciated that other ingredients may be added, for example glycerol or glucose, to adjust the tonicity of the emulsion. Suitable emulsions will typically contain up to 20% oil, for example, between 5 and 20%. The fat emulsion will preferably comprise fat droplets between 0.1 and 1.0 &mgr;m, particularly 0.1 and 0.5 &mgr;m, and have a pH in the range of 5.5 to 8.0.
Particularly preferred emulsion compositions are those prepared by mixing an active compound with Intralipid™ or the components thereof (soybean oil, egg phospholipids, glycerol and water).
Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid compositions may contain suitable pharmaceutically acceptable excipients as set out above. Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably sterile pharmaceutically acceptable solvents may be nebulised by use of inert gases. Nebulised solutions may be breathed directly from the nebulising device, or the nebulising device may be attached to a face mask, tent or intermittent positive pressure breathing machine. Solution, suspension or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.
The anesthetic may be used alone or often in combination with other anesthetics simultaneously administered. Put another way, it will be appreciated that when using any combination described herein, both the compound of melatonin or its
Cook Rebecca
McKee Voorhees & Sease, P.L.C.
University of Iowa Research Foundation
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