Formulations and use of controlled-release indole alkaloids

Details Formulations and use of controlled-release indole alkaloids Formulations and use of controlled-release indole alkaloids

2000-07-11

2002-07-09

Prats, Francisco (Department: 1651)

Drug, bio-affecting and body treating compositions

Plant material or plant extract of undetermined constitution...

C424S775000, C424S489000, C424S490000, C424S492000

Reexamination Certificate

active

06416793

ABSTRACT:

1. DESCRIPTION OF THE FIELD
This invention relates to the use of a new formulation of indole phytochemicals to promote their absorption. In particular, the phytochemicals suitable for use according to the present invention are the indoles found in extracts of the bark of
Pausinystalia yohimbe
(yohimbine, corynanthine and rauwolscine) and ibogaine, a chemical derived from the rain forest shrub
Tabernanthe iboga
. The compositions of the invention may be formulated starting from the natural material in which the indole phytochemical is naturally found (i.e., bark or bark extracts) or from the pure dietary indoles themselves. Preparations of such phytochemicals are described which promote improved absorption of insoluble dietary substances and promote the effects of said phytochemicals. This facilitated absorption of poorly soluble dietary substances amplifies the useful dietary influences of such substances.
2. BACKGROUND OF THE INVENTION
Some phytochemicals found in edible plants have importance in health promotion due to activity which promotes improved fat metabolism. This activity results from support for the action of catecholamine hormones which trigger the release of stored fatty acids from fat cells.
Yohimbine is a dietary indole and one of a family of stereoisomers (i.e., yohimbine, corynanthine and rauwolscine) found in extracts from the bark of
Pausinystalia yohimbe
. This group of compounds posses a number of uses as modulators of catecholamine hormone action. Apart from possible medical uses as an anti-depressant, as a therapy for male impotence, and to promote salivation, an important application of yohimbe alkaloids is as a means of inducing mobilization of stored fat through blocking the action of catecholamines at &agr;-adrenergic receptors. Blocking the &agr;2-adrenergic receptors on the surface of fat cells (adipocytes) results in greater influence of competing &bgr;-adrenergic receptors promoting more active breakdown and release of stored triglycerides. This causes the release of non-esterified free fatty acids into the general circulation for use as a metabolic energy source during dieting and exercise (Lafontan and Betuing, “Regulation of Fat-Cell Function by &agr;-2 Adrenergic Receptors,” Advances in Pharmacology, 42, 496-8 (1998)). This peripheral action of yohimbe alkaloids combines with a separate central nervous system activity and the subsequent &agr; adrenergic blocking results in suppression of appetite. Together these actions make
Pausinystalia yohimbe
alkaloids desirable as compounds to facilitate weight loss in overweight and obese individuals.
Currently, many weight-loss promoting dietary supplements use “catecholamine-mimics” from natural sources like Ma Huang, containing ephedrine, and Bitter Orange Extract (Citrus Aurantium), containing synephrine. Both the endogenously produced catecholamine hormones, norepinephrine and epinephrine, and the natural product “catecholamine-mimics” have been shown to promote the release of stored fatty acids during reduced calorie diets and sustained exercise. However, this use of ephedrine, synephrine, and other catecholamine related drugs like amphetamine and phenylpropanolamine is plagued by a host of side effects and risks. These side effects include excess catecholamine-like activity and result in tremor, sleeplessness, and uncontrolled high blood pressure in susceptible individuals.
Unlike direct acting catecholamines and related natural products, yohimbine is an indole alkaloid which acts indirectly to induce the release and more efficient action of catecholamines already present in the central and peripheral nervous system. Yohimbine has been demonstrated to both increase circulating levels of norepinephrine (Berlan, et al., “Plasma Catecholamine Levels and Lipid Mobilization Induced by Yohimbine in Obese and Non-Obese Women,” International Journal of Obesity, 15, 305-15 (1991)), and to promote fat loss during calory restricted dieting (Zahorska-Markiewicz, et al., “Adrenergic Control of Lipolysis and Metabolic Responses in Obesity,” Hormone Metabol. Res., 18, 693-7 (1986)). Yohimbine acts by increasing circulating norepinephrine, which activates &bgr;-adrenergic receptors on fat cells, and by directly occupying and blocking &agr;-adrenergic receptors. These combined effects, i.e., supporting norepinephrine release and blocking the specific inhibition of norepinephrine mediated mobilization of stored fat, promotes a more efficient release of stored fatty acids. This can promote more rapid weight loss during a program of reduced food intake and low intensity exercise.
Yohimbine, however, demonstrates poor absorption when taken orally without special formulation. The low solubility and poor absorption of the yohimbe family of indoles has been demonstrated through pharmacokinetic study of yohimbine and rauwolscine. When administered, yohimbine and rauwolscine have only brief and variable plasma half lives (0.5 to 1 hour) and a limited bioavailability of less than 30% (Guthrie, et al., “Yohimbine Bioavailability in Humans,” European J Clin Pharmacol, 39, 409-11 (1990)). Instead of the brief and unpredictable peak which follows ingestion of unformulated yohimbe extract or isolated yohimbine, a prolonged low level of circulating yohimbine and its active metabolites is a more desirable and safer approach to facilitate weight loss (Le Corre, P. Dollo, G, et al. “Biopharmaceutics and Metabolism of Yohimbine in Humans,” Eur J. Pham Sci, 9(1): 79-84 (1999)). The processing of natural yohimbe extract to provide more complete, more sustained, and more controlled absorption is needed. Modifying the absorption of active indoles from yohimbe extract would provide a dietary supplement which limits peak blood levels to more safely promote lipolysis through peripheral &agr; adrenergic blocking activity. The unique central action of yohimbine and its metabolites to increase circulating levels of norepinephrine and therefore, to curb appetite, would be reduced but still present and prolonged.
As a result, a need exists to increase the absorption and prolong the bioavailability of yohimbine and other similar alkaloids from
Pausinystalia yohimbe
. Formulations of indoles which promote more complete absorption and more sustained release into the circulation can be used to increase the effectiveness of these substances. Processing these phytochemicals for better absorption will also provide for their use in promoting weight loss at a lower oral dose. Further, since side effects from yohimbine relate to peak blood levels and cross over into the central nervous system, formulations for controlled release are also safer. Regulated and sustained absorption of yohimbe alkaloids will increase their usefulness in promoting weight loss which requires persistent, low levels to support the greatest cumulative release of stored fat.
The improved absorption of cruciferous indoles, particularly diindolylmethane (DIM) and related indoles from the precursor phytochemical, glucobrassicin, has been the subject of a United States patent application (U.S. patent application Ser. No. 09/053,180, filed on Apr. 1, 1998). The objective of this patent was to provide significant absorption of DIM and other poorly soluble hydrophobic natural products which were not absorbed sufficiently without processing. This contrasts with the present invention in which the objective of processing is to modify the pattern of absorption of alkaloids in
Pausinystalia yohimbe
bark extracts,
Tabernanthe iboga
extracts, purified yohimbine, purified ibogaine, purified yohimbine and purified corynanthine, for improved safety and controlled release. In particular, processing methods for yohimbe extract eliminates a brief, potentially toxic, early peak and introduces sustained, controlled-release of yohimbine alkaloids for a period of hours.
Other applications of formulated DIM are the subject of separate United States patent applications detailing methods and formulations for promoting weight loss (U.S. patent application Ser. No. 09/404,112, filed on Sep. 23, 1

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