Drug – bio-affecting and body treating compositions – Plant material or plant extract of undetermined constitution... – Containing or obtained from piper
Reexamination Certificate
2000-05-26
2004-06-08
Prats, Francisco (Department: 1651)
Drug, bio-affecting and body treating compositions
Plant material or plant extract of undetermined constitution...
Containing or obtained from piper
C424S725000, C424S773000, C210S656000, C210S690000, C210S691000, C210S692000
Reexamination Certificate
active
06746695
ABSTRACT:
BACKGROUND
1. Field of the Invention
This invention relates to methods of extracting and purifying bioactive substances from various plants and herbs. More specifically the invention relates to methods of extracting and separating bioactive substances from various plants and herbs using supercritical fluid extraction and/or fluorocarbon solvent extract. The present invention further relates to separation of bioactive substances contained in extracts using packed column supercritical fluid chromatography. The present invention also relates to formulations, pharmaceutical preparations and dietary supplements which may be prepared with the extracted bioactive substances and use of such pharmaceutical preparations and dietary supplements to treat various human ailments.
2. Description of the Background
Throughout history humans have ingested and otherwise consumed a wide variety of plants and herbs, and extracts of such plants and herbs to help alleviate aches and pains, improve immunity to infection, treat various illnesses, or even to induce relaxation or stress reduction.
One plant that has been commonly ingested by the people of the South Pacific to induce relaxation is called Kava Root. K. Schubel, J. Soc. Chem. Ind., 43, 766 (1924); A. G. Van Veen, Rec. Trav. Chim., 58, 52 (1939). Kava root consists of the dried rootstock and/or shoots of Piper methysticum Forst (Family: Piperaceae). The Kava root is most typically ingested by drinking an aqueous macerate (pulverized Kava root mixed with water) known as the beverage Kava.
First attempts to identify the active compounds within Kava root were made over a hundred years ago. Those efforts resulted in the identification of kavalactones, also known as kavapyrones. More than ten kavalactones as well as four other substances have been identified in the Kava root to date, including kavain, dihydrokavain (a.k.a. marindinin), methysticin, dihydromethysticin, yangonin, and desmethoxyyangonin. V. Lebot, M. Merling, and L. Lindstrom, “Kava the Pacific Drug”, Yale University Press, New Haven, Conn. (1992). These compounds are neutral, nitrogen-poor compounds that may be specifically referred to as substituted d-lactones and substituted a-pyrones. The lactone ring is substituted by a methoxy group in the C3 position, and the differences in the compounds lie in the degree of unsaturation (e.g. yangonin, desmethyoxyyangonin, kavain and methysticin) or by bezene substitution (e.g. dihydrokavain and dihydromethysticin), as shown in FIG.
24
.
The particular kavalactones in a Kava root extract vary depending upon its origin. Different species of kavalactones have been found to have varying physiological effects in vivo depending on their molecular structure. All naturally occurring kavalactones contain an enolic double bond between C3 and C4. The dienolides of the yangonin type appear to be pharmacologically inert. In the enolides, the effective optimum varies as a function of the hydrogenation of the double-bonded C7. For example, kavain has the strongest effect as a local anesthetic, dihydromethysticin as a spasmolytic, and dihydrokavain as an intensifier of narcosis. R. Hansel, Characterization and Physiological Activity of Some Kava Constituents Pacific Science, July 1968, Vol. XXII: pp293-313.
Further, the particular kavalactones present depend upon whether, in addition to rhizome parts, roots and stems of the plant are included in the extract. High quality extracts of the Kava root are sold based upon the total kavalactone content, rather than upon analysis of the individual lactones contained therein. The concentration ranges of total kavalactone levels in the Kava root extracts employed, e.g. in Germany are generally within the range of 30 to 55 weight percent.
Although many types of kavalactones have been identified, no simple and efficient method is available for both extraction of the root and separation of each individually extracted lactone. The traditional extraction method (e.g. steam distillation) usually involved mixing 100 grams of root with a suitable quantity of distilled water producing a slurry having a volume of approximately 200 mL. A. R. Furgiuele, W. J. Kinnard, M. D. Aceto, and J. P. Buckley, J. Pharmaceutical Sci., 54, 248 (1965). The slurry was steam distilled and the first 100 mL of distillate was collected, filtered and lyophilized. The yield for each extraction was about 50 mg. Alternately, a liquid-solid extraction at room temperature has been reported wherein the above slurry was intimately mixed in a Waring blender for 15 minutes. The mixture was then filtered and lyophilized. In certain cases, rather than lyophilization, the filtrate was subjected to successive extractions with chloroform. This purification operation basically removed impurities from the aqueous layer. The extraction yield for these methods varied depending on the solvent and methodology used.
Modern Kava root extracts are commonly manufactured using ethanol as a solvent because kavalactones arc readily soluble in ethanol. The extractable materials are in the form of a yellowish brown paste or powder, which is then tested to assure proper concentrations of kavalactones.
A plant that has been commonly ingested by the people of Mexico and other Latin American countries is
Byrsonima crassifolia
(Nanche). The medicinal importance of this tropical tree, which is indigenous to Mexico, has been documented historically since the sixteenth century. Traditional healers use the plant to treat gastrointestinal disorders, especially diarrhea and dysentery.
To date, about 21 chemical substances have been extracted from the dried leaves and bark of the tree, including &bgr;-sitosterol and betulin (triterpenes), pipecolic acid and proline (amino acids), and catechin and quercetin (flavonoids). Béjar, E., et al., Constituents of
Byrsonima crassifolia
and their spasmogenic activity, Int. J. Pharmacog. 1995, 33:1, 25-32. The discovery of pipecolic acid is significant in that it is a rare compound in nature and is an important intermediate in a number of pharmacological preparations which demonstrate therapeutic effect for stroke, Parkinson's disease, Alzheimer's disease, and other. neurological and vascular disorders. Prior to the discovery of pipecolic acid in
Byrsonima crassifolia
, preparations containing pipecolic acid were derived from various cultured micro-organisms.
Traditional healers prepared aqueous solutions of Byrsonima as teas. It was recently discovered that aqueous extracts of Byrsonima contain only catechin. However, when methanol is used to extract bioactive substances from Byrsonima, a wide variety of triterpenes, amino acids and flavonoids can be isolated.
Plants in the genera Aesculus and Crataegus are known to contain bioactive substances which affect the heart and circulatory system. Galenical preparations of, for example,
Crataegus oxyacantha, C. azarolus, C. monogyna, C. pentagyna, C. laevigata
and
C. nigra
have been used in European herbalism for centuries for these purposes.
Crataegus pinnatifida
has been used for similar purposes in Traditional Chinese Medicine for even longer. Likewise the use of
Aesculus hippocastanum
in Europe for the treatment of circulatory disorders is well documented. The effect has been attributed to aescin, a mixture of triterpene glycosides which have an anti-exudative and vascular tightening effect. While these European and Asian species have been the subject of a great deal of research, co-generic species endemic to the New World have been largely ignored.
Aesculus californica
, commonly known as ‘California buckeye’ in English and ‘berruco’ in Spanish, had been used by the native tribes and early colonists of California for a variety of purposes. The dried bark of the tree was used for toothaches, the fresh seeds were eaten after leaching out the bitter principles, and the unprocessed fruits were used to treat hemorrhoids, as a fish poison, and as an abortifacient.
Analyses of the seeds of
Aesculus californica
by several groups have revealed the presence of a number of known bio
Ashraf-Khorassani Mehdi
Martin Michael Z.
Taylor Larry
Armadillo Pharmaceuticals, Inc.
Morrison & Foerster / LLP
Prats Francisco
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