Organic compounds -- part of the class 532-570 series – Organic compounds – Oxygen containing
Reexamination Certificate
2001-05-11
2003-12-09
Shippen, Michael L. (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Oxygen containing
Reexamination Certificate
active
06660891
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to methods for the production and isolation of D-chiro-inositol (DCI) from plant extracts. Specifically the present invention provides a method to produce D-chiro-inositol from a precursor moiety by hydrolysis in an aqueous acid, preferably HCl. More specifically, the present invention relates to a method for the efficient production of DCI by a process involving the extraction of D-pinitol from soy hulls followed by conversion thereof to DCI.
2. Background Art
D-chiro-inositol (DCI) is a rare isomer of inositol that has been implicated as having a role in the activity of insulin on anabolic metabolism. It has been found that insulin resistance correlates with deficiencies of DCI, and that supplementation with oral DCI improves insulin sensitivity in insulin resistant individuals. Clinical research supports the utility of DCI for treatment of diseases characterized by insulin resistance. For example, in a recent Phase II clinical study with 44 women afflicted with polycystic ovary syndrome (PCOS), administration of DCI (1200 mg/day for 6-8 weeks) resulted in ovulation by 86% of the patients, contrasted to ovulation in only 27% of the control (placebo) subjects (Nestler, J. E. et al.,
New Engl. J. Med.
340:1314-1320 (1999)). Similarly, in a clinical study of subjects with impaired glucose tolerance, administration of DCI (1200 mg/day for 2 weeks) restored glucose tolerance and insulin secretion to normal levels (Kessler et al.,
Diabetes Abst.
58
th Scientific Sessions,
#1385, A358 (1998)).
A source of DCI is the aminoglycoside kasugamycin, a fermentation product of
Streptomyces kasugaspinus
and
Streptomyces kasugaensis,
which contains a molecule of DCI bound through a glycosidic linkage to the aminosugar kasugamine. Treatment of kasugamycin with strong acid cleaves this glycosidic linkage, liberating DCI and kasugamine, along with various other nitrogen-containing side products.
Several processes exist for producing DCI from kasugamycin, each with unique attendant disadvantages or limitations. The first process disclosed (Kennington et al, U.S. Pat. No. 5,091,596) involved large quantities of ion-exchange resins being used to neutralize the hydrolysis mixture and to purify the DCI. A subsequent approach (Sato et al., U.S. Pat. No. 5,714,643) employed a strongly acidic ion exchange resin, rather than aqueous acid, to effect the hydrolysis, but also required large quantities of ion exchange resin to purify the resulting DCI.
As noted, both of these processes required large quantities of resin, and the subsequent costly evaporation of accompanying large quantities of aqueous solution. If these processes were scaled up to manufacture the quantities of DCI required to satisfy the PCOS or Type 2 diabetic population, the processing of such quantities of aqueous solution could be cost prohibitive.
Another approach for preparing DCI from kasugamycin is acetolysis (Riley et al., U.S. Pat. No. 5,463,142; U.S. Pat. No. 5,932,774). While this process obviated the need for ion exchange chromatography, it required a number of distinct process steps, including: (i) acetylation/hydrolysis of kasugamycin; (ii) purification of crude DCI hexaacetate; (iii) deacetylation of the purified hexaacetate; and (iv) isolation of DCI. Each step adds to the cost of the process and thus could limit the economic viability of manufacturing DCI using this approach.
Alternatively, D-Pinitol (the 3-O-methyl ether of DCI) may also serve as a useful precursor to DCI. Originally discovered in pine stumps (Anderson,
Indus. Eng. Chem.
45:593:596 (1953)) D-pinitol is also present in a wide variety of renewable, leguminous plants including soy (see for example Oslund et al. U.S. Pat. Nos. 5,550,166 and 5,827,896). D-Pinitol has been found in virtually all parts of the soy plant including whole plant, whole beans, soy flour, flakes and hulls.
In view of its high therapeutic potential and the ongoing studies involving treatment with DCI, there remains a need in the art for a simple and efficient process to manufacture large quantities of DCI without any of the disadvantages of present methods.
BRIEF SUMMARY OF THE INVENTION
The present invention provides methods to produce D-chiro-inositol (DCI) from crude plant extracts containing at least one carbohydrate or oligosaccaride that comprises D-chiro-inositol as a structural component comprising the steps:
(a) preparing a reaction solution comprising a D-chiro-inositol precursor in a solution of about 6 N to 12 N HCl; and
(b) reacting the solution of step (a) at a temperature in the range of about 65° C. to about 110° C. for a period of time sufficient to convert the D-chiro-inositol precursor to D-chiro-inositol.
Surprisingly, reaction of the plant extract carbohydrates in concentrated HCl results in the in conversion of most types of carbohydrates into an insoluble byproduct but does not affect the solubility or structural integrity of D-chiro-inositol. Therefore this single reaction provides D-chiro-inositol that is substantially free of other contaminating carbohydrates, thus eliminating the need for subsequent purification techniques.
The present invention also provides pharmaceutical formulations comprising DCI prepared by the methods provided herein and a pharmaceutically acceptable carrier. These formulations are useful in treating mammalian metabolic diseases where the causative factor or a complicating factor is characterized by abnormal glucose metabolism and/or decreased insulin sensitivity. These mammalian metabolic diseases include, but are not limited to, the following: diabetes mellitus and its chronic complications; gestational diabetes; pre-eclampsia; obesity; hyperlipidemia and/or dyslipidemia; atherosclerosis; hypertension; cardiovascular disease; AIDS; cancer; wasting and/or cachexia; sepsis; trauma, such as associated with bums, malnutrition and/or stress; aging; autoimmune diseases, such as lupus; endocrine diseases; hyperuricemia; polycystic ovary disease; and complications arising from athletic activity or inactivity.
DETAILED DESCRIPTION OF THE INVENTION
The phrase “D-chiro-inositol (DCI) precursor” as used herein refers to a plant extract containing one or more carbohydrates or oligosaccarides wherein at least a portion of which comprises a D-chiro-inositol moiety as a structural component. D-chiro-inositol (DCI) precursors may include, for example but not by way of limitation, D-chiro-inositol, D-pinitol (the 3-O-methyl ether of DCI), ciceritol (a pinitol digalactoside), 1D-2-O-alpha-D-galactopyranose-chiro-inositol, fagopyritols (alpha-galactosyl-D-chiro-inositol derivatives), and the like.
Preferred D-chiro-inositol precursors are plant extracts including pine needles, pine stumps, chick peas, orange peels, Bougainvillea leaves, alfalfa, soy beans, soy plant, soy flakes, soy hulls, and other legumes. In one embodiment, soy hulls are extracted to yield a D-chiro-inositol precursor containing a quantity of D-pinitol.
I. D-Chiro-Inositol Precursors Extraction from Plant Materials
According to this embodiment of the present invention, a quantity of plant material, such as soy hulls, is treated with a solvent or mixture of solvents under suitable time and temperature conditions so as to obtain a solution of the D-chiro-inositol precursors and other soluble products. The solvent or solvents may be any solvent known and available to those skilled in the art in which the D-chiro-inositol has a sufficient solubility to permit it to be separated from the plant material. Illustrative examples of suitable solvents include, but are not limited to, the following: water; acidified water; lower aliphatic alcohols, such as methanol, ethanol and isopropanol; and mixtures of water and one or more alcohols. The time and temperature employed for this step of the inventive process will depend upon the specifics of the extraction, such as the particular solvent employed, and may be determined empirically by one skilled in the art.
The solution of D-chiro-inositol may the
Campbell A. S.
Johnson, Jr. Leland L.
Leonard Patrick
Miller Paul
Plourde Robert
Insmed Incorporated
Shippen Michael L.
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