Drug – bio-affecting and body treating compositions – Solid synthetic organic polymer as designated organic active... – Aftertreated polymer
Reexamination Certificate
2001-06-29
2003-10-28
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Solid synthetic organic polymer as designated organic active...
Aftertreated polymer
C424S451000, C424S464000, C424S489000, C424S436000, C424S078080, C424S164100
Reexamination Certificate
active
06638498
ABSTRACT:
FIELD OF THE INVENTION
The present invention is related to novel molecularly imprinted polymers, and in particular to improvements in the production of molecularly imprinted polymers (MIPs), as well as to these specific MIPs, and to the use of MIPs for specific applications. The MIPs of the present invention are particularly suitable for binding to, and thereby removing, toxins in the gastrointestinal tract. As an exemplary implementation, the present invention is described with regard to the removal of bile acids and bile salts from the gastrointestinal tract. In addition, the present invention is also useful for treatment of various diseases which are related to, and/or characterized by an effect of, bile acids and bile salts, such as atherosclerosis, cancer, liver disease and various diseases of the gastrointestinal tract. The MIP compounds of the present invention are also useful for combination therapy with other medications. These medications may involve mechanisms of action that lower or change the composition of bile acids and salts in the body or by a different mechanism. In addition the present invention also is useful for the diagnosis and monitoring of various diseases by selectively binding to an established marker which is then identified using known binding indicator techniques such as fluorescence. As an illustrative example for implementation, the present invention is described with regard to the diagnosis of medical conditions which are related to, and or characterized by an effect of, bile acids and/or bile salts, such as atherosclerosis, various diseases of the gastrointestinal tract, cancer and inflammatory conditions. This is achieved by determining the level of at least one specific bile acid or salt or the ratio of at least one specific bile acid or to at least a second specific bile acid or salt and determining whether these levels fall within an establish range which indicates the potential existence of the relevant disease. The analysis is performed on bile acids and or bile salts found in serum, bile, gastric contents, and feces.
BACKGROUND OF THE INVENTION
The subject of molecularly imprinted polymers has been extensively reviewed (e.g., G. Wulff,
Angew. Chem., Int. Ed. Engl.
1995, 34, 1812-1832; A. G. Mayyes and K. Mosbach,
Trends Anal. Chem.
1997, 16, 321-332; E. N. Vulfson, C. Alexander, and M. J. Whitcombe
Chem. Brit.
1997, 33, 23-26; K. Haupt and K. Mosbach,
Trends Biotechnol.
1998, 16, 468-475;
Molecular and Ionic Recognition with Imprinted Polymers,
ACS Symp. Ser. 703; R. A. Bartsch and M. Maeda, Eds.; American Chemical Society, Washington, D.C., 1998) and a number of patents on this topic have been issued [e.g., U.S. Pat. No. 4,127,730 (Wulff, G., Sarhan A.); U.S. Pat. No. 5,110,833 (Mosbach. K.); U.S. Pat. No. 5,630,978 (Domb, A.,); U.S. Pat. No. 5,587,273 (Yan, M. et al.); U.S. Pat. No. 5,872,198 (Mosbach, K. et al;)]. A schematic depiction of the formation of MIPs for deoxycholic acid (DCA) and glycodeoxycholic acid (GDCA) is shown in
FIGS. 1A and 1B
. Although the binding/recognition site is actually a family of non-homogeneous sites, the scheme illustrates how the cavities for two similar substances may differ.
The synthesis of MIPs, including those described with regard to the present invention in the “Description of the Preferred Embodiments” below, is performed with functional monomers. The monomers which were used for the present invention include all of the monomers listed in the following section. The synthesis of these monomers and related derivatives and analogs can be performed by organic chemists of ordinary skill in the art. It should be noted that although the present invention is described with regard to MIPs which bind bile acids and bile salts, this is for the purposes of description only and is not intended to be limiting in any way.
Bile Acid Sequestrants.
A number of polymers, such as cholestyramine, are used as bile acid sequestrants. Their action is based on the presence of strongly basic groups in the polymer (typically, ion exchange resin type of polymers) and they are used for cholesterol lowering and bile-related diseases. These materials are limited because they have limited potency and they also remove (bind) other required substances such as nutrients, drugs, etc. In addition, they often irritate the bowel and are not convenient or palatable to the patient. Accordingly there is a need for improved bile sequestrants. Selective MIPs which bind bile acids and salts do not remove needed nutrients, drugs or other substances and will be more potent; they will have low or no bowel irritation and have improved dosages. Importantly, the MIPs can be made so that they are selective to the more hydrophobic bile acids such as deoxycholic acid. Research shows that the more hydrophobic bile acids inhibit the removal of LDL from the blood stream and lead to a higher cholesterol blood serum level (Hueman, D. M. et al.,
J Lipid Res.
30: 1161, 1989).
While bile acids and salts serve important functions in the body, such as promoting digestion of fat, researchers have found that the more hydrophobic (water-resistant) bile acids, such as deoxycholic acid (DCA), chenodeoxycholic acid (CDCA) and lithocholic acid (LCA) facilitate higher absorption of lipids such as cholesterol and fats into the blood stream and are toxic, causing damage to cells and promoting cancer. Current research indicates that these more hydrophobic bile acids are highly significant disease-causing agents.
Additionally, research has implicated specific bile acids and bile salts as contributing to a number of diseases. For example, DCA has been implicated in the following:
Gallstones (Low-Beer, T. S., et al.,
Lancet (
1978) 2:1063-65
Colorectal cancer (Ochsenkuhn, T. et al.,
American Cancer Society
(1999) 1664-69; Hylemon P.,
Journal of Lipid Research
(1997); Bernstein C. et al.,
Cancer Research
(1999) 59, 2353-2357.)
Barrett's esophaghus and erosive esophagitis (Nehre D et al.,
Gut,
(1999) 44(5) 598-602; Kauer et al.,
Surgery,
(1997) 122(5) 874-81)
Arteriosclerosis caused by the presence of Oxidized LDL (Fuhrman B et al.,
Free Radic Biol Med
34-461997).
Inflammatory conditions promoted by the presence of COX-2 (Zhang et al.,
J Biol Chem
(1998) 273(4):2424-8).
Clearly, improved compounds such as MIPS are required with both higher and more specific binding capacity to these particular bile acids and bile salts. Furthernore, such MIPs would be useful for the treatment and/or prevention of diseases which are at least partially caused by, or otherwise related to, these specific bile acids and/or salts. Unfortunately, such MIPs are not currently available.
illustrative example
SUMMARY OF THE INVENTION
The background art neither teaches nor suggests MIPs with both higher and more specific binding capacity for particular bile acids and/or salts, for the treatment and/or prevention of diseases which are at least partially caused by, or otherwise related to, specific bile acids and/or salts.
The present invention is of improved MIPs with both higher and more specific binding capacity, including the synthesis of such MILPs, the compounds themselves, and specific applications thereof. The MIP compounds of the present invention have the advantage of being adaptable for specific targeted therapeutic and diagnostic uses and/or functionality, thereby enabling treatment and diagnosis to be more effectively performed.
As an example of a particularly preferred specific application of these compounds, the present invention encompasses the use of MIPs as sequestrants in the gastrointestinal tract, particularly in order to bind and therefore remove toxins from the gastrointestinal tract.
As a particularly preferred example of such toxins, the compounds of the present invention are useful for the binding and removal of specific bile acids and/or salts. Examples of such bile acids and/or salts include, but are not limited to, a bile acid such as deoxycholic acid (DCA) or the tauro- or glyco-conjugates of DCA. The bile acid or bile conjugate
Green Bernard S.
Priwler Morris
Di Nola-Baron Liliana
G. E. Ehrlich (1995) Ltd.
Page Thurman K.
Semorex Inc.
LandOfFree
Molecularly imprinted polymers for the treatment and... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Molecularly imprinted polymers for the treatment and..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Molecularly imprinted polymers for the treatment and... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3112449