Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
1999-03-18
2002-07-02
Dees, Jose′ G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S465000, C424S474000, C424S480000, C424S725000
Reexamination Certificate
active
06413546
ABSTRACT:
FIELD OF THE INVENTION
The invention is generally related to the fields of pharmaceuticals, compressed tablet formulations and methods of manufacturing tablets. In particular, the invention is directed to novel tablets comprising isoflavone-containing plant extract, particularly, extracts from fruits of plants from the Leguminosae family, and water-insoluble polysaccharides, and methods of manufacturing same.
BACKGROUND OF THE INVENTION
Isoflavones are naturally occurring glucosides found in many plants, particularly soybeans. As soybean is a rich protein source and soy is used as a dietary supplement, isoflavones are found in many foods and drinks. Isoflavone-containing soy proteins are used in the food industry to replace or extend meat, milk, egg, and other protein sources in traditional food products. One of the key factors limiting the use of soy protein concentrate, especially in nutritional beverages, milk replacers, and dairy products, is the soy taste present in the final product. Soy concentrates are also not widely used in nutritional beverages, milk replacers, and dairy products because of the presence of soy fiber as an insoluble component, causing an undesirable “mouthfeel.” Administration of isoflavone-containing concentrates, as plant extracts, in the form of a tablet would eliminate undesirable “mouthfeel” and taste problems. However, isoflavone-containing plant extracts, because of their unique physiochemical properties, have not been reported to have been successfully formulated into a pressed tablet that can disintegrate in a reasonably short period of time. It has been a challenge to formulate isoflavone-containing plant extracts into pressed disintegratable tablets.
Even more significant than their use as a dietary supplement is the finding that isoflavones have many potential pharmaceutical uses. For example, isoflavones have been reported to be possible anti-cancer agents, see, e.g., Messina (1991) J. of the American Cancer Institute 83:542-545; Charland (1998)
Int J Mol Med
2:225-228. Daidzein and genistein glucuronides, major isoflavone metabolites, may be partly responsible for the anti-cancer biological effects of isoflavones due to their estrogen receptor binding ability and natural killer (NK) cell activation, see, e.g., Zhang (1999)
J Nutr
129:399-405; Lu (1998)
Am. J. Clin. Nutr
. 68(6 Suppl):1500S-1504S. Soy genistein has been reported to be a chemopreventive agent against breast and prostate cancer in humans, see, e.g., Peterson (1991) Biochem. Biophysical Res. Corn. 179:661-667; Peterson (1993) Prostate 22:335-345. Isoflavone, an isoflavone synthesized from soy daidzein, is being tested to prevent and treat osteoporosis and other metabolic bone diseases, see, e.g., Head (1999)
Altern. Med. Rev
4:10-22. Atherosclerosis was reduced in animals fed diets containing soy protein compared with those fed diets with animal protein; the components of soy protein that lower lipid concentrations are extractable by alcohol, i.e., they include the isoflavones genistein and daidzein (see, e.g., Anthony (1998)
Am. J. Clin. Nutr
. 68(6 Suppl):1390S-1393S.) It is also believed that daidzein and its metabolites, o-desmethylangolensin and dihydrodaidzein, are useful for altering the concentration of cholesterol constituents in the blood by increasing the concentration of high-density lipoprotein cholesterol and decreasing the concentration of low density lipoprotein cholesterol, see, e.g., Potter, et al., U.S. Pat. No. 5,855,892. However, to date it is not economical to administer these isoflavone components and metabolites in any purified form. Thus, the only economically practical means to administer these agents are as plant extracts, i.e., isoflavone-containing plant extracts, from, e.g., fruits of leguminous plants such as soybeans, red clover, Schigandra, and the like.
It would be preferable to administer plant extracts as compressed (solid) tablets for oral administration due to reasons of stability, economy, simplicity and convenience of dosing. However, most plant extracts (including isoflavone-containing plant extract), because of their unique physiochemical properties, are difficult to formulate into a compressed tablet form capable of dissolving in the stomach in a reasonably short period of time (e.g., a disintegration time at least about 30 minutes in gastric fluid). The difficulties in manufacturing plant extract-containing pressed tablet products are due to their physiochemical properties. The extracts contain fine particles that cause poor flow of the formulation and affects tablet compression.
Furthermore, the gel-forming nature of the plant extract makes it difficult to obtain a tablet with a reasonable disintegration time (e.g., at least about 30 minutes in gastric fluids). For example, soy plant extract, when exceeding 50% by weight in a tablet, tends to retard the disintegration time even in the presence of normally very efficient “super-disintegrants,” such as croscarmellose sodium. It is the hygroscopicity of the plant extract that has impeded development of a one-tablet-per-dose formula using a direct compression approach.
Thus, there exists a great need for plant extract-containing compressed tablets with sufficient hardness to withstand packaging and handling, yet able to be administered orally, i.e., capable of dissolving in an aqueous environment similar to that found in the stomach (i.e., gastric juices) in a reasonable period of time (about 30 minutes or less). It would further be advantageous if such tablets could be made economically. The present invention fulfills these and other needs.
SUMMARY OF THE INVENTION
This invention provides for the first time pressed tablets comprising isoflavone-containing plant extracts, and methods of manufacturing them, that have advantageous physical-chemical properties and are economical to produce.
The invention provides physiologically acceptable tablets comprising an isoflavone-containing plant extract and a compressed tablet formulation that comprises a water-insoluble polysaccharide, wherein the amount of the water-insoluble polysaccharide in the tablet comprises at least about 15% of the dry weight of the tablet. In alternative embodiments, the water-insoluble polysaccharide is a plant water-insoluble polysaccharide, the plant water-insoluble polysaccharide is a soybean plant water-insoluble polysaccharide, and the soybean plant water-insoluble polysaccharide is Emcosoy® polysaccharide. In one embodiment, the isoflavone-containing plant extract is from the fruit of a plant from the Leguminosae family, and, in a preferred embodiment, a soy bean extract.
In alternative embodiments, the water-insoluble polysaccharide in the invention's tablets comprise between about 15% to about 25% of the dry weight of the tablet; and between about 21% to 22% of the dry weight of the tablet.
In other embodiments, the amount of the isoflavone-containing plant extract in the tablets comprise between about 10% to about 85%, about 20% to about 75%, about 30% to about 70%, and about 45% to about 65% of the dry weight of the tablet.
In one embodiment, the tablets can dissolve in a gastric fluid within at least about 30 minutes; in a preferred embodiment, the tablets can dissolve in less than about 15 to 16 minutes.
The tablets of the invention can further comprise a micronized fatty acid, which, in alternative embodiments, is present in the tablet at amounts between about 1% to about 5% of the dry weight of the tablet, and, about 2% of the dry weight of the tablet. The tablets of the invention can further comprise a silica gel, which, in alternative embodiments, is in an amount between about 1% to about 5% of the dry weight of the tablet, and, about 2% of the dry weight of the tablet. In a preferred embodiment, the micronized fatty acid is a micronized stearic acid.
In various embodiments, the tablets of the invention are suitable for delivery to a body cavity, including the oral, buccal or sublingual cavities, and swallowing. The tablet formulations of the invention can further comprise at least one
Bombardelli Ezio
Fix Joseph A.
He Min Michael
Kang Maria L.
Link Martin
Dees Jose′ G.
George Konata M.
Indena S.p.A.
Townsend and Townsend / and Crew LLP
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