Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1996-11-20
2001-10-16
Lee, Howard C. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S053000, C536S123100, C536S123130, C536S114000
Reexamination Certificate
active
06303584
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention is generally in the area of methods for making polysaccharides which include attached lipophilic groups, but which remain water-soluble.
Modified polysaccharides have been isolated from natural sources or synthesized chemically and their biological activities studied. Starches containing bound protein and lipid groups have been isolated from plant components such as seeds. See, e.g., Tharanathan et al.,
Starch
, 42:247-251 (1990).
Fatty acid esters of polysaccharides have been produced by treatment of the polysaccharides with fatty acid chlorides or anhydrides or by ester exchange, and the alkyl ethers of polysaccharides have been produced by several methods (Methods in Carbohydrate Chemistry, vol. II (1963) Ed., R. L. Whistler and M. L. Wolfrom, Academic Press, New York; Section VI and V). However, most previous studies of this type have involved high degrees of derivatization with relatively short hydrocarbon chains, such as acetate esters or methyl ethers. Highly derivatized products of this type are generally water-insoluble. JP 60233560 to Fujirebio K.K. discloses a method of measuring lipase activity using as the enzyme substrate a water soluble fatty acid ester of a low molecular weight oligosaccharide such as dextran. JP 87209721 to Sugiyama Industrial Chemical Institute discloses the preparation of water soluble fatty acid esters of hydrolyzed starch for use as emulsifiers and detergents.
The synthesis of cyclodextrin derivatives, modified by the attachment of fatty acids or alcohols, which may be used as bile acid absorption agents, is described in DE 4 136 325 to Ahlers et al. PCT WO 95/12620 to Alpha-Beta Technology, Inc. discloses derivatized polysaccharide bile acid sequestrants for reducing cholesterol which include a hydrophobic, cationic ligand coupled to a polysaccharide substrate.
Acetylated mannans “acemannans” are long-chain polydispersed beta-1,4-linked mannan polymers interspersed with O-acetyl groups which are isolated from the
Aloe vera
leaf. Acemannans have been reported to have antitumor activity and to be useful as adjuvants. Harris et al.,
Mol. Biother
. 3:207-213 (1991). Acetylated mannans also have been reported to be useful for regulating blood cholesterol levels; for reducing inflammation and infection; as an immunostimulant; and as an antiviral. U.S. Pat. Nos. 5,441,943 and 5,308,838 to Carpenter et al.; PCT WO 93/08810 to Carrington Lab, Inc.; and U.S. Pat. Nos. 5,118,673 and 5,106,616 to Carpenter et al. Acemannans also have been shown to induce human cytokines. Marshall et al., Abstract presented at the American Academy of Allergy and Immunology, Chicago, Ill., March, 1993.
It is an object of the invention to provide lipid-modified polysaccharides which are water-soluble, biocompatible and can be used in a variety of different biomedical applications. It is a further object of the invention to provide water soluble, lipid-modified forms of arabinogalactan which can be used in different applications, for example, to promote the formation of stable emulsions, to increase drug solubility, and to serve as adjuvants. It is another object of the invention to provide methods for making and using a range of such modified forms of arabinogalactan in different biomedical applications.
SUMMARY OF THE INVENTION
Arabinogalactan compositions are provided which are useful in a wide variety of different biomedical applications. In one embodiment, water soluble lipidated arabinogalactans are provided which include arabinogalactan with a limited proportion of hydrophobic groups, such as long-chain hydrocarbon groups, covalently attached to free hydroxyl groups on the arabinogalactan. The lipidated arabinogalactans are water soluble and biocompatible and are useful in a wide variety of different biomedical applications. The lipidated arabinogalactans can be used, for example, to inhibit cell adhesion, and to inhibit infection or inflammation. The lipidated arabinogalactans further may be used as adjuvants, to inhibit metastasis, and in other therapeutic applications.
DETAILED DESCRIPTION OF THE INVENTION
Water soluble lipidated forms of arabinogalactan are provided which are useful in a wide variety of different applications, particularly biomedical applications. Water soluble lipidated arabinogalactan may be used for example, to form stable emulsions, to increase the solubility of sparingly water soluble drugs, to inhibit cell adhesion, for metastasis control, as a bile acid sequestrant, or as an adjuvant. The lipidated arabinogalactan includes a limited proportion of lipophilic groups, such as long chain hydrocarbons bonded to the polysaccharide, e.g., by ether or by ester linkages, to modify its biological activity, while advantageously retaining water solubility properties. Due to the water solubility and low toxicity, the lipidated arabinogalactans are useful in a wide range of therapeutic applications.
Arabinogalactan
Arabinogalactan (“AG”) is a water-soluble polysaccharide which can be isolated from trees of the genus Larix, particularly
Larix occidentalis
(western larch). Arabinogalactan may constitute up to 35% of the total heartwood of some species. Stout, “Larch Arabinogalactan” in
Industrial Gums
, R. L. Whistler Ed., Academic Press, New York, pp. 307-310, 1959. It is highly water soluble and can be purified from larch chips.
As used herein, the term “arabinogalactan,” unless otherwise specified, includes naturally occurring or synthetic arabinogalactan, portions of arabinogalactan, such as degradation products, and chemically or biochemically modified arabinogalactan or portions thereof which have been modified using methods available in the art.
In one preferred embodiment, ultrarefined arabinogalactan is used to form the lipidated water soluble arabinogalactan compositions. Methods for the preparation of ultrarefined arabinogalactan are disclosed in U.S. Pat. No. 5,116,969, the disclosure of which is incorporated herein by reference. Ultrarefined arabinogalactan of greater than 95%, or optionally, greater than 99.9% purity (Larex UF™) is available from Larex, International, St. Paul, Minn. As defined herein “ultrarefined arabinogalactan” refers to arabinogalactan, isolated from a plant source such as trees of the genus Larix, with a purity greater than 95%. In a preferred embodiment, the molecular weight of the ultrarefined arabinogalactan is between about 10,000 and 30,000 daltons (by size exclusion chromatography with pullulan reference).
Arabinogalactan from Larix trees is useful since it is extremely water-soluble, occurs naturally with a very narrow molecular weight distribution, and is highly branched and thus not subject to viscosity problems. Arabinogalactan also is highly biocompatible and is non-toxic.
Water Soluble Lipidated Arabinogalactan
Structure
Lipidated arabinogalactan molecules which include attached lipophilic groups but which are water soluble are provided. Preferably the solubility of the lipidated arabinogalactan compound is at least about 0.1%. As used herein, the phrase “lipidated arabinogalactan” refers to arabinogalactan covalently attached to a lipophilic group. Preferred lipophilic groups include long chain hydrocarbon groups. Other lipophilic groups include steroids, terpenes, fat soluble vitamins, phytosterols, terpenoids, phospholipids, glycerols, and natural or synthetic fats. The lipophilic group may be attached to the arabinogalactan either directly or via a linking group. For example, the free hydroxy groups on the arabinogalactan may be linked to hydrocarbon chains via an ether or ester linkage.
The water soluble lipidated arabinogalactan is defined in one embodiment by the formula:
AG-R-L
where:
AG is arabinogalactan;
L is a lipophilic group, preferably a branched or straight chain saturated or unsaturated hydrocarbon including between about one to 90 carbons, for example between about 4 and 30 carbons, or alternatively between about 10 and 20 carbons, and is most preferably a C
4
-C
30
straight chain saturated hydrocarbon, for example C
10
-C
18
s
Lee Howard C.
Mueting, Raasch & Gerhardt, P.A.
The University of Montana
White Everett
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