Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-01-14
2001-11-13
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
Reexamination Certificate
active
06316424
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to sulfated phosphatidylinositols, and their use in therapy or as a component of a drug delivery system for a therapeutic agent. More particularly, the present invention relates to the preparation and characterization of sulfated phosphatidylinositols, and their use in pharmaceutical compositions and in methods of treating a disease.
BACKGROUND OF THE INVENTION
A variety of sulfated polymers exhibit antiviral activity against human immunodeficiency virus (HIV). Baba et al.,
Antimicrobial Agents and Chemotherapy
, 34(1), 134-138 (1990), discloses using sulfated polyvinyl alcohol, dextran sulfate, or a sulfated copolymer of acrylic acid and vinyl alcohol to inhibit HIV replication and giant cell formation. In similar studies, Mohan et al.,
Antiviral Research
, 18, 139-150 (1992), discloses sulfonic acid polymers, such as poly(4-styrenesulfonic acid), poly(anetholesulfonic acid), poly(vinylsulfonic acid), poly(2-acrylamido-2-methyl-l-propanesulfonic acid), and dextran sulfate, to inhibit HIV and syncytium formation. Other investigators prepared curdlan galactose sulfate, curdlan arabinose sulfate, and lentinan sulfate from respective, nonsulfated polysaccharides. In vitro studies revealed that these sulfated polysaccharides inhibit HIV infection, block cell-fusion events, and inhibit reverse transcriptase (RT) activity (see Yoshida et al.,
Biochemical Pharmacology
, 37(15), 2887-2891 (1988)).
Other investigators (see, for example, Gustafson et al.,
J. Nat. Can. Inst
., 81(16), 1254-1258 (1989), and Ohta et al.,
Chem. Pharm. Bull
., 46(4), 684-686 (1998)) found that certain sulfolipids inhibited the cytopathic effects of the HIV virus and inhibited syncytium formation. However, these sulfolipids are natural products, which are isolated from marine algae using a cumbersome process to yield small amounts of sulfolipid. For example, a relatively large amount of algae (e.g., 300 grams (g) dry weight) is collected, and the sulfolipid is extracted from the algae using organic solvents, then purified. This process provides about 3.1 milligrams (mg) of the purified sulfolipid for an overall yield of 0.0010%. In yet another study, Barzu et al.,
J. Med. Chem
., 36, 3546-3555 (1993), discloses that naturally occurring sulfated polysaccharides, such as heparin, dermatan sulfate, and several chemically modified heparins, inhibited giant-cell formation normally associated with HIV infection.
Accordingly, polymers and polysaccharides having a plurality of sulfur-containing acid groups have demonstrated a positive antiviral effect on HIV in vitro. Harrop et al.,
Glycobiology
, 8(2), 131-137 (1998), explains this behavior by showing that radiolabelled heparin, which is a naturally occurring sulfated polysaccharide, binds to specific glycoproteins on the viral envelope, thereby inhibiting the human immunodeficiency virus from binding to its natural host cell receptor, CD4.
Although the above-discussed sulfated polymers and polysaccharides showed promise in vitro, therapeutic responses in vivo were disappointing. A significant number of the sulfated polymeric materials are not only cost prohibitive, but also exhibit a low efficacy and a low bioavailability in vivo when administered intravenously. The sulfated polymeric materials also demonstrate a strong, undesirable anticoagulant effect. Accordingly, it would be an advance in the art to provide a compound that demonstrates the therapeutic, e.g., antiviral, advantages of sulfated polymeric materials, while overcoming their disadvantages, in the management of AIDS, for example. The present invention is directed to such compounds.
SUMMARY OF THE INVENTION
The present invention is directed to sulfated phosphatidylinositols and their use in therapy. More particularly, the present invention is directed to the preparation and characterization of sulfated phosphatidylinositols having the idealized structure (I), wherein each R, independently, is H, SO
3
H, or SO
−
3
,
Therefore, one aspect of the present invention is the preparation and characterization of sulfated phosphatidylinositols.
Another aspect of the present invention is the use of a sulfated phosphatidylinositol in therapy to treat a disease. The sulfated phosphatidylinositols can be used as the active agent to treat the disease, or as a component of a drug delivery system of a pharmaceutical composition which contains an additional therapeutic agent.
Another aspect of the present invention is to provide a pharmaceutical composition that can be administered to an individual to treat an acute or chronic disease.
Another aspect of the present invention is the use of a sulfated phosphatidylinositol as a component of a drug delivery system for a more efficacious delivery of a therapeutic agent to a target site within an individual.
Yet another aspect of the present invention is a method of treating a disease or condition comprising administering to an individual a therapeutically effective amount of a sulfated phosphatidylinositol. The disease or condition, for example, can be the treatment, suppression, or prevention of AIDS.
Yet another aspect of the present invention is to provide a pharmaceutical composition containing a therapeutic agent and a drug delivery system, wherein the drug delivery system comprises a sulfated phosphatidylinositol and an amphiphilic compound, wherein the composition can be administered to an individual in a liquid form, either orally or by injection.
Still another aspect of the present invention is to provide a pharmaceutical composition containing a therapeutic agent and a sulfated phosphatidylinositol in a lyophilized form, such that the therapeutic agent can be administered to an individual in a solid form. Such a solid composition is especially useful for the oral administration of a therapeutic agent to an individual.
Another aspect of the present invention is to provide a pharmaceutical composition containing a therapeutic agent and a sulfated phosphatidylinositol that is site specific for improved delivery of the therapeutic agent and improved treatment of the disease of concern.
Still another aspect of the present invention is to provide a method of treating a disease comprising administering to an individual a therapeutically effective amount of a pharmaceutical composition comprising a drug delivery system and a therapeutic agent. The drug delivery system comprises a sulfated phosphatidylinositol and an amphiphilic compound. The drug delivery system more effectively delivers the therapeutic agent to the target site of interest within the individual.
These and other novel aspects and advantages of the present invention will become apparent from the following detailed description of the preferred embodiments taken in conjunction with the figures.
REFERENCES:
patent: 5194654 (1993-03-01), Hostetter et al.
patent: 2255070 (1997-11-01), None
patent: 0 293 826 (1988-12-01), None
patent: WO 93/21191 (1993-10-01), None
Yoshida et al., “Sulfation of the immunomodulating polysaccharide lentinan: A novel strategy for antivirals to human immunodeficiency virus (HIV),”Biochemical Pharmacology, vol. 37, No. 15, pp. 2887-2981 (1988).
Weislow et al., “New soluble-formazan assay for HIV-1 cytopathic effects: Application to high-flux screening of synthetic and natural products for ADIS-antiviral activity, ”Journal of the National Cancer Institute, vol. 81, No. 8, pp. 577-586 (1989).
Gustafson et al., “AIDS-antiviral sulfolipids from cyanobateria (blue-green algae),”Journal of the National Cancer Institute, vol. 81, No. 16, pp. 1254-1258 (1989).
Baba et al., “Novel sulfated polymers as highly potent and selective inhibitors of human immunodeficiency virus replication and giant cell formation,”Antimicrobial Agents and Chemotherapy, vol. 34, No. 1, pp. 134-138 (1990).
Mohan, et al., “Sulfonic acid polymers as a new class of human immunodeficiency virus inhibitors,”Antiviral Research, pp. 139-150 (1992).
Bàrzu et al., “Preparation and anti-HIV activity of O-acylated heparin and dermatan sulfate derivatives with lo
Dadey Eric J.
Mei Xiao-Hui
Fay Zohreh
Marshall Gerstein & Borun
The Board of Trustees of the University of Illinois
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