Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2001-03-27
2003-11-11
Wilson, James O. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S023000, C514S974000, C514S034000, C514S256000
Reexamination Certificate
active
06645946
ABSTRACT:
TECHNICAL FIELD
Methods and compositions are provided that relate to the administration of a toxic agent to a subject in a formulation in which toxicity is substantially reduced.
BACKGROUND
Many therapeutic agents typified by chemotherapeutics are effective at treating a particular condition, but may at the same time have toxic side effects for the patients that significantly impact the quality of life for the patient. These toxic side effects may arise through the biological action of the agents. For example, a majority of chemotherapy agents kill cancer cells by acting on cells that are actively dividing and replicating. These agents unfortunately do not discriminate between cancer cells and actively dividing normal cells such as blood cells forming bone marrow, cells in the digestive tract, hair follicles, and reproductive cells. Because the chemotherapeutic agents are toxic, the effectiveness of the drug is limited because dosage levels and treatment frequency cannot exceed tolerance levels for non-cancerous cells. Moreover, the chemotherapy regimen often dramatically diminishes the quality of a patient's life through its physical and emotional side effects.
In attempts to overcome the problems of toxicity, chemotherapeutic agents have been targeted to tumor cells by covalently binding the agent to a carrier macromolecule that binds a specific receptor on the surface of a target cell. The carrier molecule is commonly a protein or glycoprotein but may also be a carbohydrate. Limitations of this approach include the ability of the conjugate to effectively and selectively bind the drug target.
An alternative approach to treating patients is to search for therapeutic agents that act on targets that are only associated with diseased tissue. For example, certain cancer drugs are being developed that inhibit angiogenesis, an activity that is essential for growth of a tumor but not otherwise essential in an adult subject except for wound healing or during the menstrual cycle. Another approach is to inhibit tumor metastasis. Potential anti-metastatic agents include a class of modified citrus pectins which are polysaccharides that prevent metastasis of primary tumors by acting as antagonists for growth factors that interact with cell receptors to prevent metastasized cells from lodging at a secondary site (Platt et al. J. Natl Cancer Inst. 84, 438-442 (1992); U.S. Pat. No. 5,801,002, Raz, U.S. Pat. No. 5,895,784). Carbohydrate binding proteins have also been used to prevent metastasis of tumors. These compounds are galactose specific carbohydrate binding proteins that bind to galactose binding sites on metastatic cells and interfere with cell-cell interactions necessary during metastasis. (Platt: U.S. Pat. No. 5, 681,923). Simple sugars such as methyl-&agr;-D lactoside and lacto-N-tetrose have been shown to inhibit metastasis of B 16 melanoma cells, while D-galactose and arabinogalactose inhibited liver metastasis of L-1 sarcoma cells (Beuth et al. J. Cancer Res. Clin. Oncol. 113, 51, 1987).
Despite the increasing resources applied to develop new therapies for cancer, survival rates for most cancer patients have not materially improved over the last 15 years (American Cancer Society, 1995 “Cancer Facts & Figures”). In most cases, particularly when a tumor is not detected at an early stage, cancer chemotherapy merely partially prolongs a patient's life, often for only a few months. Given the rigors of repeated chemotherapeutic treatments, and taking into account the low response rates and the modest effects on survival time, significant toxicity and side effects which reduce the patient's quality of life have become a major issue. Increasing efficacy of a drug can be translated into decreasing of the dosage of the drug, and decreasing its toxicity. Further, decreasing of toxicity per se leads to improvement of the patient's quality of life.
However effective a therapeutic agent may be in modifying an abnormal biological condition, undesirable toxic side-effects impinge on the optimum use of the agents.
SUMMARY
In an embodiment of the invention, a method is provided for delivering an effective dose of a therapeutic agent to a subject in a formulation that reduces the toxic side effects of the agent that includes the step of providing a polysaccharide, for example a galactomannan, combining the polysaccharide with the effective dose of the agent to form a mixture; and administering the mixture to the subject. The agent may be a chemotherapeutic agent. Moreover, the mixture may be administered parenterally.
In a further embodiment, a method is provided for treating a cancer in a subject, comprising: administering parenterally an effective dose of a chemotherapeutic agent in a mixture with an effective dose of a galactomannan.
An example of a galactomannan is a polysaccharide having a size is in the range of 20,000-600,000 D or in the range of 90,000 to 415,000 D or in the range of 40,000-200,000 D. In specific examples, the galactomannan may have an average size of 83,000D or 215,000D. In a further embodiment of the invention, the galactomannan is isolated from an isolate from
Gleditsia triacanthos
. In a further embodiment, a hydrolysis product of the gcalactomannan is obtained which is has a lower molecular weight than the isolated non-modified form. In other embodiments of the invention, a galactomannan is obtained which is a derivative of an isolate from
Medicago falcata.
In embodiments of the invention, a galactomannan is used to reduce toxicity of a therapeutic agent when it is mixed with the agent prior to administration. The galactomannan may be a &bgr;1,4 D-galactomannan. Moreover, the galactomannan may include a ratio of 2.0-3.0 mannose to 0.5-1.5 galactose. The ratio of mannose to galactose may be 2.6 mannose to 1.5 galactose or 2.2 mannose to 0.9 galactose or 1.13 mannan to 1 galactose or 2.2 mannose to 1 galactose.
The ratio of galactomannan to chemotherapeutic agent in the mixture may be in the range of 0.1:1 w/w to 10:1 w/w. In an embodiment of the invention, the mixture has a reduced toxicity of greater than 50% compared with the same dose of the agent absent galactomannan. The mixture may have a reduced toxicity of greater than 80% compared with the same dose of the agent absent galactomannan.
In an embodiment of the invention, the therapeutic agent is a chemotherapeutic agent, for example, adriamycin or 5-Fluorouracil (5-FU).
A further embodiment of the invention provides a method for use in treating a cancer including any of chronic leukemia, breast cancer, sarcoma, ovarian carcinoma, rectal cancer, throat cancer, melanoma, colon cancer, bladder cancer, lung cancer, mammary adenocarcinoma, gastrointestinal cancer, stomach cancer, prostate cancer, pancreatic cancer, or Kaposi's sarcoma.
In an embodiment of the invention, a cancer therapeutic formulation with reduced toxicity includes an effective dose of a galactomannan, and an effective dose of a chemotherapeutic agent in a mixture. The formulation may further include a cancer therapeutic in which the formulation is in a powder form or in a liquid form.
DETAILED DESCRIPTION OF EMBODIMENTS
The following terms shall have the meanings indicated herein and in the claims, unless required otherwise by the context.
The term “subject” is defined here and in the claims as a mammal including a human in need of therapy for, or susceptible to, a condition or its sequelae. The subject may include dogs, cats, pigs, cows, sheep, goats, horses, rats, and mice and humans. The term “subject” does not exclude an individual that is normal in all respects.
The term “patient” shall mean a human subject who has presented at a clinical setting with a particular symptom or symptoms suggesting the need for treatment.
The term “polysaccharide” refers to polymers comprised primarily of monomers of one or more sugars and substituted sugars. When isolated from nature, polysaccharide preparations comprise molecules that are heterogeneous in molecular weight.
“Efficacy” of a therapeutic agent refers to the relationship b
Klyosov Anatole
Platt David
Gaudet Stephen J.
McIntosh III Traviss C.
Perkins Smith & Cohen LLP
Pro-Pharmaceuticals, Inc.
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