Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Matrices
Reexamination Certificate
2001-07-23
2002-12-24
Rose, Shep K. (Department: 1614)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Matrices
C424S485000, C514S449000
Reexamination Certificate
active
06497904
ABSTRACT:
TECHNICAL FIELD
This invention relates to pharmaceutical formulations comprising pharmacologically active agents, biocompatible carriers, and solvents and the like. More particularly, the invention relates to pharmaceutical formulations containing Golgi apparatus disturbing agents such as, for example, brefeldin A. This invention also relates to methods of treating cellular proliferative diseases in patients in need of such therapy.
BACKGROUND
Local cancer chemotherapy involves the introduction of an anti-cancer agent near or within a tumor. As a potential cure for some cancers, local chemotherapy has generated a tremendous interest among researchers and health care providers, in part because local chemotherapy (in contrast to systemic delivery) avoids or minimizes the potential for systemic toxicity, and in part because the target site can be exposed to higher concentrations of the active agent than possible with conventional chemotherapy. Thus, local chemotherapy can provide a useful tool in the treatment of some cancers.
Local chemotherapy is not, however, without drawbacks. One problem associated with local chemotherapy is insufficient retention of the chemotherapeutic agent at the target site (i.e., the diseased organ or tissue). Another problem with local chemotherapy (and many types of chemotherapy, for that matter) is the insoluble or slightly soluble nature of the active agent. Thus, the ability of local chemotherapy to offer a cure for some cancers has been compromised by retention and/or solubility problems associated with previously known or suggested chemotherapeutic agents and formulations.
The proposed solutions to these problems either do not fully address these drawbacks or create their own additional drawbacks. One often-cited approach is to employ a sustained release delivery system of a pharmacologically active anti-cancer agent. It is believed that locally administered, sustained release delivery systems allow high doses of the anti-cancer agent to be delivered while ensuring sufficient retention at the target site. Theoretically, such an approach would both increase efficacy and limit toxicity. To date, however, such approaches have not been effective. Thus additional agents and formulations are needed in order to bring the full potential of local chemotherapy to fruition.
Recently, there has been a significant interest in Golgi apparatus disturbing agents, particularly brefeldin A, due to its reported anti-tumor activity. Brefeldin A (BFA) was first described to be an antifungal, cytotoxic, and cancerostatic antibiotic. Haerri, et al. (1963)
Chem. Abs.
59:5726h. Brefeldin A was also reported to have anti-viral properties. Tamura et al. (1968)
J. Antibiotics
21:161-166. In recent years, brefeldin A has been studied extensively as a protein transport inhibitor. It is believed that brefeldin A can reversibly disrupt the Golgi apparatus, thereby affecting protein transport through the cytoplasm. Domes et al. (1989)
J. Cell Biol.
109:61-72 (1989); Lippincott-Schwartz et al. (1991)
J. Cell Biol.
112:567-577. It is now known that brefeldin A induces retrograde membrane transport from Golgi to the endoplasmic reticulum (ER). Dinter et al.(1998)
Histochem. Cell Biol.
109:571-590. Currently brefeldin A is primarily used as a tool by researchers to interfere with the processing and sorting of finished proteins in order to more fully understand protein trafficking.
Due to solubility and related toxicity problems of brefeldin A, it has not yet been used successfully as an active agent in a pharmaceutical formulation. U.S. Pat. No. 4,608,078 to Acker et al. reported preparation of derivatives of brefeldin A in order to overcome solubility problems, but these derivatives still exhibited toxicity and insufficient solubility. In 1997, preparation and antitumor activity of water-soluble derivatives of brefeldin A were disclosed in U.S. Pat. No. 5,696,154 to Malspeis et al. These derivatives were claimed to be suitable for intravenous delivery in animals and humans. However, these analogs have been tested only in vitro and in very small amounts, which may not produce desired therapeutic effects in vivo. Thus, there remains a need for pharmaceutical formulations which can deliver, inter alia, insoluble or slightly soluble active agents such as brefeldin A and other Golgi apparatus disturbing agents, for the treatment of cellular proliferative diseases. There is a further need for pharmaceutical formulations of brefeldin A.
SUMMARY OF THE INVENTION
Accordingly, it is a primary object of the invention to address the aforementioned needs in the art and provide a pharmaceutical formulation comprising a Golgi apparatus disturbing agent as will be described in detail herein.
It is another object of the invention to provide a pharmaceutical formulation comprising brefeldin A as will be described in detail herein.
It is yet another object of the invention to provide such a formulation which significantly reduces the drawbacks associated with other types of local chemotherapy.
It is still another object of the invention to provide such a formulation which provides for sustained release of the active agent.
It is yet another object of the invention to provide such a formulation which increases the solubility of an otherwise insoluble or slightly soluble active agent.
It is a further object of the invention to provide a method of treating a cellular proliferative disease comprising administering to a patient in need thereof the pharmaceutical formulation of the invention as described in detail herein.
Additional objects, advantages and novel features of the invention will be set forth in part in the description which follows, and in part will become apparent to those skilled in the art upon examination of the following, or may be learned by practice of the invention.
In a first embodiment, then, a pharmaceutical formulation for treating a cellular proliferative disease in a patient is provided comprising: a therapeutically effective amount of a Golgi apparatus disturbing agent; a biocompatible carrier; and a solvent.
The Golgi apparatus disturbing agent can be any agent known to interfere with the functioning of the Golgi apparatus but it is preferred that the Golgi disturbing apparatus disturbing agent is brefeldin A. The biocompatible carrier can comprise any substantially non-antigenic and non-toxic compound that can serve to increase the solubility of the active agent and/or provide a sustained release profile of the active agent following administration of the pharmaceutical formulation. Preferred carriers include polysaccharides and particularly preferred polysaccharides are selected from the group consisting of chitin, chitosan, and combinations thereof. It is preferred also that the biocompatible carrier is covalently linked to brefeldin A.
In another embodiment, a method of treating a cellular proliferative disease is provided comprising administering to a patient in need thereof a pharmaceutical formulation comprising: a therapeutically effective amount of a Golgi apparatus disturbing agent; a biocompatible carrier; and a solvent.
The method of treating includes injecting the pharmaceutical formulation directly or nearly directly to the target site (e.g., an area exhibiting cellular proliferative disease). Preferably, the method is useful for treating proliferative selected from the group consisting of brain cancer, bladder cancer, breast cancer, colorectal cancer, head and neck cancer, liver cancer, prostate cancer, and ovarian cancer.
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Kim Vickie
Reed & Associates
Rose Shep K.
LandOfFree
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