Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2001-08-28
2002-12-03
Azpuru, Carlos (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S501000, C424S502000
Reexamination Certificate
active
06488952
ABSTRACT:
RELATED APPLICATIONS
There are no previously filed, or currently any co-pending applications, anywhere in the world.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to biocompatible materials for systemic and local delivery of therapeutic agents directly within or upon body tissues and, more particularly, to a semisolid therapeutic delivery system and combination semisolid, multiparticulate therapeutic delivery system for therapeutic agents.
2. Description of the Related Art
Approximately 35,000 new brain tumors are diagnosed in adults annually in the U.S. Central nervous system (CNS) malignancies, specifically malignant gliomas, account for 2.5% of all cancer related deaths. Malignant gliomas are the third leading cause of cancer related deaths of persons between the ages of 15 and 34.
In view of the fact that CNS malignancy research has been limited in comparison to other areas of cancer research, this particular malignancy will almost assuredly rise as one of the leading causes of cancer deaths in the U.S.
Malignant gliomas result in tumor formation within the central nervous system. These tumors rapidly grow and infiltrate normal tissues, which result in enlarged tumors compressing normal brain tissue, and in turn, cause abnormality and usually necrosis within the tumor itself, thus requiring removal of the tumor.
Conventional methods of cancer treatment include surgical removal, radiation and chemotherapy. Surgical removal is the initial treatment of choice. Subsequent radiation therapy operates to effectuate physical damage to malignant cells so as to render them incapable of cell division. Chemotherapy generally involves administering drugs that alter the normal structure, function and replication of DNA. Chemotherapy has generally been of limited utility in malignant gliomas due to the fact that most chemotherapeutic agents have very poor penetration into the central nervous system. As a result, clinicians are forced to dose these agents in an aggressive manner in order to increase the systemic concentration to force the drug into the central nervous system. Such aggressive therapy often results in dose proportional systemic side effects such as depression and impairment of normal bone marrow function, which leaves the patient susceptible to a multitude of infections due to the depletion of normal white blood cells. In addition, these agents are toxic to many organ systems including the liver, kidneys, and lungs.
Consequently, conventional treatment methods with respect to malignant gliomas have resulted in a very dismal long-term prognosis, with a mean 24-month survival of
15-20
% of patients. Thus, approximately 85% of patients suffering from a malignant glioma will die within the first two years following diagnosis. This stems from an unusually high rate of tumor recurrence due to incomplete surgical resection. Malignant cells usually infiltrate normal tissue surrounding the primary focus itself and are left behind; hence the need for radiation and chemotherapy following surgical removal of the tumor.
In order to remedy inefficient delivery of chemotherapeutic agents so as to prevent reoccurrence of malignant tumors, pharmaceutical scientists developed the concept of local drug delivery. This concept involves the instillation or application of a drug directly to a sight of action; i.e., the brain. This theoretical strategy led to the development of a drug loaded wafer composed of a biodegradable, polyanhydride polymer, manufactured under the brand name Biodel® by Guilford Pharmaceuticals Inc., Baltimore, Md. The chemical name for the polymer system is poly[bis(p-carboxyphenoxy)propane: sebacic acid]. The drug-loaded wafers, Gliadel® Wafers, are of a solid, disc-shaped configuration approximately the size of a dime. Each wafer is approximately 1.4 centimeters in diameter, approximately 1 mm in thickness and weighs approximately 200 milligrams. Each wafer contains approximately 7.7 milligrams of a drug called BCNU, or carmustine. The chemical name for BCNU is 1,3-bis[2-chloroethyl]-1-nitrosourea. Historically, BCNU has been the common drug choice in the treatment of malignant gliomas primarily due to its ability to penetrate into the central nervous system from the systemic circulation in relatively high concentrations compared to other chemotherapeutic agents.
However, there are various problems associated with the implantation of Gliadel® Wafers. Firstly, due to the rigid nature of the wafer's configuration, the size and shape of the resection pocket may represent a significant problem and limitation of therapy. The clinically recommended dose of wafers to date has been from 6-8 wafers, which yields approximately between 46.2 and 61.6 milligrams BCNU. However, often in an attempt to retain as much viable brain tissue as possible, neurosurgeons find that the resection pocket contains insufficient void space to implant the entire course of therapy. In addition, in the very common case of an irregularly shaped tumor, the physical constraints may also compromise the therapeutic benefit. Further, in the case of a large tumor, the wafers, once secured in the resection pocket, may leave a considerable portion of the surface area without direct contact to the tissue.
Consequently, the rigid nature of the wafers seriously limits the ability of the system to directly contact all areas of tissue directly adjacent to the implants. The unexposed areas of tissue may contain tumor cells, thus leaving such cells untreated and viable. This results in areas receiving a preferential drug exposure while tissues which are removed from direct contact with the wafer(s) receive either sub-optimal or, conceivably, no therapy.
In addition, after a neurosurgeon has removed the bulk of a tumor and has lined the resection pocket with Gliadel® Wafers, a large void volume remains. Neurosurgeons pack this void with bio-absorbent materials such as Gelfoam® (absorbable gelatin sponge) to secure the placement of the disks and to prevent brain tissue from herniating into the resection pocket. Thus the large void volume, which could be used for drug delivery, is inefficiently utilized.
There are also many practical problems associated with the handling of Gliadel® Wafers. The wafers are extremely fragile and often break into pieces when removed from their protective packaging. The manufacturer recommends that once a wafer has been broken into 3 or more pieces, it must be discarded.
In addition, the wafers must be maintained at a refrigerated temperature of 0° C. or colder for stability reasons. If the wafers are left at room temperature for 6 or more hours, they must be discarded.
Furthermore, with respect to economic factors, acquisition costs for 8 wafers is approximately $12,000 to $15,000. Patient cost is significantly higher and given the current lack of strongly significant efficacy data, third party coverage is limited. Thus patient treatment is often prohibitively expensive.
Accordingly, there is a need for a semisolid delivery system and combination semisolid, multiparticulate delivery system for delivery of therapeutic agents systemically and locally to tissues after implantation, deposition or injection. This system efficiently utilizes the entire cavity, excavation, or void volume to increase drug dosages, optimizes the uniform delivery and consistent distribution of therapeutic agents to large, small and irregularly shaped compartments and to allow easy injection, placement or surgical implantation. The development of the multiparticulate and semisolid delivery system fulfills this need.
A search of the prior art did not disclose any patents that read directly on the claims of the instant invention; however, the following references were considered related.
U.S. Pat. No. 6,028,164 issued in the name of Loomis describes cross-linked compositions formed from a water insoluble copolymer having a bio-resorbable region wherein such compositions when placed in contact with an aqueous environment form hydrogels, which are us
Jones, II Curtis E.
Kennedy John P.
Azpuru Carlos
Martin P. Jeff
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