Microencapsulated compounds and method of preparing same

Details Microencapsulated compounds and method of preparing same Microencapsulated compounds and method of preparing same

1995-05-04

2003-04-29

Saunders, David (Department: 1644)

Drug, bio-affecting and body treating compositions

Immunoglobulin, antiserum, antibody, or antibody fragment,...

C424S145100, C424S158100, C424S491000, C424S499000, C514S002600, C530S350000, C530S387100, C530S388240, C530S389200

Reexamination Certificate

active

06555110

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates generally to the field of drug delivery systems. More particularly, the present invention relates to a method for microencapsulating drugs using biodegradable nonantigenic materials and also to microencapsulated compositions that are targeted either to macrophages, other phagocytic cells of the immune system, or a diseased organ, which phagocytize the microspheres and digest the coating, releasing the intact drug or active fragment thereof intracellularly or at the site of attachment Such compositions are useful in treating and preventing disease.
BACKGROUND OF THE ART
Drug delivery technology can bestow new leases on the lives of seemingly ineffective or inefficient drugs by targeting them specifically to sites of action. In this manner, unwanted systemic side effects are obviated and dose requirements are substantially reduced. Macrophage mediated delivery of drugs has been suggested as an alternative for treatment of several types of diseases. Modern immunology has acknowledged the importance of the monocyte and its mature counterpart, the macrophage as the prime antigen presenting cell in immune interactions. As an extension of this function it can be theorized that macrophages may be utilized to present immunoactive drugs to relevant components of the immune system such as lymphocytes in an effort to modulate their function.
Systemic elimination systems developed by the body to attack and eliminate foreign material include macrophages and Kupffer cells. For the purposes of the present invention the term macrophage includes Kupffer cells, when appropriate. Macrophages are cells widely distributed in many tissues of the body including lympho-hemopoietic organs, skin, gut, other portals of entry and the nervous system. They are found in direct contact with the blood (monocytes, sinus-lining Kupffer cells) or extravascular space, and undergo complex migrations as they enter tissues after production mainly within the bone marrow of the adult. As mobile and long-lived cells the mononuclear phagocytes play central roles as effector cells in inflammatory reactions and cell mediated immune responses. Monocytes produced in the bone marrow are released into the blood stream where they circulate with an estimated half life of 8-9 hours. Most experimental evidence indicates that the monocytes migrate into tissue to replace senescent tissue macrophages, and differentiate into cells of varied morphological and functional characteristics. Although definitive information on density and tissue distribution of these cells is still not available it is clear that the tissue content of mononuclear phagocytes, often associated with the vasculature greatly exceeds the bone marrow replicative pool. These cells, in a real sense are the first line of defense, followed by secondary waves of granulocytes, lymphocytes and monocytes from the circulation.
The term “activated macrophage” refers to cells with increased phagocytic activity, increased content of acid hydrolases, more active metabolism, and, more importantly, an increased microbicidal capacity. Macrophages become activated following specific immunity involving the T lymphocyte. The T lymphocyte represents the specific branch of the cellular response which, in some way or another (most likely via secretion of soluble products), activates macrophages. The activated macrophages display considerable enhancement in their capacity to curb bacterial growth. Although macrophage activation clearly follows immune activation of the T cells, it can also result from direct interaction of certain bacterial products or other chemicals with the macrophage. Unstimulated macrophages or non-activated macrophages generate low and variable cytokine activity. However, as with enzyme secretion, the secretion of these lymphocyte-stimulatory activities can be modulated. Two conditions produce an increase in activity: one is a phagocytic challenge, the second is exposure to activated T lymphocytes. Exposure of macrophages to bacteria, antigen-antibody complexes, latex beads, or endotoxin results in a marked increase (up to 10 times) in the activity tested, both in mitogenic response of the thymocytes and in antibody formation. This increase is seen for 1 to 2 days, and then decays away. The presence of activated T cells, which by themselves were not responsible for the activities, markedly enhances their production. The highest mitogenic activity found in cell culture results from the addition of a small number of the activated T cells to the macrophage culture.
The term phagocytosis is used to describe the internalization of large particles, such as those visible by light microscope, mostly viruses and bacteria. Uptake occurs by close apposition of a segment of plasma membrane to the particle's surface, excluding most if not all of the surrounding fluid. The phenomenon of phagocytosis seen in living cells in tissue culture or in-vivo has been well described. Phagocytosis is a process that occurs in three stages: attachment, ingestion, and digestion of the particles. The activated macrophage possessing a ruffled surface at the leading edge pushes out processes towards a particulate substance and rapidly flows around it. The entire process may only take a few minutes. Once ingested, the material may be totally digested, it may persist in the form of an indigestible residue, or it may actually fill up the whole cell, and if toxic may kill the cell. When the particle is too large for one cell to ingest, several cells flow around it and form a capsule. After ingestion, the vesicle which forms around the phagocytized particle, the phagosome fuses with one or more iysosomes to form a secondary lysosome or phagolysosome. The lysosome is a membranous bag of hydrolytic enzymes to be used for the controlled intracellular digestion of ingested materials. The hydrolytic enzymes contained in the lysosome are thus discharged into the enlarged vacuole to degrade the contents.
The deleterious effects of immune modulated diseases that manifest themselves due to improper recognition of “self” from “non-self” may be effectively reduced using this mode of drug delivery. Rheumatoid arthritis (RA) is one such disease affecting a large percent of the geriatric population. And while macrophages may not be a primary target for the virus causing acquired immune deficiency syndrome (AIDS), they have been implicated as carriers of the virus.
Cytokines are polypeptide hormones which have a variety of physiologic activities intended to “up-regulate” and/or “down-regulate” the immune system.
The cytokine cascade, although not fully elucidated, involves the release of a number of molecules, including tumor necrosis factor alpha (TNFa), interleukin-1 beta (IL1&bgr;), interleukin-2 (IL2), interleukin-6 (IL6), interleukin-8 (IL8), colony stimulating factors (CSF), interferons (IFN), interleukin-1 receptor antagonist (IL1-ra) as well as other interleukins whose function is still not completely understood from monocytes, macrophages, lymphocytes, and other tissues throughout the body. These cytokines act both locally and systemically to recruit other white blood cells to the site of infection, activate macrophages, increase antibody production, produce fever, hyperlipidemia, hyperglycemia, and directly activate natural killer and lymphokine activated killer lymphocytes thereby destroying tumor cells. In cancer patients, the concentration of cytokines such as tumor necrosis factor alpha (TNFa) and interleukin-1 beta (IL1-&bgr;) have been observed to be decreased during active tumor growth. Administration of macrophage/immune activators such as microencapsulated macrophage colony stimulating factor have been shown to reduce cancer mortality and lead to increases in local TNFa and IL1&bgr; concentration. Alternatively, administration of microencapsulated TNFa and IL1&bgr; may activate cellular immunity and increase tumoricidal activity of T-lymphocytes through upregulation of macrophage induced T-cell clonal expansion.
Although this response is usu

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