Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Liposomes
Reexamination Certificate
1997-09-03
2001-01-23
Kishore, Gollamudi S. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Liposomes
C428S402200, C436S829000
Reexamination Certificate
active
06177099
ABSTRACT:
BACKGROUND OF THE INVENTION
SIALIC ACID: An N-acyl derivative of neuraminic acid.
NEURAMINIC ACID: A synthetically-derived sialic acid. The Chemical Abstracts Index names for this molecule are: D-glycero-D-galacto-2-Nonulopyranosidonic acid, methyl 5-amino-3, 5-dideoxy-(9C1); or D-glycero-D-galacto-Nonulopyranosidonic acid, methyl 5-amino-3, 5-dideoxy-(8Cl). Another name for this molecule is Methoxyneuraminic Acid, or Beta-Methoxy Neuraminic Acid. As ordered by the applicant form Sigma Chemical Company, P.O. Box 14508, St. Louis, Mo. 63178, it is named Neuraminic Acid Beta-Methyl-Glycoside (pfs), product number N 5380 (1992 Catalog).
NEURAMINIDASE: An enzyme of the hydrolase class that is in blood and which catalyzes the hydrolysis of glucosidic linkages between a sialic acid residue and a hexose or hexosamine residue at the non-reducing terminal of oligosaccharides in glycoproteins, glycolipids and proteoglycans.
LIPOSOME: A spherical particle in an aqueous medium, formed by a lipid bilayer enclosing an aqueous compartment.
BACKGROUND OF THE INVENTION
Liposomes, also known as vesicles, have been designed to encapsulate a cargo of pharmacological agents useful for in vivo purposes such as the diagnosis and treatment of various diseases and conditions. These cargo-carrying liposomes have, experimentally, shown potential for being site-specific carrier systems for a variety of such agents. Agents so delivered to designated sites in vivo demonstrate significantly enhanced therapeutic indices. Concurrently, decrease in unwanted side effects and wasted portions of dosages is achieved. Agents not so couried spread to nonspecific and often undesirable areas of the body, and possibly cause side effects.
The advantages of the prior art in vivo carrier system have been offset, however, by the deleterious effects of the body's reticuloendothelial system (the “RES”), mainly the liver and spleen. The RES acts to screen the body's circulation. The RES will gradually scavenge from the circulation all material it considers foreign and unwanted. Liposomes have certain physical characteristics which render them susceptible to removal by the RES. Once recognized, liposomes, whether given a site-specific molecule for so-called “targeted” delivery or not, are quickly phagocytosed by the RES along with their cargo. This prior revolutionary carrier system has, until the present invention, and the processor invention of U.S. Pat. No. 4,501,728, remained hampered by the RES, the body's own defense mechanism.
In said earlier invention, U.S. Pat. No. 4,501,728, the sialic acid mechanism for RES avoidance was a system consisting essentially of a biochemical membrane having sialic acid residues that mask the surface membrane from recognition by the RES cells.
Despite the successful application of sialic acid residues to the liposome carrier system, liposomes so disguised from the RES were nevertheless eventually subject to enzymatic action of endogenous neuraminidase in the blood. Specifically, it was found that neuraminidase cleaves the chemical bond between sialic acid and its attached sugar (galactose), thereby allowing the galactose (sugar) on the surface of the liposome to be recognized by the RES's Ashwell receptor of the liver.
Enzymatic removal of the sialic acid is time-dependent. Liposomes intended to circulate for longer periods of time in the vascular system or until attracted to a binding-site, are removed by the RES once the sialic acid mask is compromised or lost.
Along with finding a means to mask the liposome from the RES, it is generally an objective in the art of drug delivery to discover an appropriate site-specific binding molecule. Once discovered, the binding molecule can be incorporated into the liposome. Such masked liposome with its binding molecule, when introduced in vivo, will evade the RES and will carry a designated cargo to a predetermined binding site in the body. When delivered, the cargo is then released to perform its designated function.
SUMMARY OF THE INVENTION
This invention is embodied by the product of a procedure of applying to the external surface of a liposome carrier system, two types of substituent molecules. One such molecule masks the liposome from the RES and is sel ected from the class consisting of those chemicals which are classed biologically as synthetically-derived molecules that prevent phagocytosis by the body's RES and which cannot be degenerated and separated from the liposome by the action of circulating endogenous enzymes.
The other molecule is one which binds to or is bound by a specific site in the body and which is incorporated as part of the liposome carrier. The combined result of the liposome carrier with these two types of substituent molecules, is highly effective delivery of the liposome's therapeutic or diagnostic cargo to a specific body site, having evaded the body's RES.
It is an object of this invention to create a composition of matter for in vivo administration of therapeutic or diagnostic agents, comprising a lipid membrane structure in the form of a liposome or vesicle, a second component which is a synthetically derived molecule that prevents recognition of the liposome or vesicle by the RES and which cannot be cleaved from the liposome or vesicle by the action of endogenous enzymes, and a third component which is a molecule that binds the liposome or vesicle to a specific site in the body and which can be present for site-specific delivery or absent for non-specific delivery of the therapeutic or diagnostic agents in vivo.
This invention is the discovery that superior site specific delivery of the liposome's cargo is obtained by the combined effect of using synthetically-derived RES-avoidance molecules that cannot be cleaved by circulating endogenous enzymes, with site-specific binding molecules that find or are found by a receptor at a desired site in the body.
This invention is also the discovery that superior systemic circulation of liposomes without site-specific delivery, can be achieved using the aforementioned synthetic masking molecules without the site-binding molecule component.
REFERENCES:
patent: 4861597 (1989-08-01), Kida et al.
patent: 5169635 (1992-12-01), Ono et al.
patent: 5567432 (1996-10-01), Lau
Geho W. Blair
Lau John R.
Heller Ehrman White & McAuliffe LLP
Kishore Gollamudi S.
SDG, Inc.
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