Ligand-targeted emulsions carrying bioactive agents

Details Ligand-targeted emulsions carrying bioactive agents Ligand-targeted emulsions carrying bioactive agents

2000-10-27

2004-01-13

Kishore, Collamudi S. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Liposomes

C424S001210, C424S001370, C424S009321, C424S009510, C424S094300, C514S937000

Reexamination Certificate

active

06676963

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to ligand-targeted emulsions that incorporate biologically active agents on or in their particle surface, and more particularly, to such novel emulsions that are especially useful for the treatment of disease with bioactive agents that have improved risk/benefit profiles when applied specifically to selected cells, tissues or organs.
As used herein, the following terms have the definitions set forth:
Direct conjugation of ligand to the emulsion particle refers to the preparation of a ligand-particle complex before administration wherein the ligand is either adsorbed through ionic, electrostatis, hydrophobic or other noncovalent means to the particle surface (e.g. acylated-antibody), or chemically linked to the surface through covalent bonds to a component of the lipid surface such as a “primer material” (e.g. thio-ether or ester bond), or intrinsically incorporated into the lipid surfactant membrane as a component of the membrane (e.g. a lipid derivatized to a peptiodomimetic agent).
Indirect conjugation refers to the use of avidin biotin where the complex is formed in vivo in two or more steps. An example would be giving the biotinylated antibody first, followed by avidin, and followed by the biotinylated emulsion particle. Any other sequential multistep chemical linking system that could be utilized in vivo is envisioned to produce the same end result, i.e. the close and specific apposition of the emulsion particle to a targeted cell or tissue surface.
Primer material refers to any constituent or derivatized constituent incorporated into the emulsion lipid surfactant layer that could be chemically utilized to form a covalent bond between the particle and a targeting ligand or a component of the targeting ligand (if it has subunits).
Prolonged association of the emulsion particle with the surface of the targeted cell or tissue is in contradistinction to the transient interaction that an unbound particle, existing free in extracellular body fluids, would achieve. By binding the particle to the cell surface, the continued circulation of the nanoparticle through the body is halted. The affixed particle is able to interact with the target cell surface over an extended period of time. The exact amount of time may be variable, but is meant to exceed that of more transient nontargeted contact between particles and cell surfaces by orders of magnitude.
Surfactant is a term derived from SURFace ACTive AgeNT. A Surfactant is a compound that contains a hydrophilic and a hydrophobic segment. When added to water or solvents, a surfactant reduces the surface tension of the systems for the following purposes emulsifying or dispersing in the present application. Our preferred surfactants are phospholipids and cholesterol but include those lipids that are mentioned in our previous application and the additional detergents specified in our invention disclosure.
Ligand is a molecule that binds to another molecule, used in this application to refer to a small targeting molecule that binds specifically to another molecule on a biological surface separate and distinct from the emulsion particle itself. The reaction does not require nor exclude a molecule that donates or accepts a pair of electrons to form a coordinate covalent bond with a metal atom of a coordination complex.
Emulsion technology is very old and distinct from the more modern liposome technology. This is exemplified by the prolific research and patent literature involving liposomes since the 1963 report by Bangham (Physical structure and behavior of lipids and lipid enzymes., Adv Lipid Res, 1963; 1:65-104). Bangham originally characterized emulsions as “either temporary or permanent dispersions of oils or hydrophobic material in water or vice versa” and liposomes as “ . . . ‘myelins’ and ‘myelinics’ . . . irrevocably associated with the structures obtained when certain phospholipids are dispersed in water. . . . The unit structure is a biomolecular tube of lipids, separated from its adjacent concentric tube by a layer of water.” In later years liposomes have been elegantly described as “vesicles in which an aqueous volume is entirely enclosed by a membrane composed of lipid molecules . . . (which) form spontaneously when these lipids are dispersed in aqueous media. . . . The liposome membrane forms a bilayer structure which is in principle identical to the lipid portion of natural cell membranes.” Liposomes may be prepared by a variety of techniques and have single or multiple membrane layers. They are distinctly different and more complex than emulsions.
Drugs can be incorporated into liposomes within either the internal aqueous phase or within one or more of the lipid bilayer membranes and liposomes can be coupled to ligands of various types. Because of the bilayer nature of a liposome membrane, lipophilic drugs incorporate into both the inner and outer leaflets of the bilayer. Drugs, bound to the inner leaflet layer are unavailable for immediate delivery by contact facilitated delivery as opposed to lipid encapsulated emulsions. For multilamellar liposomes, most of the drug will be internalized within the liposome and not readily available for contact facilitated delivery to a target cell. To extend circulatory half-life, liposomes have been modified with polymerized lipids or the addition of polyethylene glycol to enhance in vivo survivability. Both modifications protect the particles from lipid exchange with other cells and lipoproteins.
“An emulsion is a heterogeneous system, consisting of at least one immiscible liquid intimately dispersed in another in the form of droplets, whose diameters, in general, exceed 0.1&mgr;. Such systems possess a minimal stability, which may be accentuated by such additives as surface-active agents, finely-divided solids, etc.” (Becher P. Emulsion: Theory and Practice, New York, N.Y.; Reinhold Publishing Corporation; 1965) “The phase which is present in the form of finely divided droplets is called the dispersion or internal phase; the phase which forms the matrix in which these droplets are suspended is called the continuous or external phase . . . Surface active or other agents which are added to increase stability . . . are known as emulsifiers or emulsifying agents. Stability is also increased by mechanical devices such as simple stirrers, homogenizers or colloid mills.”
Liquid perfluorocarbon emulsions are specialized formulations with various medical and oxygen transport applications. They are especially useful medically as contrast media, for various biological imaging modalities such as nuclear magnetic resonance, ultrasound, x-ray, computed tomography, F-magnetic resonance imaging, and position emission tomography, as oxygen transport agents or “artificial bloods,” in the treatment of heart attack, stroke, and other vascular obstructions, as adjuvants to coronary angioplasty and in cancer radiation treatment and chemotherapy. The fluorocarbon emulsion can be used to deliver drugs and medicines soluble in or transportable by the emulsion.
Long et al. U.S. Pat. No. 4,987,154 discloses that fluorocarbon emulsions can deliver therapeutic agents, medicines and drugs throughout the body, tissue and organs by at least two modes: 1) within the fluorocarbon phase or 2) by complexing of the agent, medicine or drug with the surfactant membrane. Long et al. cite examples of medicines, drugs and therapeutic agents that can be dissolved in the fluorocarbon including diazepam, cyclosporin, rifampin, clindamycin, isoflurane, halothane and enflurane. Examples of medicines, therapeutic agents and drugs that do not dissolve in fluorocarbon, but can be complexed with, for example, a lecithin membrane include mannitol, tocopherol, streptokinase, dexamethasone, prostaglandin E, interleukin, gentamycin and cefoxitin. Antibiotics may be delivered transcutaneously through the skin when added to a fluorocarbon emulsion. Furthermore, proteins such as thrombolytic agents, hormones or enzymes can be transported and delivered by fluorocarbon emulsions.
Delivery of d

Affiliated with

Also associated with

Rating

Ligand-targeted emulsions carrying bioactive agents does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Ligand-targeted emulsions carrying bioactive agents, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Ligand-targeted emulsions carrying bioactive agents will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3228908