Nanoparticles and microparticles of non-linear hydrophilic-hydro

Details Nanoparticles and microparticles of non-linear hydrophilic-hydro Nanoparticles and microparticles of non-linear hydrophilic-hydro

1996-03-25

1999-12-28

Smith, Lynette R. F.

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Particulate form

424489, 424497, 424498, 424502, 424451, 424462, 424 7808, 5147723, 514784, 514963, 51440221, 42840224, A61K 950, A61K 914, A61K 916, A61K 948

Patent

active

060078456

DESCRIPTION:

BRIEF SUMMARY
This invention is in the area of biodegradable block copolymers and nanoparticles and microparticles for the controlled delivery of biologically active material and diagnostic purposes made from the polymers.


BACKGROUND OF THE INVENTION

A major challenge in the area of the parenteral administration of biologically active materials is the development of a controlled delivery device that is small enough for intravenous application and which has a long circulating half-life. Biologically active materials administered in such a controlled fashion into tissue or blood are expected to exhibit decreased toxic side effects compared to when the materials are injected in the form of a solution, and may reduce degradation of sensitive compounds in the plasma.
A number of injectable drug delivery systems have been investigated, including microcapsules, microparticles, liposomes and emulsions. A significant obstacle to the use of these injectable drug delivery materials is the rapid clearance of the materials from the blood stream by the macrophages of the reticuloendothelial system (RES). For example, polystyrene particles as small as sixty nanometers in diameter are cleared from the blood within two to three minutes. By coating these particles with block copolymers based on poly(ethylene glycol) and poly(propylene glycol), their half-lives were significantly increased. L. Illum, S. S. Davis, "The organ uptake of intravenously administered colloidal particles can be altered by using a non-ionic surfactant (poloxamer 338)", FEBS Lett., 167, 79 (1984).
Liposomal drug delivery systems have been extensively considered for the intravenous administration of biologically active materials, because they were expected to freely circulate in the blood. It was found, however, that liposomes are quickly cleared from the blood by uptake through the reticuloendothelial system. The coating of liposomes with poly(ethylene glycol) increases their half life substantially. The flexible and relatively hydrophilic PEG chains apparently induce a stearic effect at the surface of the liposome that reduces protein adsorption and thus RES uptake. T. M. Allen, C. Hansen, Biochimica et Biophysica Acta, 1068, 133-141 (1991); T. M. Allen, et al., Biochimica et Biophysica Acta, 1066, 29-36 (1991); V. Torchilin, A. Klibanov, "The Antibody-linked Chelating Polymers for Nuclear Therapy and Diagnostics", Critical Reviews in Therapeutic Drug Carrier Systems, 7(4), 275-307 (1991); K. Maruyama, et al., Chem. Pharm. Bull., 39(6), 1620-1622 (1991); M. C. Woodle, et al., Biochimica et Biophysica Acta; 193-200 (1992); and D. D. Lassic, et al., Biochimica et Biophysica Acta, 1070, 187-192 (1991); and A. Klibanov, et al., Biochimica et Biophysica Acta, 1062, 142-148 (1991).
European Patent Application Nos. 0 520 888 A1 and 0 520 889 A1 disclose nanoparticles made from linear block copolymer of polylactic acid and poly(ethylene glycol) for the controlled administration of biologically active materials. The applications do not disclose how to modify the copolymer to vary the profile of drug release or how modifying the copolymer would affect distribution and clearance of the delivery devices in vivo. The applications also do not teach how to prepare nanoparticles that are targeted to specific cells or organs, or how to prepare nanospheres that are useful for gamma-imaging for diagnostic purposes.
In U.S. Ser. No. 08/690,370 filed Jul. 23, 1993, injectable particles are described which are formed of a biodegradable solid core containing a biologically active material and poly(alkylene glycol) moieties on the surface or of block copolymers of the poly(alkylene glycol) moieties with biodegradable polymers, which exhibit increased resistance to uptake by the reticuloendothelial system.
It would be desirable to have other types of particles for the controlled delivery of materials that are not rapidly cleared from the blood stream by the macrophages of the reticuloendothelial system, and that can be modified as necessary to target specific cells or organs or manipul

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