Drug – bio-affecting and body treating compositions – Digestive system regulator containing solid synthetic...
Reexamination Certificate
1997-06-27
2002-12-10
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Digestive system regulator containing solid synthetic...
C424S078130, C424S078170, C424S078180, C424S489000, C424S490000, C424S497000, C428S407000
Reexamination Certificate
active
06491903
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to novel globular amphiphilic polymers. More specifically, the present invention relates to low polydispersity particles comprising amphiphilic copolymers, having a crosslinked shell domain, which can be permeable, and an interior core domain. The present invention also relates to methods for producing the particles. The invention particles can be used in a variety of applications, including removal of hydrophobic contaminants from aqueous solutions, recording materials, hydraulic fluids, coatings, chromatography, electrophoresis, drug delivery, catalysis, salvation, fat substitutes, delivery of herbicides and pesticides, combinatorial chemistry, DNA delivery, phase transfer reactions, and as fillers and reinforcement agents for plastics.
2. Description of Related Art
There is an interest in new classes of polymeric materials that have new and advanced physical, chemical, and mechanical properties. For example, Y. H. Kim reported hyperbranched polymers in
Advanced Materials
, 4, 764 (1992). Macrocycles were described by Y. Gan, et al. in
Polymer Preparation
, 34(1), 69 (1993). Rotaxanes were reported by Y. X. Shen, et al. in
Macrocycles
, 25, 2058 (1992). Two dimensional polymeric sheets have also been described (Stupp, S. I., et al.,
Science
, 259, 59 (1993)).
Other polymeric materials with new and unusual behavior include dendrimers, described by D. A. Tomalia, et al. in
Angewandte Chemie International Edition English
, 29, 138 (1990). A review article on dendrimers is Ardoin, N., et al.,
Bulletin de la Société Chimie
, 132(9), 875 (1995). Another review of dendrimer research is found in
Advances in Dendritic Materials
, Ed. G. R. Newkome, JAI Press, Greenwich, Conn., 1994-95, Vol. 1-2.
Products created from these polymers possess unusual behavior when compared to traditional linear polymers. For example, rigid sphere and micellar dendrimers can encapsulate molecules and act as carriers or pharmaceutical delivery agents (Jansen, J. F. G. A., et al.,
Advanced Materials
, 7(6), 561 (1995). Another example of how dendrimers can be used as carriers or pharmaceutical delivery agents is described by Hawker, C. J., et al.,
Journal of the Chemical Society, Perkins Transactions
, 1, 1287 (1983)).
However, dendrimers are costly, time-consuming to synthesize, limited in their chemistry, and limited in their size range.
Block copolymers consisting of segments that possess different properties (for example, solubility, polarity, and rigidity) are well known to self-assemble into polymer micelles when placed in an appropriate solvent. Examples are found in Quin, A., et al.,
Macromolecules
, 27, 120-26 (1994); Astafieva, Il, et al.,
Macromolecules
, 26, 7339-7352 (1993); and Kataoka, K. et al.,
Journal of Controlled Release
, 24, 119-132 (1993). However, these assembled structures are most often held together by hydrophobic interactions, which are not as strong as covalent bonds, and can be easily destroyed upon dilution of the solution containing polymer micelles, or by shear forces. Once the hydrophobic interactions are destroyed, the structures disassemble. Also, such structures typically have very short life times, for example less than a second.
Core-shell type polymer nonoparticles having a cross-linked core have been prepared from diblock copolymer films (Ishizu, K., et al.,
Polymer
-
Plastics Technology and Engineering
, 31(7&8), 607 (1992); Saito, R., et al., Polymer, 35, 866 (1994)). Another example of core-crosslinked polymer nonoparticles is the stars described by Martin, M. K., et al., “Anionic Polymerization,” Ed. J. E. McGrath, ACS Symposium Series 166, American Chemical Society, 1981, pp. 557-590. Stars are limited in having only one polymerizable group per surfactant molecule. Other polymer nonoparticles with cross-linked cores have been prepared from cross-linkable diblock copolymers (Guo, A., et al.,
Macromolecules
, 29, 2487 (1996)). The solid, cross-linked cores limit the absorptive properties, rigidity, and structures of these nanoparticles.
Until now, attempts to prepare core-shell type polymer nanoparticles having a crosslinked shell domain and an interior core domain have been unsuccessful. For example, D. Cochin, et al. reported in
Macromolecules
, 26, 5755 (1993) that attempts to prepare shell-crosslinked micelles failed when using amphiphilic molecules such as N-n-alkyl-N,N-dimethyl-N-(vinylbenzyl)ammonium chlorides.
S. Hamid and D. Sherrington reported in a kinetic analysis of micellar shell crosslinking, “On the contrary these kinetic parameters suggest that rapid exchange of polymerizable amphiphiles during the kinetic lifetime of a propagating radical should allow the possibility of growth to a high polymer (in reacting micelles at the expense of non-reacting ones), and the formation of particles of much bigger dimensions than micelles (i.e., a situation analogous to normal emulsion polymerization).” They suggest that “monomer exchange is too rapid to form a ‘polymerized micelle’.” (Hamid, S. and Sherrington, D., “Polymerized Micelles: Fact of Fancy?”
Journal of the Chemical Society, Chemical Communications
, p. 936 (1986).)
L. Zhang, et al. reported in Science, 272, 1777 (1996) that morphological changes of micelles prepared in aqueous media from highly asymmetric polystyrene-b-poly(acrylic acid) can be obtained by the addition of calcium chloride, sodium chloride, or hydrochloric acid. Such morphological changes included clumping or clustering or bridging between micelles. The morphologically changed micelles are limited in their use because of their propensity to clump and because the stability of this system is highly dependent on pH and ionic strength.
Presently, there has not been a successful synthesis from amphiphilic agents or surfactants of a low polydispersity nanoparticle having a permeable, covalently crosslinked shell domain and an interior core domain. The references discussed above demonstrate continuing efforts to provide such a means of carrying or delivering chemical agents such as pharmaceuticals.
SUMMARY OF THE INVENTION
The present invention furthers the efforts described above by providing novel low polydispersity particles, pharmaceutical, agricultural, and other compositions, and methods of use therefor.
Accordingly, among its various aspects, the present invention provides low polydispersity globular macromolecules, particles, or nanoparticles as shown in
FIG. 1
, wherein the particles comprise amphiphilic copolymers, having a crosslinked shell domain or peripheral layer, which can be permeable, and an interior core domain.
The particles of the present invention can comprise a hydrophilic, crosslinked, permeable shell domain and a hydrophobic interior core domain. The amphiphilic copolymers of the particles of the present invention can be crosslinked via functional groups within the hydrophilic shell domain. Such crosslinking can be achieved by condensation reactions, addition reactions, or chain polymerization reactions.
In another embodiment of the present invention, the particles comprising amphiphilic copolymers, having a crosslinked shell domain and an interior core domain, comprise a hydrophobic, crosslinked shell domain, which can be permeable, and a hydrophilic interior core domain. The amphiphilic copolymers of these particles can be crosslinked via functional groups within the hydrophobic shell domain by condensation reactions, addition reactions, or chain polymerization reactions.
In yet another embodiment, the present invention provides a composition comprising amphiphilic copolymers, haveing a crosslinked shell domain, which can be permeable, and an interior core domain.
In another aspect, the present invention provides a pharmaceutical composition, comprising particles comprising amphiphilic copolymers having a crosslinked shell domain, which can be permeable, and an interior core domain, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or diluent. The pharmaceu
Forster Denis
Jacob Gary S.
Warner James M.
Fubara Blessing
Page Thurman K.
Senniger Powers Leavitt & Roedel
Washington University
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