Nanogel networks including polyion polymer fragments and...

Details Nanogel networks including polyion polymer fragments and... Nanogel networks including polyion polymer fragments and...

2001-12-21

2004-02-24

Riley, Jezia (Department: 1637)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Matrices

C424S001850, C424S130100, C424S600000, C424S486000, C521S025000, C523S404000, C523S414000, C514S001000, C514S002600, C514S04400A, C525S326100

Reexamination Certificate

active

06696089

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to polymer technology, specifically polymer networks having at least one cross-linked polyion polymer fragment, in particular a polyanion, and at least one nonionic water-soluble polymer fragment, and compositions thereof.
BACKGROUND OF THE INVENTION
Conventional methods for the design of new drugs can be extremely difficult and time-consuming. For a new drug to be effective, it must be precisely matched to its molecular target. Moreover, once such a molecule is discovered, the new drug candidate must be soluble, bioavailable, nontoxic, and resistant to metabolic enzymes. Modifications to such a new molecule, necessary to satisfy these requirements, often have an adverse effect on the drug's therapeutic efficacy. Because of these complexities, conventional drug design can be a very costly, time-consuming process.
Recent advances in combinatorial chemistry technology have attempted to address these difficulties, however the problem of making such molecules soluble, bioavailable, resistant to metabolic enzymes, and capable of penetrating through membranes often remains unsolved.
The drug delivery industry has addressed some of these problems by incorporating drugs into carriers. In drug delivery assisted products, the time of development is somewhat shortened to approximately seven years, and the average cost is decreased. Unfortunately, many drug delivery systems still have several serious limitations in view of the problems discussed above.
SUMMARY OF THE INVENTION
The invention relates to copolymer networks having at least one cross-linked polyion polymer fragment and at least one nonionic water-soluble polymer fragment. These networks are in the nanometer size range. The copolymer networks are referred to as “nanogels”.
This invention further relates to compositions of the nanogel networks of cross-linked polymer fragments of nanometer size range in which the nonionic water-soluble fragments contain hydrophilic and hydrophobic chain segments. The chain segments self assemble in an aqueous environment within the nanogel network volume resulting in formation of hydrophobic domains in each nanogel species that can incorporate and release nonpolar molecules or polar molecules containing non-polar parts. The aggregation of the nanogels through hydrophobic interactions between individual nanogels particles resulting in a formation of a precipitate or a bulk structure, such as a bulk gel, is undesirable. Accordingly, it is preferred that nanogels form stable dispersions.
This invention further relates to compositions having nanogel networks of cross-linked polymer fragments (defined herein as “polymer networks”) and a suitable biological agent or agents.
The invention also relates to combinatorial drug delivery, or combinatorial formulation. The invention reduces the time and cost required for creating desired drug compounds, which are not only immediately ready for clinical trial, but also possess a number of important characteristics increasing the probability of ultimate success. In contrast to combinatorial chemistry, however, the invention does not discover new drug structures per se or alter the desirable drug characteristics themselves, but instead provides optimal compositions of a desired drug solving the drug's problems relating to solubility, bioavailability, resistance to metabolic enzymes, toxicity, membrane transport, and site specific delivery. Using a biological agent molecule as a starting point, the invention identifies new compositions with characteristics sought for the optimal performance of the selected molecule.
DETAILED DESCRIPTION
The invention thus relates to new chemical molecules having polymer networks of cross-linked polyion polymer fragments and nonionic polymer fragments. The dispersed polymer networks combine the properties of both polymer gels and colloidal particles. Polymer networks can contain both low molecular mass and polymer biological agents including, small molecules, oligo- and polysaccharides, polypeptides and proteins, polynucleotides such as RNA or DNA, and the like.
The invention also provides a method of identifying a biological agent composition of choice to create a cross-linked polymer network composition that will render a biological agent soluble, bioavailable, resistant to metabolic enzymes, non-toxic, freely traveling through membranes and into cells, or having desired release characteristics in the body. By using polymer networks which differ in the length and polymer fragment structure, and preparing composition corresponding libraries, the invention provides for rapid complexing and identification of compositions of biological agents with desired properties.
The invention further relates to biological compositions having polymer networks and biological agents. Dispersed polymer networks are capable of being transported in the body to a disease site, crossing biological barriers (such as the blood-brain barrier, and intestinal epithelium), entering cells, crossing cell membranes, and being transported to a target site inside a cell. These polymer network particles can be physically or chemically coupled with targeting molecules providing for site-specific delivery and recognition in the body.
The use of polymer fragments with dual functionality in polymer networks, such as polyionic polymers and nonionic water-soluble or water-swellable polymers, permits great variation in the properties of these systems by varying the lengths and/or chemical structure of the polymer fragments. This design of polymer network carriers provides for tremendous versatility with simple chemical structures and permits optimized drug delivery and drug release for enhanced performance with a variety of drugs and drug delivery applications. Particularly, (i) the longevity of circulation in the blood can be varied, (ii) biodistribution in the body can be varied to achieve site-specific drug delivery and release, and (iii) the rate of release can be varied (seconds, days, weeks, etc.). This versatility of the polymer networks permits selection of drug compositions that are most efficient and safe (i.e., have the best “therapeutic index”) for a very broad variety of drugs.
This invention also provides for a method of identifying cross-linked polymer network and biological agent compositions that can be applied to pharmaceutics and biopharmaceutics diagnostics and imaging, immunology, veterinary, agriculture, and other areas where the properties of biological agents exhibited during interaction with a living organism or cell can be improved through formulation.
Biological agents suitable for use in accordance with the invention include agents useful for diagnostics or imaging, or that can act on a cell, organ or organism to create a change in the functioning of the cell, organ or organism. This includes, but is not limited to pharmaceutical agents, genes, vaccines, herbicides and the like.
The invention can be used in combination with high throughput screening of actual composition libraries, and can further utilize mathematical concepts, which have been found to be beneficial in combinatorial chemistry.
Definitions
As used herein, the terms below have the following meaning:
Backbone:
Used in graft copolymer nomenclature to
describe the chain onto which the graft is
formed.
Biological agent:
An agent that is useful for diagnosing or
imaging or that can act on a cell, organ or
organism, including but not limited to drugs
(pharmaceuticals) to create a change in the
functioning of the cell, organ or organism.
Biological property:
Any property of biological agent or biological
agent composition that affects the action of this
biological agent or biological agent
composition during interaction with a
biological system.
Block copolymer:
A combination of two or more chains of
constitutionally or configurationally different
features linked in a linear fashion.
Branched polymer:
A combination of two or more chains linked to
each other, in which the end of at least one
chain is bonded at some point along the

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