United States Patent:  6,063,370

Assignee:  The Board of Trustees of the University of Illinois (Urbana, IL)

Filed:  October 2, 1998

Novel macromolecular drug complexes containing a drug, like insulin, and a polymer having a plurality of acid moieties, like carboxyl moieties or phosphonic acid moieties, are disclosed. Compositions containing the macromolecular complexes are administered to individuals suffering from a disease, and the complexes release the drug, in vivo, to treat the disease, and to reduce, eliminate, or reverse complications associated with the disease.

SUMMARY OF THE INVENTION

The present invention is directed to a novel drug delivery system, wherein a drug is complexed with a polymer having a plurality of acid moieties. The macromolecular complexes treat the underlying disease, e.g., insulin to treat diabetes, and complications associated with the disease, e.g., prevent or reverse the vascular problems associated with diabetes. The present macromolecular drug complexes can be water soluble or water insoluble at neutral pH. Therefore, the macromolecular drug complex can be administered in a variety of dosage forms.

More particularly, the present invention is directed to a macromolecular drug complex containing a drug and a polymer having a plurality of acid moieties and a weight average molecular weight (M_w) of about 1,000 to about 50,000. In accordance with an important aspect of the present invention, the drug contains at least one quaternary ammonium nitrogen atom for binding to, and complexing with, the polymer. Preferred drugs are polypeptides or proteins. The polymer contains a plurality of acid moieties for complexing with the drug. The acid moiety can be a carboxyl group, sulfate group, sulfonate group, phosphonic acid group, phosphoric acid group, phenolic group, or a similar acid moiety.

Another aspect of the present invention is to provide a macromolecular drug complex wherein the polymer is a naturally-occurring polymer or a synthetic polymer.

Another aspect of the present invention is to provide a macromolecular drug complex containing a drug and a polymer in a weight ratio of drug to polymer of about 10 to about 90 to about 90 to about 10.

Yet another aspect of the present invention is to provide a water-soluble macromolecular drug complex containing a drug and a salt form of the polymer, wherein the complex can be administered to an individual in a liquid form.

Still another aspect of the present invention is to provide a water insoluble macromolecular drug complex containing a drug and the free acid form of the polymer, wherein the complex can be administered to an individual in a solid form. Such a macromolecular drug complex is especially useful for oral administration of a drug to an individual.

Another aspect of the present invention is to provide a macromolecular drug complex that can be administered to an individual to treat an acute or chronic disease and to alleviate, eliminate, or reverse complications associated with the disease.

Another aspect of the present invention is to provide macromolecular drug complexes that remain intact and do not dissociate immediately after administration, and that are capable of releasing the drug in vivo to treat a disease.

Still another aspect of the present invention is to provide a macromolecular drug complex wherein the drug is insulin, methotrexate, isoniazid, chloroquine phosphate, a polypeptide, or a protein.

Another aspect of the present invention is to provide a macromolecular drug complex containing insulin and a polymer selected from the group consisting of polyacrylic acid and polyvinylphosphonic acid.

Yet another aspect of the present invention is to provide a macromolecular insulin complex that treats diabetes and that prevents, alleviates, or reverses vascular complications that are associated with diabetes and that are left unchecked by conventional insulin formulations.

One other aspect of the present invention is to provide alternate routes of administration for the safe, easy, and effective delivery of insulin, especially to provide an oral route of administration for insulin.

Claim 1 of 31 Claims

1. A macromolecular drug complex comprising:

(a) a drug having at least one quaternary ammonium nitrogen atom; and

(b) a polymer having a plurality of acid moieties and a weight average molecular weight of about 2,000 to about 12,000, wherein the acid moieties of the polymer are selected from the group consisting of carboxyl, phosphate, phosphonate, sulfate, sulfonate, phenolic, and mixtures thereof, for noncovalent complexing with the quaternary ammonium nitrogen atom of the drug,

wherein the complex is water-insoluble at an acidic pH and has a weight ratio of the drug to the polymer in the complex is about 10:90 to about 90:10, and wherein the formation of the macromolecular drug complex is confirmed by the CF-MALLS technique.

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