Polymers having benzeneboronic acid groups and insulin complexes of same of a sugar response type

• US 5,478,575 A
• Filed: 03/26/1993
• Issued: 12/26/1995
• Est. Priority Date: 10/19/1989
• Status: Expired due to Fees

• Current Assignee: NOF Corporation
• Original Assignee: NOF Corporation
• Inventors: Shiino, Daijiro, Waki, Kazunori, Kitano, Shigeru, Koyama, Yoshiyuki, Kataoka, Kazunori, Okano, Teruo, Yokoyama, Masayuki, Sakurai, Yasuhisa, Murata, Yoshishige, Miyazaki, Tsuyoshi
• Primary Examiner(s): Kulkosky, Peter F.
• Application Number:
  US08/037,383
• Time in Patent Office: 1,005 Days
• Field of Search: 424/488, 424/487, 514/866
• US Class Current: 424/487
• CPC Class Codes: A61K 47/32 Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers , poly(meth)acrylates, or polyvinyl pyrrolidone
• CPC Class Codes: A61K 47/36 Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• CPC Class Codes: A61K 47/58 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
• CPC Class Codes: A61K 47/61 the organic macromolecular compound being a polysaccharide or a derivative thereof
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00

Abstract

The present invention provides a polymer complex of a sugar response type having boronic acid groups in the polymer. Medicines may be contained or linked, preferably, the medicines have hydroxy groups. The polymer having boronic acid groups and the medicine having hydroxy groups may be linked by boronic acid ester bonds. The complex may also comprises polymers having boronic acid groups and polymers having hydroxy groups, and these polymers may be cross-linked.

Claims

1. A method for treating diabetes comprising,

administering a polymer insulin complex to a diabetic patient wherein insulin is released from said complex in response to a sugar concentration in blood of the diabetic patient,

wherein the polymer insulin complex contains at least one polymer having benzene boronic acid groups and insulin or an insulin derivative having hydroxy groups;

said polymer having a molecular weight between 5,000 and 300,000, the content of benzene boronic acid monomers forming said polymer having boronic acid groups being 0.1 to 30 mole % and the at least one polymer being a homopolymer or copolymer of 3-acryloylaminobenzeneboronic acid, 3-methacryloylaminobenzenebornonic acid or 4-vinybenzeneboronic acid, and

wherein said polymer insulin complex releases 0 to 500 micrograms per milliliter of said insulin or said insulin derivative having hydroxy group in response to 0 to 500 milligrams per deciliter of sugar in the blood of said diabetic patient such that an increase in blood sugar causes an increase in said insulin or said insulin derivative being released from said polymer insulin complex.

2. A polymer insulin complex of a sugar response type for delivery of insulin or its derivative to blood in the treatment of diabetes comprising at least one polymer having benzene boronic acid groups and insulin or an insulin derivative having hydroxy groups;

the molecular weight being 5000-300,000, the content of benzene boronic acid monomers forming the at least one polymer having benzene boronic acid groups being 0.1 to 30 mole % and said at least one polymer being a homopolymer or a copolymer of 3-acryloylaminobenzeneboronic acid, 3-methacryloylaminobenzeneboronic acid or 4-vinylbenzeneboronic acid, and a releasable amount of insulin or its derivative being 0-500 μ

g/ml in response to sugar concentration of 0-500 mg/dl.

3. The polymer insulin complex as claimed in claim 2, wherein the polymer having benzene boronic acid groups is a copolymer of 3-acryloylaminobenzeneboronic acid and N-vinylpyrrolidone, and said complex further comprises a polyvinyl alcohol.

4. The polymer insulin complex as claimed in claim 2, wherein the insulin is glucosylated insulin or tris (hydroxymethyl) aminomethane insulin.

5. The polymer insulin complex as claimed in claim 2, wherein the polymer is a copolymer of 3-methacryloylaminobenzeneboronic acid/2-hydroxyethyl methacrylate/ethyleneglycol dimethacrylate, 3-methacryloylaminobenzeneboronic acid/2-hydroxyethyl methacrylate/diethyl-aminoethyl methacrylate, 3-methacryloylaminobenzeneboronic acid/N, N-dimethylacrylamide/ethyleneglycol dimethacrylate, 3-methacryloylaminobenzeneboronic acid/N, N-dimethylacrylamide/glycerol monomethacrylate/ethyleneglycol dimethacrylate, 3-acryloylaminobenzeneboronic acid/N, N-dimethylacrylamide/glycerol monomethacrylate/ethyleneglycol dimethacrylate, 3-methacryloylaminobenzeneboronic acid/N, N-dimethylacrylamide/N, N'"'"'-methylenebisacrylamide, 3-methacryloylaminobenzeneboronic acid/N, N-dimethylacrylamide/ethyleneglycol dimethacrylate, or 3-methacryloylaminobenzeneboronic acid/acrylamide/glycerol monomethacrylate/N, N'"'"'-methylenebisacrylamide and insulin is glucosylated insulin or tris (hydroxy-methyl) aminomethane insulin.