Reversible gel-forming composition for sustained delivery of bio-affecting substances, and method of use

• US 5,599,534 A
• Filed: 08/09/1994
• Issued: 02/04/1997
• Est. Priority Date: 08/09/1994
• Status: Expired due to Fees

• Current Assignee: Kenneth J. Himmelstein
• Original Assignee: University of Nebraska
• Inventors: Baustian, Cara L., Himmelstein, Kenneth J.
• Primary Examiner(s): AZPURU, CARLOS A
• Application Number:
  US08/287,694
• Time in Patent Office: 910 Days
• Field of Search: 424/78.04, 424/427, 424/428, 514/912, 514/913, 514/914, 514/915
• US Class Current: 424/78.04
• 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 47/38 Cellulose; Derivatives thereof
• CPC Class Codes: A61K 9/0014 Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• CPC Class Codes: A61K 9/0048 Eye, e.g. artificial tears

Abstract

Reversibly gel-forming compositions for sustained delivery of bio-affecting substances are disclosed. The compositions exhibit significant changes in viscosity in response to changes in pH. The compositions contain relatively low concentrations of a stable combination of at least one pH-responsive gelling polymer and at least one other thermally nonresponsive polymer. The compositions are preferably formulated to include one or more therapeutic or diagnostic agents for administration as a liquid that will gel in situ or for topical application as a pre-formed gel.

Claims

1. A reversibly gelling composition for sustained delivery of a therapeutic or diagnostic agent, said composition exhibiting a reversible increase in viscosity in response to variation in pH over a pre-determined range, said composition comprising an aqueous solution including about 0.01% to 10.0% (w/w) of at least one pharmaceutically acceptable pH-responsive gelling polymer and about 0.01% to 20.0% (w/w) of at least one other pharmaceutically acceptable thermally nonresponsive polymer.

2. The composition of claim 1, which exhibits a reversible increase in viscosity in response to increasing pH.

3. The composition of claim 2, wherein said at least one pH-responsive gelling polymer comprises acidic groups.

4. The composition of claim 3, wherein said pH-responsive gelling polymer is a carboxy vinyl polymer of monomers selected from the group consisting of acrylic acid, alkylacrylic acids, cycloalkylacrylic acids, arylacrylic acids and alkylcrotonic acids.

5. The composition of claim 1, which exhibits a reversible increase in viscosity in response to decreasing pH.

6. The composition of claim 5, wherein said pH-responsive gelling polymer comprises basic groups.

7. The composition of claim 6, wherein said pH-responsive gelling polymer is selected from the group consisting of amino derivatives of polyacrylate and polyalkylacrylates.

8. The composition of claim 1, wherein said other polymer is a thermally nonresponsive hydroxyalkyl cellulose.

9. The composition of claim 8, wherein said other polymer is hydroxypropylmethylcellulose.

10. The composition of claim 2, wherein said pH-responsive gelling polymer is polyacrylic acid and said other polymer is hydroxypropylmethylcellulose.

11. The composition of claim 10, wherein said aqueous solution comprises about 0.05-2.0% (w/w) polyacrylic acid and about 0.05-5.0% (w/w) hydroxypropylmethylcellulose.

12. The composition of claim 11, wherein said aqueous solution comprises about 0.3% (w/w) polyacrylic acid and about 1.5% (w/w) hydroxypropylmethylcellulose.

13. The composition of claim 1, which further comprises a salt in an amount effective to modify the viscosity of said aqueous solution.

14. The composition of claim 13, wherein said salt is present in a salt to polymer ratio of about 0.001 to 0.5.

15. The composition of claim 1, which further comprises an effective amount of a therapeutic or diagnostic agent.

16. A pharmaceutical composition that includes:

a) a pH-responsive reversibly gelling delivery vehicle comprising an aqueous solution including about 0.01% to 10.0% (w/w) of at least one pharmaceutically acceptable pH-responsive gelling polymer and about 0.01% to 20.0% (w/w) of at least one other pharmaceutically acceptable thermally nonresponsive polymer; and

b) an effective amount of a therapeutic or diagnostic agent.

17. A pharmaceutical composition as claimed in claim 16, wherein said therapeutic or diagnostic agent is selected from the group consisting of analgesics, anesthetics, antiarthritics, antiinflammatory substances, antiasthmatics, antibacterials, anticoagulants, anticonvulsives, antidepressants, antidiabetics, antifungals, antihistaminics and decongestants, anti-hypertestive compounds, antiparasitics, antipsychotics, antivirals, carbonic anhydrase inhibitors, antineoplastics, immunosuppressive agents, miotics, anticholinergics, muscle relaxants, mydriatics, nucleic acids and oligonucleotides, ophthalmic agents, peptides and proteins, contrast agents, dyes, fluorescent compounds, radiotracers and lubricating agents.

18. A pharmaceutical composition as claimed in claim 17, wherein said therapeutic or diagnostic agent is an ophthalmic agent.

19. A pharmaceutical composition as claimed in claim 18, wherein said ophthalmic agent is selected from the group consisting of anti-glaucoma substances, dyes, fluorescent compounds, epinephrine, thereof, hyperosmotic agents, lubricating agents, substances for determining pupillary response, antibacterials, antifungals, antivirals, anti-inflammatory agents, analgesics, nucleic acids, oligonucleotides, peptides and proteins.

20. A pharmaceutical composition as claimed in claim 17, which is formulated as an eye drop.

21. A method for sustained delivery of a therapeutic or diagnostic agent to a patient, said method comprising administering to said patient a pharmaceutical composition that includes an effective amount of said therapeutic or diagnostic agent, disposed within a pH-responsive reversibly gelling delivery vehicle comprising an aqueous solution including about 0.01% to 10.0% (w/w) of at least one pharmaceutically acceptable pH-responsive gelling polymer and about 0.01% to 20.0% (w/w) of at least one other pharmaceutically acceptable thermally nonresponsive polymer.

22. A method according to claim 21, wherein said pharmaceutical composition is administered by a route selected from the group consisting of ophthalmic, nasal, oral, otic, topical, rectal, vaginal and urinary tract.