Reversible gelation compositions and methods of use

• US 5,252,318 A
• Filed: 06/15/1990
• Issued: 10/12/1993
• Est. Priority Date: 06/15/1990
• Status: Expired due to Term

• Current Assignee: Allergan, Inc. (Canada) (Abbvie Incorporated)
• Original Assignee: Allergan, Inc. (Canada) (Abbvie Incorporated)
• Inventors: Himmelstein, Kenneth J., Joshi, Abhay, Ding, Shulin
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): AZPURU, CARLOS A
• Application Number:
  US07/539,061
• Time in Patent Office: 1,215 Days
• Field of Search: 424/2, 424/422, 424/78.04, 514/912, 514/913, 514/914, 514/915
• US Class Current: 424/78.04
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/18 Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
• 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 9/0019 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
• CPC Class Codes: A61K 9/0048 Eye, e.g. artificial tears
• CPC Class Codes: A61K 9/06 Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels composition of ointments, creams or gels A61K47/00
• CPC Class Codes: A61K 9/1647 Polyesters, e.g. poly(lactide-co-glycolide)

Abstract

Reversibly gelling aqueous compositions are disclosed which undergo significant changes in viscosity in response to substantially simultaneous changes in both temperature and pH. The compositions are formed of relatively low concentrations of a stable combination of at least one pH-sensitive reversibly gelling polymer and at least one temperature-sensitive reversibly gelling polymer. The compositions can be formulated to exhibit a sol-gel transition over a wide range of conditions and viscosities and may be modified to incorporate a pharmaceutical compound for utilization as droppable or injectable drug delivery systems which will gel following administration to a physiological system for the sustained delivery of such pharmaceutical compounds.

Claims

1. An aqueous pharmaceutical composition of matter exhibiting the property of reversible gelation in response to substantially simultaneous variations in both temperature and pH over predetermined ranges, said composition comprising:

an aqueous solution including approximately 0.1% to 30% by weight thermally-sensitive gelling polymer and approximately 0.01% to 10% by weight pH sensitive gelling polymer whereby said aqueous composition exhibits a reversible viscosity change ranging between approximately 200 to 1,000,000 cP in response to substantially simultaneous variations in both temperature and pH over respective ranges between approximately 0°

C. to 60°

C. and pH 2.5 to pH 7.5.

21. The composition of claim 1 wherein said at least one thermally-sensitive gelling polymer is selected from the group consisting of alkylcellulose, hydroxyalkyl cellulose, block copolymers of polyoxyethylene and polyoxypropylene, and tetrafunctional block polymers of polyoxyethylene and polyoxypropylene and ethylenediamine.

22. The composition of claim 1 wherein said at least one thermally-sensitive gelling polymer is methylcellulose.

23. The composition of claim 1 wherein said at least one pH-sensitive gelling polymer is an acidic polymer.

24. The composition of claim 23 wherein said acidic polymer is a carboxyl containing polymer.

26. The composition of claim 1 wherein said at least one thermally-sensitive gelling polymer is methylcellulose and said at least one pH-sensitive gelling polymer is polyacrylate.

27. The composition of claim 26 therein said aqueous composition comprises approximately 0.1% to 5% by weight methylcellulose and approximately 0.01% to 10% polyacrylate.

28. The composition of claim 26 wherein said aqueous composition comprises approximately 1% by weight methylcellulose and approximately 0.3% by weight polyacrylate.

29. The composition of claim 1 further comprising a viscosity modifying amount of salt.

30. The composition of claim 29 wherein said salt is selected from the group consisting of univalent and divalent dissociable ionic compounds.

31. The composition of claim 29 wherein said salt is present in a salt-to-polymer ratio of approximately 0.001 to 0.5.

32. The composition of claim 1 further comprising an effective amount of a pharmaceutical medicament or diagnostic compound.

33. The composition of claim 32 wherein said pharmaceutical medicament or diagnostic compound is incorporated in a microparticulate drug delivery system.

34. The composition of claim 32 wherein said pharmaceutical medicament or diagnostic compound is selected from the group consisting of anti-bacterial substances, anti-histamines and decongestants, anti-inflammatorics, miotics and anti-cholinergics, mydriatics, anti-glaucoma compounds, anti-parasitics, anti-viral compounds, carbonic anhydrase inhibitors, diagnostic agents, ophthalmic agents, chelating agents, immunosuppressive agents, anti-metabolites, anesthetics, anti-fungal compounds, amoebacidal compounds, trichomonacidal agents, analgesics, anti-arthritics, anti-asthmatics, anti-coagulants, anti-convulsants, anti-depressants, anti-diabetics, anti-neoplastics, anti-psychotics, anti-hypertensive agents, muscle relaxants, proteins, peptides and lubricating agents.

35. The pharmaceutical composition of claim 1 further comprising a viscosity modifying effective concentration of salt in a salt-to-polymer ratio of 0.045 to 0.075.

36. A drug delivery system comprising the aqueous composition of claim 1 and an effective concentration of an ophthalmic drug.

37. The drug delivery system of claim 36 wherein said drug is incorporated in a microparticulate drug delivery system.

38. The drug delivery system of claim 36 wherein said ophthalmic drug is selected from the group consisting of anti-bacterial substances, anti-histamines and decongestants, anti-inflammatorics, miotics and anti-cholinergics, mydriatics, anti-glaucoma compounds, anti-parasitics, anti-viral compounds, carbonic anhydrase inhibitors, diagnostic agents, ophthalmic agents, chelating agents, immunosuppressive agents, anti-metabolites, anesthetics, anti-fungal compounds, amoebacidal compounds, trichomonacidal agents, analgesics, anti-arthritics, anti-asthmatics, anti-coagulants, anti-convulsants, anti-depressants, anti-diabetics, anti-neoplastics, anti-psychotics, anti-hypertensive agents, muscle relaxants, proteins, peptides, and lubricating agents.

39. An aqueous injectable drug delivery composition for injection into a body to treat a condition requiring pharmacological treatment or diagnosis comprising the composition of claim 1 and an effective concentration of a drug selected from the group consisting of anti-bacterial substances, anti-histamines and decongestants, anti-inflammatorics, miotics and anti-cholinergics, mydriatics, anti-glaucoma compounds, anti-parasitics, anti-viral compounds, carbonic anhydrase inhibitors, diagnostic agents, ophthalmic agents, chelating agents, immunosuppressive agents, anti-metabolites, anesthetics, anti-fungal compounds, amoebacidal compounds, trichomonacidal agents, analgesics, anti-arthritics, anti-asthmatics, anti-coagulatns, anti-convulsants, anti-depressants, anti-diabetics, anti-neoplastics, anti-psychotics, anti-hypertensive agents, muscle relaxants, proteins, peptides and lubricating agents.

2. An aqueous pharmaceutical composition of matter exhibiting the property of reversible gelation in response to substantially simultaneous variations in both temperature and pH over predetermined ranges, said composition comprising:

an aqueous solution including approximately 0.1% to 30% by weight thermally-sensitive gelling polymer and approximately 0.01% to 10% by weight pH sensitive gelling polymer whereby said aqueous composition exhibits a reversible viscosity change ranging between approximately 200 to 1,000,000 cP in response to substantially simultaneous variations in both temperature and pH over respective ranges between approximately 25°

C. to 37°

C. and pH 4.5 to pH 7.4.

3. The composition of claim 2 wherein said at least one thermally-sensitive gelling polymer is selected from the group consisting of alkylcellulose, hydroxyalkyl cellulose, block copolymers of polyoxyethylene and polyoxypropylene, and tetrafunctional block polymers of polyoxyethylene and polyoxypropylene and ethylenediamine.

4. The composition of claim 2 wherein said at least one thermally-sensitive gelling polymer is methylcellulose.

5. The composition of claim 2 wherein said at least one pH-sensitive gelling polymer is an acidic polymer.

6. The composition of claim 5 wherein said acidic polymer is a carboxyl containing polymer.

7. The composition of claim 6 wherein said carboxyl containing polymer is polyacrylate.

8. The composition of claim 2 wherein said at least one thermally-sensitive gelling polymer is methylcellulose and said at least one pH-sensitive gelling polymer is polyacrylate.

9. The composition of claim 8 wherein said aqueous composition comprises approximately 0.1% to 5% by weight methylcellulose and approximately 0.01% to 10% polyacrylate.

10. The composition of claim 8 wherein said aqueous composition comprises approximately 1% by weight methylcellulose and approximately 0.3% by weight polyacrylate.

11. The composition of claim 2 further comprising a viscosity modifying amount of salt.

12. The composition of claim 11 wherein said salt is selected from the group consisting of univalent and divalent dissociable ionic compounds.

13. The composition of claim 11 wherein said salt is present in a slat-to-polymer ratio of approximately 0.001 to 0.5.

14. The composition of claim 2 further comprising an effective amount of a pharmaceutical medicament or diagnostic compound.

15. The composition of claim 14 wherein said pharmaceutical medicament or diagnostic compound is incorporated in a microparticulate drug delivery system.

16. The composition of claim 14 wherein said pharmaceutical medicament or diagnostic compound is selected from the group consisting of anti-bacterial substances, anti-histamines and decongestants, anti-inflammatorics, miotics and anti-cholinergics, mydriatics, anti-glaucoma compounds, anti-parasitics, anti-viral compounds, carbonic anhydrase inhibitors, diagnostic agents, ophthalmic agents, chelating agents, immunosuppressive agents, anti-metabolites, anesthetics, anti-fungal compounds, amoebacidal compounds, trichomonacidal agents, analgesics, anti-arthritics, anti-asthmatics, anti-coagulants, anti-convulsants, anti-depressants, anti-diabetics, anti-neoplastics, anti-psychotics, anti-hypertensive agents, muscle relaxants, proteins, peptides and lubricating agents.

17. The pharmaceutical composition of claim 2 further comprising a viscosity modifying effective concentration of salt in a salt-to-polymer ratio of 0.045 to 0.075.

18. A drug delivery system comprising the aqueous composition of claim 2 and an effective concentration of an ophthalmic drug.

19. The drug delivery system of claim 18 wherein said ophthalmic drug is incorporated in a microparticulate drug delivery system.

20. The drug delivery system of claim 18 wherein said drug is selected from the group consisting of anti-bacterial substances, anti-histamines and decongestants, anti-inflammatories, miotics and anti-cholinergis, mydriatics, anti-glaucoma compounds, anti-parasitics, anti-viral compounds, carbonic anhydrase inhibitors, diagnostic agents, ophthalmic agents, chelating agents, immunosuppressive agents, anti-metabolites anesthetics, anti-fungal compounds, amoebacidal compounds, trichomonacidal agents, analgesics, anti-arthritics, anti-asthmatics, anti-coagulatns, anti-convulsants, anti-depressants, anti-diabetics, anti-neoplastics, anti-psychotics, anti-hypertensive agents, muscle relaxants, proteins, peptides, and lubricating agents.

25. The composition of claim 6 wherein said carboxyl containing polymer is polyacrylate.