Claims for Patent: 6,025,339

Summary for Patent: 6,025,339

Title:	Composition, kit and method for treatment of disorders associated with bronchoconstriction and lung inflammation
Abstract:	A method of reducing bronchoconstriction in a subject in need of such treatment is disclosed. The method comprises administering to the subject an antisense oligonucleotide molecule directed against the A.sub.1 or A.sub.3 adenosine receptor in an amount effective to reduce bronchoconstriction. The method is useful for treating patients afflicted with asthma. Pharmaceutical formulations are also disclosed.
Inventor(s):	Nyce; Jonathan W. (Greenville, NC)
Assignee:	East Carolina University (Greenville, NC)
Application Number:	08/757,024
Patent Claims:	1. A pharmaceutical composition, comprising an oligonucleotide (oligo) in aerosol form, which is effective for alleviating bronchoconstriction or lung inflammation when administered to a mammal, wherein the oligo is antisense to the initiation codon, the coding region or the 5' and 3' intronexon junctions of a gene encoding the adenoshie A.sub.1 receptor or antisense to an adenosine A.sub.1 receptor mRNA; and a pharmaceutical carrier. 2. The pharmaceutical composition of claim 1, wherein the oligo comprise at least one mononucleotide linking residue selected from the group consisting of methylphosphonate, phosphotriester, phosphorothioate, phosphorodithioate, boranophosphate, formacetal, thioformacetal, thioether, carbonate, carbamate, sulfate, sulfonate, sulfamate, sulfonamide, sulfone, sulfite, sulfoxide, sulfide, hydroxylamine, methylene(methyimino), methyleneoxy (methylimino) and phosphoramidate residues. 3. The pharmaceutical composition of claim 2, wherein the all mononucleotide linking residues of the oligo are selected from the group consisting of methylphosphonate, phosphotriester, phosphorothioate, phosphorodithioate, boranophosphate, formacetal, thioformacetal, thioether, carbonate, carbamate, sulfate, sulfonate, sulfamate, sulfonamide, sulfone, sulfite, sulfoxide, sulfide, hydroxylamine, methylene(methyimino), methyleneoxy (methylimino) and phosphoramidate residues. 4. The pharmaceutical composition of claim 1, wherein the antisense to the initiation codon of a gene encoding an adenosine A.sub.1 receptor or antisense to an adenosinie A.sub.1 receptor mRNA. 5. The pharmaceutical composition of claim 1, wherein the oligo is a DNA. 6. The pharmaceutical composition of claim 1, wherein the oligo is an RNA. 7. The pharmaceutical composition of claim 1, wherein the oligo is antisense to the intron-exon junction of an adenosine A.sub.1 receptor gene or antisense to an adenosine A.sub.1 receptor mRNA. 8. The pharmaceutical composition of claim 1, wherein the oligo comprises about 10 to up to about 60 mononucleotides. 9. The pharmaceutical composition of claim 7, wherein the oligo comprises about 18 up to about 21 mononucleotides. 10. The pharmaceutical composition of claim 1, wherein the oligo is antisense to the coding region of a gene encoding the adenosine A.sub.1 receptor or antisense to an adenosine A.sub.1 receptor mRNA. 11. The pharmaceutical composition of claim 1, wherein the oligo is SEQ. ID NOS: 1 or 7 to 952; or SEQ. ID NOS: 1 or 7 to 952, wherein at least one mononucleotide linking residue is selected from the group consisting of methylphosphonate, phosphotriester, phosphorothioate, phosphorodithioate, boranophosphate, formacetal, thioformacetal, thioether, carbonate, carbamate, sulfate, sulfonate, sulfamate, sulfonamide, sulfone, sulfite, sulfoxide, sulfide, hydroxylamine, methylene(methyimino), methyleneoxy (methylimino) and phosphoramidate residues. 12. The pharmaceutical composition of claim 11, wherein the oligo is selected from SEQ. ID NOS: 7 to 952; or SEQ. ID NOS: 7 to 952; wherein at least one mononucleotide linking residue is selected from the group consisting of methylphosphonate, phosphotriester, phosphorothioate, phosphorodithioate, boranophosphate, formacetal, thioformacetal, thioether, carbonate, carbamate, sulfate, sulfonate, sulfamate, sulfonamide, sulfone, sulfite, sulfoxide, sulfide, hydroxylamine, methylene(methyimino), methyleneoxy (methylimino) and phosphoramidate residues. 13. The pharmaceutical composition of claim 11, wherein the oligo has at least one phosphorothioate mononucleotide linking residue. 14. The pharmaceutical composition of claim 13, wherein all mononucleotide linking residues are phosphorothioate residues. 15. The pharmaceutical composition of claim 11, wherein the oligo is selected from SEQ. ID NOS: 1 or 7 to 952. 16. The pharmaceutical composition of claim 15, wherein the oligo is SEQ. ID NO: 7. 17. The pharmaceutical composition of claim 16, wherein the oligo is SEQ. ID NO: 7, wherein all momonucleotide linking residues are phosphorothioate residues. 18. The pharmaecutical composition of claim 11, wherein the oligo ia selected from SEQ. ID NOS: 1 or 7 to 952, wherein at least one mononucleotide linking residue is selected from the group consisting of methylphosphonate, phosphotriester, phosphorothioate, phosphorodithioate, boranophosphate, formacetal, thioformacetal, thioether, carbonate, carbamate, sulfate, sulfonate, sulfamate, sulfonamide, sulfone, sulfite, sulfoxide, sulfide, hydroxylamine, methylene(methyimino), methyleneoxy (methylimino) and phosphoramidate residues. 19. The pharmaceutical composition of claim 15, wherein the oligo is selected from SEQ. ID NOS: 8 to 952. 20. The pharmaceutical composition of claim 19, wherein the oligo is selected from SEQ. ID NOS; 8 to 952 wherein at least one mononucleotide linking residue is a phosphorothioate residue. 21. The pharmaceutical composition of claim 20, wherein all mononucleotide linking residues are phosphorothioate residues. 22. The pharmaceutical composition of claim 1, wherein the carrier is selected from the group consisting of solid and liquid carriers. 23. The pharmaceutical composition of claim 1, further comprising an agent selected from the group consisting of antioxidants, flavoring agents, volatile oils, buffering agents, dispersants, surfactants, propellants and preservatives. 24. The pharmaceutical composition of claim 1, wherein the oligo is present in an amount of about 0.1 to about 100% w/w of the composition. 25. The pharmaceutical composition of claim 24, wherein the oligo is present in an amount of about 0.1 up to about 40% w/w of the composition. 26. The pharmaceutical composition of claim 25, wherein the nucleic acid is present in an amount of about 0.1 up to about 20% w/w of the composition. 27. The pharmaceutical composition of claim 1, wherein the carrier comprises a hydrophobic carrier. 28. The pharmceutical composition of claim 27, wherein the carrier comprises lipid particles or vesicles. 29. The pharmaceutical composition of claim 28, wherein the vesicles comprise liposomes and the particles comprise microcrystals. 30. The pharmaceutical composition of claim 28, wherein the vesicles comprise liposomes which comprise the antisense oligo. 31. The pharmaceutical composition of claim 28, wherein the particles comprise a lipid selected from the group consisting of N-(1-(2,3-dioleoxyloxi) propyl)-N,N,N-trimethyl-ammoniommethylsulfate. 32. The pharmaceutical composition of claim 27, comprising liquid or solid respirable particles. 33. The pharmaceutical composition of claim 27, which is an aerosol composition. 34. The pharmaceutical composition of claim 1, comprised in a capsule or cartridge. 35. The pharmaceutical composition of claim 27, comprising solid particles of the oligo. 36. The pharmaceutical composition of claim 27, comprising a suspension or solution of the oligo. 37. The pharmaceutical composition of claim 36, wherein the oligo is suspended or dissolved in a solvent or mixture of solvents. 38. The pharmaceutical composition of claim 37, wherein the solvent is selected from the group consisting of chlorofluorocarbons or chlorofluorocarbons with co-solvents, and the pharmaceutical composition further comprises an agent selected from the group consisting of surfactants, antioxidants and flavoring agents. 39. The pharmaceutical composition of claim 35, which is comprised within a capsule or cartridge. 40. The pharmaceutical composition of claim 23, comprising a surfactant. 41. A method of treating an adenosine A.sub.1 receptor mediated respiratory disease or condition associated with bronchoconstriction or lung inflammation, comprising administering directly to the respiration of a mammalian subject in need of such treatment an aerosol of the pharmaceutical composition of claim 1 comprising an amount of the oligo effective for alleviating bronchoconstriction and/or lung inflammation. 42. The method of claim 41, wherein the pharmaceutical composition comprises respirable particles comprising the oligo. 43. The method of claim 41, wherein the disease or condition comprises lung inflammation. 44. The method of claim 41, wherein the disease or condition comprises a respiratory disease or condition associated with bronoconstriction or lung inflammation. 45. The method of claim 41, wherein the disease or condition comprises asthma. 46. The method of claim 41, wherein the mammalian subject is non-human. 47. The method of claim 41, wherein the mammalian subject is a human. 48. The method of claim 41, wherein the oligo is administered in an amount of about 0.01 to about 150 mg/kg body weight. 49. The method of claim 48, wherein the oligo is administered in an amount of about 1 to about 100 mg/kg body weight. 50. The method of claim 49, wherein the oligo is administered in an amount of about 10 up to about 50 mg/kg body weight. 51. The method of claim 41, being a prophylactic method. 52. The method of claim 41, being a therapeutic method. 53. The method of claim 41, wherein the pharmaceutical composition further comprises an agent selected from the group consisting of antioxidants, flavoring agents, volatile oils, buffering agents, dispersants, surfactants, propellants and preservatives. 54. The method of claim 53, wherein the pharmaceutical composition comprises a surfactant. 55. The method of claim 41, wherein the oligo is antisense to the coding region or the initiation codon of a gene encoding the adenosine A.sub.1 receptor or antisense to an adenosine A.sub.1 receptor mRNA, wherein at least one mononucleotide linking residue is selected from the group consisting of methylphosphonate, phosphotriester, phosphorothioate, phosphorodithioate, boranophosphate, formacetal, thioformacetal, thioether, carbonate, carbamate, sulfate, sulfonate, sulfamate, sulfonamide, sulfone, sulfite, sulfoxide, sulfide, hydroxylamine, methylene(methyimino), methyleneoxy (methylimino) and phosphoramidate residues. 56. The method of claim 55, wherein all mononucleotide linking residues of the oligo are selected from the group consisting of methylphosphonate, phosphotriester, phosphorothioate, phosphorodithioate, boranophosphate, formacetal, thioformacetal, thioether, carbonate, carbamate, sulfate, sulfonate, sulfamate, sulfonamide, sulfone, sulfite, sulfoxide, sulfide, hydroxylamine, methylene(methyimino), methyleneoxy (methylimino) and phosphoramidate residues. 57. The method of claim 41, wheren the oligo is SEQ. ID NOS: 1 or 7 to 952; or SEQ. ID NOS: 1 or 7 to 952, wherein at least one mononucleotide linking residue is selected from the group consisting of methylphosphonate, phosphotriester, phosphorothioate, phosphorodithioate, boranophosphate, formacetal, thioformacetal, thioether, carbonate, carbamate, sulfate, sulfonate, sulfamate, sulfonamide, sulfone, sulfite, sulfoxide, sulfide, hydroxylamine, methylene(methyimino), methyleneoxy (methylimino) and phosphoramidate residues. 58. The method of claim 57, wherein the oligo is selected from SEQ. ID NO: 7 to 952; or SEQ. ID NO: 7 to 952, wherein at least one mononucleotide linking residue is selected from the group consisting of methyphosphonate, phosphotriester, phosphorothioate, phosphorodithioate, boranophosphate, formacetal, thioformacetal, thioether, carbonate, carbamate, sulfate, sulfonate, sulfamate, sulfonamide, sulfone, sulfite, sulfoxide, sulfide, hydroxylamine, methylene(metthyimino), methyleneoxy (methylimino) and phosphoramidate residues. 59. The method of claim 58, wherein the oligo is SEQ. ID NOS: 1 or 7 to 952, wherein at least one mononucleotide linking residue is a phosphorothioate residue. 60. The method of claim 57, wherein all mononucleotide linking residues are phosphorothioate residues. 61. The method of claim 59, wherein the oligo is selected from SEQ. ID NOS: 7 to 952, wherein at least one mononucleotide linking residue is selected from the group consisting of methylphosphonate, phosphotriester, phosphorothioate, phosphorodithioate, boranophosphate, formacetal, thioformacetal, thioether, carbonate, carbamate, sulfate, sulfonate, sulfamate, sulfonamide, sulfone, sulfite, sulfoxide, sulfide, hydroxylamine, methylene (methyimino), methyleneoxy (methylimino) and phosphoramidate residues. 62. The method of claim 61, wherein the oligo is selected from SEQ. ID NOS: 8 to 952, wherein at least one mononucleotide linking residue is selected from the group consisting of methylphosphonate, phosphotriester, phosphorothioate, phosphorodithioate, boranophosphate, formacetal, thioformacetal, thioether, carbonate, carbamate, sulfate, sulfonate, sulfamate, sulfonamide, sulfone, sulfite, sulfoxide, sulfide, hydroxylamine, methylene (methyimino), methyleneoxy (methylimino) and phosphoramidate residues. 63. An in vivo method of delivering an oligonucleotide (oligo) to a target adenosine A.sub.1 receptor polynucleotide, comprising administering into a malarian subject's respiration an aerosol of the composition of claim 1, comprising an amount of the adenosine A.sub.1 receptor oligo effective to reach the target A.sub.1 adenosine receptor polynucleotide. 64. The method of claim 63, wherein the aerosol comprises respirable oligo particles. 65. The method of claim 63, wherein the oligo is selected from the group consisting of oligos which are antisense to an intron-exon junction of an adenosine A.sub.1 receptor gene or antisense to an adenosine A.sub.1 mRNA; and antisense to an intron-exon junction of an adenosine A.sub.1 receptor gene or antisense to an adenosine A.sub.1 receptor mRNA, wherein the oligo comprises at least one mononucleotide linking residue selected from the group consisting of methylphosphonate, phosphotriester, phosphorothioate, phosphorodithioate, boranophosphate, formacetal, thioformacetal, thioether, carbonate, carbamate, sulfate, sulfonate, sulfamate, sulfonanide, sulfone, sulfite, sulfoxide, sulfide, hydroxylamine, methylene(methyimino), methylencoxy (methylimino) and phosphoramidate residues. 66. The method of claim 63, wherein the oligo is selected from oligos which are antisense to the coding region of a gene encoding an A1 adenosine receptor, or antisense to an A1 adenosine receptor mRNA; or oligos which are antisense to the coding region of a gene encoding an A1 adenosine receptor, or antisense to an A1 adenosine receptor mRNA, wherein at least one mononucleotide linking residue is selected from the group consisting of methylphosphonate, phosphotriester, phosphorothioate, phosphorodithioate, boranophosphate, formacetal, thioformacetal, thioether, carbonate, carbamate, sulfate, sulfonate, sulfamate, sulfonamide, sulfone, sulfite, sulfoxide, sulfide, hydroxylamine, methylene (methyimino), methyleneoxy (methylimino) and phosphoramidate residues. 67. The method of claim 63, wherein the oligo is delivered to alleviate a disease or condition associated with bronchoconstriction or lung inflammation. 68. The method of claim 67, wherein the disease or condition comprises asthma. 69. The method of claim 63, wherein the mammalian subject is a human. 70. The method of claim 63, wherein the mammalian subject is an non-human mammal. 71. The method of claim 63, wherein the oligo is administered in an amount of about 0.01 to about 150 mg/kg body weight. 72. The method of claim 71, wherein the oligo is administered in an amount of about 1 to about 100 mg/kg body weight. 73. The method of claim 72, wherein the oligo is administered in an amount of about 1 up to 50 mg/kg body weight. 74. The method of claim 67, being a prophylactic method. 75. The method of claim 67, being a therapeutic method. 76. The method of claim 63, wherein the composition further comprises an agent selected from the group consisting of antioxidants, flavoring agents, volatile oils, buffering agents, dispersants, surfactants, propellants and preservatives. 77. The method of claim 76, wherein the composition comprises a surfactant.

Details for Patent 6,025,339

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Merck Sharp & Dohme Corp.	INTRON A	interferon alfa-2b	For Injection	103132	06/04/1986		2039-02-26
Merck Sharp & Dohme Corp.	INTRON A	interferon alfa-2b	For Injection	103132			2039-02-26
Merck Sharp & Dohme Corp.	INTRON A	interferon alfa-2b	Injection	103132			2039-02-26