U.S. Patent No. 8,669,290
`Claims
`
`1. A stable aqueous liquid
`preparation comprising:
`
`(a) a first component; and
`(b) a second component;
`wherein the first component is
`2-amino-3-(4-bromobenzoyl)
`phenylacetic acid or a
`pharmacologically acceptable
`salt thereof or a hydrate
`thereof, wherein the hydrate is
`at least one selected from a 1/2
`hydrate, 1 hydrate, and 3/2
`hydrate;
`the first component is the sole
`pharmaceutical active
`ingredient contained in the
`preparation;
`the second component is
`tyloxapol and is present in
`said liquid preparation in an
`amount sufficient to stabilize
`said first component; and
`
`wherein said stable liquid
`preparation is formulated for
`ophthalmic administration.
`
`14. A stable aqueous liquid
`preparation comprising:
`(a) a first component; and
`(b) a second component;
`wherein the first component is
`2-amino-3-(4-bromobenzoyl)
`phenylacetic acid or a
`pharmacologically acceptable
`salt thereof or a hydrate
`thereof, wherein the hydrate is
`at least one selected from a 1/2
`hydrate, 1 hydrate, and 3/2
`hydrate;
`the first component is the sole
`pharmaceutical active
`ingredient contained in the
`preparation;
`the second component is
`tyloxapol;
`wherein said stable liquid
`preparation is formulated for
`ophthalmic administration;
`provided that the liquid
`preparation does not include
`mannitol.
`
`INDEPENDENT CLAIMS
`
`8. A stable aqueous liquid
`preparation comprising:
`(a) a first component; and
`(b) a second component;
`wherein the first component is
`2-amino-3-(4-bromobenzoyl)
`phenylacetic acid or a
`pharmacologically acceptable
`salt thereof or a hydrate
`thereof, wherein the hydrate is
`at least one selected from a 1/2
`hydrate, 1 hydrate, and 3/2
`hydrate
`the first component is the sole
`pharmaceutical active
`ingredient contained in the
`preparation;
`the second component is
`tyloxapol;
`wherein said stable liquid
`preparation is formulated for
`ophthalmic administration;
`and
`wherein the stable aqueous
`liquid preparation is
`characterized in that greater
`than about 90% of the original
`amount of the first component
`remains in the preparation
`after storage at about 60° C.
`for 4 weeks.
`
`STABILITY
`
`10. The stable aqueous liquid preparation of claim 8, wherein the stable aqueous liquid
`preparation is characterized in that greater than about 92% of the original amount of the first
`component remains in the preparation after storage at about 60° C. for 4 weeks.
`
`1
`
`LUPIN EX 1023
`
`

`

`U.S. Patent No. 8,669,290
`Claims
`
`20. The stable aqueous liquid preparation of claim 14, wherein the stable aqueous liquid
`preparation is characterized in that greater than about 90% of the original amount of the first
`component remains in the preparation after storage at about 60° C. for 4 weeks.
`
`22. The stable aqueous liquid preparation of claim 20; wherein the stable aqueous liquid
`preparation is characterized in that greater than about 92% of the original amount of the first
`component remains in the preparation after storage at about 60° C. for 4 weeks.
`
`PHARMACOLOGICALLY ACCEPTABLE SALTS
`
`2. The aqueous liquid preparation according to claim 1, further comprising a quaternary
`ammonium salt.
`9. The aqueous liquid preparation according to claim 8, further comprising a quaternary
`ammonium salt.
`15. The aqueous liquid preparation according to claim 14, further comprising a quaternary
`ammonium salt.
`21. The aqueous liquid preparation according to claim 20, further comprising a quaternary
`ammonium salt.
`3. The aqueous liquid preparation according to claim 1, wherein the first component is a 2-
`amino-3-(4-bromobenzoyl) phenylacetic acid sodium salt.
`
`16. The aqueous liquid preparation according to claim 14, wherein the first component is a 2-
`amino-3-(4-bromobenzoyl)phenylacetic acid sodium salt.
`
`pH
`
`6. The aqueous liquid preparation according to claim 1, wherein the pH is from about 7.5 to
`about 8.5.
`12. The aqueous liquid preparation according to claim 11, wherein the pH is from about 7.5 to
`about 8.5.
`18. The aqueous liquid preparation according to claim 17, wherein the pH is from about 7.5 to
`about 8.5.
`24. The aqueous liquid preparation according to claim 23, wherein the pH is from about 7.5 to
`about 8.5.
`
`CONCENTRATION OF COMPONENTS
`
`4. The aqueous liquid preparation according to claim 1, wherein the concentration of tyloxapol is
`from about 0.01 w/v % to about 0.05 w/v %; and
`wherein the first component is a 2-amino-3-(4-bromobenzoyl) phenylacetic acid sodium salt,
`wherein the concentration of the 2-amino-3-(4-bromobenzoyl)phenylacetic acid sodium salt is
`from about 0.01 to about 0.2 w/v %.
`
`2
`
`

`

`U.S. Patent No. 8,669,290
`Claims
`
`5. The aqueous liquid preparation according to claim 4, wherein the concentration of the 2-
`amino-3-(4-bromobenzoyl)phenylacetic acid sodium salt is about 0.1 w/v %.
`
`7. The stable aqueous liquid preparation of claim 1, wherein the stable aqueous liquid
`preparation consists essentially of:
`(a) 2-amino-3-(4-bromobenzoyl) phenylacetic acid sodium salt,
`(b) tyloxapol,
`(c) boric acid,
`(d) sodium tetraborate,
`(e) EDTA sodium salt,
`(f) benzalkonium chloride,
`(g) polyvinylpyrrolidone, and
`(h) sodium sulfite,
`wherein said liquid preparation is formulated for ophthalmic administration, and
`wherein the concentration of the 2-amino-3-(4-bromobenzoyl)phenylacetic acid sodium salt is
`from about 0.02 w/v % to about 0.1 w/v %.
`
`11. The aqueous liquid preparation according to claim 8,
`wherein the concentration of tyloxapol is from about 0.01 w/v % to about 0.05 w/v %; and
`wherein the first component is a 2-amino-3-(4-bromobenzoyl) phenylacetic acid sodium salt,
`wherein the concentration of the 2-amino-3-(4-bromobenzoyl)phenylacetic acid sodium salt is
`from about 0.01 to about 0.2 w/v %.
`
`13. The stable aqueous liquid preparation of claim 8, wherein the stable aqueous liquid
`preparation consists essentially of:
`(a) 2-amino-3-(4-bromobenzoyl)phenylacetic acid or a pharmacologically acceptable salt thereof
`or a hydrate thereof, wherein the hydrate is at least one selected from a 1/2 hydrate, 1 hydrate,
`and 3/2 hydrate;
`(b) tyloxapol;
`(c) boric acid;
`(d) sodium tetraborate;
`(e) EDTA sodium salt;
`(f) benzalkonium chloride;
`(g) polyvinylpyrrolidone; and
`(h) sodium sulfite; and
`wherein the concentration of the 2-amino-3-(4-bromobenzoyl)phenylacetic acid sodium salt is
`from about 0.02 w/v % to about 0.1 w/v %.
`
`17. The aqueous liquid preparation according to claim 16, wherein the concentration of tyloxapol
`is from about 0.01 w/v % to about 0.05 w/v % and
`the concentration of the 2-amino-3-(4-bromobenzoyl) phenylacetic acid sodium salt is from
`about 0.05 to about 0.2 w/v %.
`
`3
`
`

`

`U.S. Patent No. 8,669,290
`Claims
`
`19. The stable aqueous liquid preparation of claim 14; wherein the stable aqueous liquid
`preparation consists essentially of:
`(a) 2-amino-3-(4-bromobenzoyl)phenylacetic acid or a pharmacologically acceptable salt thereof
`or a hydrate thereof, wherein the hydrate is at least one selected from a 1/2 hydrate, 1 hydrate,
`and 3/2 hydrate;
`(b) tyloxapol;
`(c) boric acid;
`(d) sodium tetraborate;
`(e) EDTA sodium salt;
`(f) benzalkonium chloride;
`(g) polyvinylpyrrolidone; and
`(h) sodium sulfite;
`wherein the concentration of the 2-amino-3-(4-bromobenzoyl)phenylacetic acid sodium salt is
`from about 0.02 w/v % to about 0.1 w/v %.
`
`23. The aqueous liquid preparation according to claim 20,
`wherein the concentration of tyloxapol is from about 0.01 w/v % to about 0.05 w/v %; and
`wherein the first component is a 2-amino-3-(4-bromobenzoyl)phenylacetic acid sodium salt,
`wherein the concentration of the 2-amino-3-(4-bromobenzoyl)phenylacetic acid sodium salt is
`from about 0.01 to about 0.2 w/v %.
`
`25. The stable aqueous liquid preparation of claim 20, wherein the stable aqueous liquid
`preparation consists essentially of:
`(a) 2-amino-3-(4-bromobenzoyl)phenylacetic acid or a pharmacologically acceptable salt thereof
`or a hydrate thereof, wherein the hydrate is at least one selected from a 1/2 hydrate, 1 hydrate,
`and 3/2 hydrate;
`(b) tyloxapol;
`(c) boric acid;
`(d) sodium tetraborate;
`(e) EDTA sodium salt;
`(f) benzalkonium chloride;
`(g) polyvinylpyrrolidone; and
`(h) sodium sulfite;
`wherein said liquid preparation is formulated for ophthalmic administration; and
`wherein the concentration of the 2-amino-3-(4-bromobenzoyl)phenylacetic acid sodium salt is
`from about 0.02 w/v % to about 0.1 w/v %.
`
`PRESERVATIVE EFFICACY STANDARD OF EP-CRITERIA B
`
`26. The aqueous liquid preparation of claim 1, wherein the aqueous liquid preparation further
`satisfies the preservative efficacy standard of EP-criteria B of the European Pharmacopoeia as
`follows:
`
`4
`
`

`

`U.S. Patent No. 8,669,290
`Claims
`
`viable cell counts of bacteria (S. aureus, P. aeruginosa) 24 hours and 7 days after inoculation
`decrease to not more than 1/10 and not more than 1/1000, respectively, and thereafter, the cell
`count levels off or decreases; and viable cell count of fungi (C. albicans, A. niger) 14 days after
`inoculation decreases to not more than 1/10, and thereafter, the cell count keeps the same level as
`that of 14 days after inoculation.
`
`27. The aqueous liquid preparation of claim 8, wherein the aqueous liquid preparation further
`satisfies the preservative efficacy standard of EP-criteria B of the European Pharmacopoeia as
`follows:
`viable cell counts of bacteria (S. aureus, P. aeruginosa) 24 hours and 7 days after inoculation
`decrease to not more than 1/10 and not more than 1/1000, respectively, and thereafter, the cell
`count levels off or decreases; and viable cell count of fungi (C. albicans, A. niger) 14 days after
`inoculation decreases to not more than 1/10, and thereafter, the cell count keeps the same level as
`that of 14 days after inoculation.
`
`28. The aqueous liquid preparation of claim 14, wherein the aqueous liquid preparation further
`satisfies the preservative efficacy standard of EP-criteria B of the European Pharmacopoeia as
`follows:
`viable cell counts of bacteria (S. aureus, P. aeruginosa) 24 hours and 7 days after inoculation
`decrease to not more than 1/10 and not more than 1/1000, respectively, and thereafter, the cell
`count levels off or decreases; and viable cell count of fungi (C. albicans, A. niger) 14 days after
`inoculation decreases to not more than 1/10, and thereafter, the cell count keeps the same level as
`that of 14 days after inoculation.
`
`29. The aqueous liquid preparation of claim 20, wherein the aqueous liquid preparation further
`satisfies the preservative efficacy standard of EP-criteria B of the European Pharmacopoeia as
`follows:
`viable cell counts of bacteria (S. aureus, P. aeruginosa) 24 hours and 7 days after inoculation
`decrease to not more than 1/10 and not more than 1/1000, respectively, and thereafter, the cell
`count levels off or decreases; and viable cell count of fungi (C. albicans, A. niger) 14 days after
`inoculation decreases to not more than 1/10, and thereafter, the cell count keeps the same level as
`that of 14 days after inoculation.
`
`30. The aqueous liquid preparation of claim 22, wherein the aqueous liquid preparation further
`satisfies the preservative efficacy standard of EP-criteria B of the European Pharmacopoeia as
`follows:
`viable cell counts of bacteria (S. aureus, P. aeruginosa) 24 hours and 7 days after inoculation
`decrease to not more than 1/10 and not more than 1/1000, respectively, and thereafter, the cell
`count levels off or decreases; and viable cell count of fungi (C. albicans, A. niger) 14 days after
`inoculation decreases to not more than 1/10, and thereafter, the cell count keeps the same level as
`that of 14 days after inoculation.
`
`5
`
`