Pharmaceutical package for ophthalmic formulations

Abstract

A liquid formulation of an ophthalmic drug in a pharmaceutical package, for example a syringe, cartridge, or vial, made in part or in whole of a thermoplastic polymer, coated on the interior with a tie coating or layer, a barrier coating or layer, a pH protective coating or layer, and optionally a lubricity coating or layer.

What is claimed is: 
     
         1 . An ophthalmic drug in a pre-filled pharmaceutical package comprising:
 a vessel, for example a syringe barrel, cartridge, or vial, comprising a thermoplastic wall having an interior surface enclosing at least a portion of a lumen, an exterior surface, and a coating set on at least one of the interior surface and the exterior surface of the wall, the coating set comprising:
 a tie coating or layer on the interior surface or the exterior surface comprising SiO x C y H z  in which x is from about 0.5 to about 2.4 as measured by X-ray photoelectron spectroscopy (XPS), y is from about 0.6 to about 3 as measured by XPS, and z is from about 2 to about 9 as measured by at least one of Rutherford backscattering spectrometry (RBS) or hydrogen forward scattering (HFS), the tie coating or layer having a facing surface facing toward the wall, the tie coating or layer also having an opposed surface facing away from the wall; 
 a barrier coating or layer of SiO x , in which x is from about 1.5 to about 2.9 as measured by XPS, the barrier coating or layer having a facing surface facing toward the opposed surface of the tie coating or layer and an opposed surface facing away from the tie coating or layer; 
 optionally, a pH protective coating or layer of SiO x C y H z , in which x is from about 0.5 to about 2.4 as measured by XPS, y is from about 0.6 to about 3 as measured by XPS, and z is from about 2 to about 9 as measured by at least one of RBS or HFS, the pH protective coating or layer, if present, having a facing surface facing toward the opposed surface of the barrier layer and an opposed surface facing away from the barrier layer; 
   in the lumen, a liquid formulation of an ophthalmic drug suitable for intravitreal injection; and   a closure, for example a plunger or stopper, seated in the lumen having a front face facing the liquid formulation.   
     
     
         2 . The ophthalmic drug in a pre-filled pharmaceutical package according to  claim 1 , further comprising a lubricity coating or layer positioned between the pH protective coating or layer and the lumen. 
     
     
         3 . The ophthalmic drug in a pre-filled pharmaceutical package according to  claim 2 , wherein the lubricity coating or layer has the atomic proportions SiO x C y H z , in which x is from about 0.5 to about 2.4 as measured by XPS, y is from about 0.6 to about 3 as measured by XPS, and z is from about 2 to about 9 as measured by at least one of RBS or HFS. 
     
     
         4 . The ophthalmic drug in a pre-filled pharmaceutical package according to  claim 2 , wherein the lubricity coating or layer is prepared by PECVD from an organosilicon precursor. 
     
     
         5 . The ophthalmic drug in a pre-filled pharmaceutical package according to  claim 4 , wherein the lubricity coating or layer is prepared by PECVD from octamethylcyclotetrasiloxane (OMCTS) as the organosilicon precursor. 
     
     
         6 . The ophthalmic drug in a pre-filled pharmaceutical package according to  claim 1 , in which the front face of the closure seated in the lumen is covered with a fluoropolymer coating or layer, wherein the front face is facing the liquid formulation. 
     
     
         7 . The ophthalmic drug in a pre-filled pharmaceutical package according to  claim 1 , having a nominal maximum fill volume of 0.2 ml to 10 mL, alternatively 0.2 to 1.5 mL, alternatively 0.5 ml to 1.0 ml, alternatively 0.5 ml, 1.0 ml, 3 mL, or 5 mL. 
     
     
         8 . The ophthalmic drug in a pre-filled pharmaceutical package according to  claim 1 , in which the front face of the plunger has a fluoropolymer surface, optionally a molded fluoropolymer surface or a fluoropolymer coating or layer, for example a laminated fluoropolymer film, for example a film of polytetrafluoroethylene or a copolymer film of tetrafluoroethylene and ethylene, or a fluoropolymer coating. 
     
     
         9 . The ophthalmic drug in a pre-filled pharmaceutical package according to  claim 1 , wherein the ophthalmic drug suitable for intravitreal injection comprises a VEGF antagonist. 
     
     
         10 . The ophthalmic drug in a pre-filled pharmaceutical package according to  claim 4 , wherein the VEGF antagonist comprises an anti-VEGF antibody or an antigen-binding fragment of such antibody. 
     
     
         11 . The ophthalmic drug in a pre-filled pharmaceutical package according to  claim 1 , wherein the concentration of the liquid formulation of an ophthalmic drug suitable for intravitreal injection is 1 to 100 mg of a drug active agent per ml. of the liquid formulation (mg/ml), alternatively 2-75 mg/ml, alternatively 3-50 mg/ml, alternatively 5 to 30 mg/ml, and alternatively 6 or 10 mg/ml. 
     
     
         12 . The ophthalmic drug in a pre-filled pharmaceutical package according to  claim 1 , in which the liquid formulation of an ophthalmic drug suitable for intravitreal injection comprises 6 mg/mL, alternatively 10 mg/mL, of the ophthalmic drug. 
     
     
         13 . The ophthalmic drug in a pre-filled pharmaceutical package according to  claim 1 , in which the ophthalmic drug suitable for intravitreal injection further comprises:
 a buffer in an amount effective to provide a pH of the liquid formulation in the range from about 5 to about 7;   a non-ionic surfactant in the range of 0.005 to 0.02% mg./mL of complete formulation, alternatively in the range of 0.007 to 0.018% mg./mL of complete formulation, alternatively in the range of 0.008 to 0.015% mg./mL of complete formulation, alternatively in the range of 0.009 to 0.012% mg./mL of complete formulation, alternatively in the range of 0.009 to 0.011% mg./mL of complete formulation, alternatively 0.01% mg./mL of complete formulation; and   water for injection.   
     
     
         14 . The ophthalmic drug in a pre-filled pharmaceutical package according to  claim 1 , in which the ophthalmic drug suitable for intravitreal injection comprises 6 mg/mL, alternatively 10 mg/mL, of the drug active; 100 mg/mL of α, α-trehalose dihydrate, 1.98 mg/mL L-histidine; and 0.1 mg/mL Polysorbate 20 in water for injection. 
     
     
         15 . The ophthalmic drug in a pre-filled pharmaceutical package according to  claim 1 , wherein the pre-filled pharmaceutical package has a shelf life of at least six months, alternatively at least 12 months, alternatively at least 18 months, alternatively 24 months, measured at a temperature of 5° C., alternatively 25° C. 
     
     
         16 . The ophthalmic drug in a pre-filled pharmaceutical package according to  claim 1 , wherein the pre-filled pharmaceutical package is free of silicone oil on the product contacting surfaces of the pre-filled pharmaceutical package. 
     
     
         17 . The ophthalmic drug in a pre-filled pharmaceutical package according to  claim 1 , wherein the pre-filled pharmaceutical package which is free of baked-on silicone on the product contacting surfaces of the pre-filled pharmaceutical package. 
     
     
         18 . The ophthalmic drug in a pre-filled pharmaceutical package according to  claim 1 , wherein the pre-filled pharmaceutical package is a syringe comprising a barrel and a plunger, the syringe having a plunger sliding force of less than or equal to 10N for advancing the plunger in the lumen. 
     
     
         19 . The ophthalmic drug in a pre-filled pharmaceutical package according to  claim 1 , wherein the pre-filled pharmaceutical package is a syringe comprising a barrel and a plunger, the syringe having a breakout force of less than or equal to 15N, optionally less than or equal to 10N for initiating travel of the plunger in the lumen. 
     
     
         20 . The ophthalmic drug in a pre-filled pharmaceutical package according to  claim 1 , in which the ophthalmic drug suitable for intravitreal injection meets the particle count standard for particulate matter in ophthalmic solutions of USP789 as in force on Nov. 1, 2015, or Ph. Eur 5.7.1 as in force on Nov. 1, 2015, or both, at the time of filling the pre-filled syringe, alternatively after three months of storage of the pre-filled syringe at 4-8° C., alternatively after three months of storage of the pre-filled syringe at 25° C. and 60% relative humidity, alternatively after three months of storage of the pre-filled syringe at 40° C. and 75% relative humidity. 
     
     
         21 .- 75 . (canceled)