Combination products of tobramycin compounds and dexamethasone compounds

Abstract

Disclosed herein are new compositions comprising (1) an antibacterial component comprising (a) a complex comprising (i) an active pharmaceutical ingredient (API) wherein the active pharmaceutical ingredient is tobramycin, a similar compound, or a derivative of either thereof and (ii) a complexing agent, or (b) a derivative of tobramycin or a similar compound comprising one or more conjugates/derivatizing groups, wherein the complexing agent or conjugate(s) cause a detectable increase in API permeation of corneal cells, retention in corneal cells, or both, as compared to the non-complexed or non-derivatized API, and (2) an effective amount of an anti-inflammatory agent, such as dexamethasone or another dexamethasone compound. This disclosure also describes new methods of using such compositions, producing such compositions, and the like.

What is claimed is: 
     
         1 . A pharmaceutical formulation comprising:
 (1) an ophthalmologically suitable complex, the complex comprising
 (a) a pharmaceutically effective amount of tobramycin or an ophthalmologically suitable and anti-bacterial derivative thereof; and 
 (b) polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer (PCL-PVAc-PEG) or a derivative thereof, wherein the PCL-PVAc-PEG or derivative thereof is present in an amount such that an amount of the complex is generated which is sufficient to (1) promote the uptake of the tobramycin or derivative thereof by corneal cells at a statistically significant level as compared to the free (non-complexed) tobramycin or derivative thereof; (b) promote the retention of the tobramycin or derivative thereof by corneal cells at a statistically significant level as compared to the free (non-complexed) tobramycin or derivative thereof; (c) detectably reduce the amount of time required to reach a significant reduction in the level of a mammalian eye infected with the infective agent at a statistically significant level as compared to the free (non-complexed) tobramycin or derivative thereof; or (d) exhibit any combination of (a)-(c); and 
   (2) a pharmaceutically effective amount of dexamethasone or a pharmaceutically acceptable derivative thereof.   
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the dexamethasone or the pharmaceutically suitable derivative thereof is present in a concentration of about 0.02-about 0.15% w/v. 
     
     
         3 . The pharmaceutical composition of  claim 2 , wherein the dexamethasone or the pharmaceutically suitable derivative thereof is dexamethasone. 
     
     
         4 . The pharmaceutical composition of  claim 3 , wherein the tobramycin or tobramycin derivative is tobramycin present in an amount of about 0.3-about 3% w/v of the composition. 
     
     
         5 . The pharmaceutical composition of  claim 4 , wherein when an effective amount of a pharmaceutical composition is administered to a human eye the concentration of tobramycin permeating the surface of the cornea of the eye is at least about 15% greater after 15 minutes than the amount of tobramycin that permeates the surface of the cornea from administration of a corresponding amount of a composition consisting of tobramycin at 0.3% w/w, benzalkonium chloride at 0.01% w/v, boric acid at 1.24% w/v, sodium sulfate at 0.152% w/v, sodium chloride at 0.278% w/v, tyloxapol at 0.1% w/v, sodium hydroxide and/or sulfuric acid, and purified water to a human eye. 
     
     
         6 . The pharmaceutical composition of  claim 1 , wherein the effective amount of the composition prevents detectable or significant growth of a bacterial infective agent for a period of at least about 6 hours after administration. 
     
     
         7 . A method of reducing the level of bacterial agents in a mammalian eye of a patient diagnosed with a bacterial infection of the eye comprising administering no more than twice per day an effective amount of an ophthalmologically suitable composition that is formed by mixing a pharmaceutically effective amount of tobramycin or a derivative thereof and an amount of an ophthalmologically suitable amphoteric complexing agent causing the formation of a tobramycin-complexing agent complex that significantly enhances the permeability of the tobramycin in the composition into the cornea of the eye. 
     
     
         8 . The method of  claim 7 , wherein the method is at least as effective in reducing the level of bacterial agents as treating a similarly infected eye three times per day with a composition consisting of tobramycin at 0.3% w/w, benzalkonium chloride at 0.01% w/v, boric acid at 1.24% w/v, sodium sulfate at 0.152% w/v, sodium chloride at 0.278% w/v, tyloxapol at 0.1% w/v, sodium hydroxide and/or sulfuric acid, and purified water. 
     
     
         9 . The method of  claim 7 , wherein the method comprises administering the composition no more than once per day. 
     
     
         10 . The method of  claim 7 , wherein the complexing agent comprises a 3- to 5-member nitrogenous ring and at least one carboxylate group. 
     
     
         11 . The method of  claim 10 , wherein the composition further comprises an ophthalmologically suitable antiinflammatory agent in a concentration of about 0.02-about 0.15% w/v of the composition. 
     
     
         12 . The method of  claim 11 , wherein the antiinflammatory agent is dexamethasone or a pharmaceutically suitable derivative thereof. 
     
     
         13 . The method of  claim 12 , wherein the complex is present in an amount of about 0.3-about 3% w/v. 
     
     
         14 . The method of  claim 7 , wherein the method results in a concentration of tobramycin or derivative thereof permeating the surface of the cornea which is at least about 15% greater after 15 minutes from application than a corresponding amount of tobramycin in a composition consisting of tobramycin at 0.3% w/w, benzalkonium chloride at 0.01% w/v, boric acid at 1.24% w/v, sodium sulfate at 0.152% w/v, sodium chloride at 0.278% w/v, tyloxapol at 0.1% w/v, sodium hydroxide and/or sulfuric acid, and purified water. 
     
     
         15 . A method of reducing the level of a bacterial agent present in a mammalian eye and concurrently reducing an amount of inflammation associated with the presence of the bacterial agent in the mammalian eye or its adnexa comprising administering to the eye an effective amount of an ophthalmologically suitable pharmaceutical formulation, the formulation comprising an effective amount of one or more antiinflammatory agents and a complexed compound, the complexed compound comprising:
 (1) an effective amount of an antibacterial active pharmaceutical ingredient comprising tobramycin or a derivative thereof, and   (2) means for forming an ophthalmologically suitable complex comprising the tobramycin or derivative thereof,   
       wherein the means for forming an ophthalmologically suitable complex detectably increases the amount of tobramycin in corneal cells of a mammalian eye after a period of at least about 60 minutes from administration by at least about 25% as compared to the free (non-complexed) tobramycin or derivative thereof. 
     
     
         16 . The method of  claim 15 , wherein the antiinflammatory agent is dexamethasone or a pharmaceutically suitable derivative thereof. 
     
     
         17 . The method of  claim 16 , wherein the dexamethasone or the pharmaceutically suitable derivative thereof is present in the composition in a concentration of about 0.02-about 0.15% w/v. 
     
     
         18 . The method of  claim 17 , wherein the dexamethasone or the pharmaceutically suitable derivative thereof is dexamethasone. 
     
     
         19 . The method of  claim 18 , wherein the complex is present in an amount of about 0.3-about 3% w/v. 
     
     
         20 . The method of  claim 15 , wherein the formulation further comprises a means for establishing an osmolality of the formulation of about 250 to about 350 mOsm/Kg.