Proteins stabilized with polysaccharide gums

Abstract

Described are heat stable aqueous solutions or gels comprising a biologically effective amount of a protein and an effective stabilizing amount of a polysaccharide gum as well as heat stable solutions or gels suitable for use in an implantable drug delivery device at body temperature. Also disclosed are lyophilized compositions having biologically activity, where such lyophilized compositions are formed by lyophilozing the stabilized solutions or gels of the invention. Such lyophilized powders can be used after reconstitution with an amount of aqueous that provide an effective stabilizing concentration of polysaccharide and a pharmaceutically acceptable amount of therapeutic protein particularly against thermal and oxidative stress.

What is claimed is:  
     
         1 . A heat stable aqueous solution or gel comprising a biologically effective amount of a protein and a stabilizing effective amount of a polysaccharide gum material.  
     
     
         2 . A heat stable aqueous solution or gel according to  claim 1  containing one or more minor amounts of a pharmaceutically acceptable excipient.  
     
     
         3 . A heat stable aqueous solution or gel according to  claim 1  wherein said protein comprises an enzyme, an antibody, a hormone, a growth factor, and a cytokine.  
     
     
         4 . A heat stable aqueous solution or gel according to  claim 3  wherein said protein is a hormone.  
     
     
         5 . A heat stable aqueous solution or gel according to  claim 3  wherein said protein is a cytokine.  
     
     
         6 . A heat stable aqueous solution or gel according to  claim 1  wherein said gum comprises gum arabic, guar gum, xanthan gum, locust bean gum, tragacanth gum, gum karaya, and gum ghatti.  
     
     
         7 . A heat stable aqueous solution or gel according to  claim 6  wherein said gum is gum arabic.  
     
     
         8 . A heat stable aqueous solution or gel according to  claim 6  wherein said gum is present at from about 5%(w/v) to about 50%(w/v) or the gum's solubility limit, and wherein when gum Arabic is selected, the concentration is over 10%(w/v).  
     
     
         9 . A heat stable aqueous solution or gel according to  claim 8  wherein said gum is present above 10%(w/v) to about 50%(w/v), or the gum's solubility limit.  
     
     
         10 . A heat stable aqueous solution or gel according to  claim 9  wherein said gum is present at from about 20% (w/v) to about 50% (w/v), or the gum's solubility limit.  
     
     
         11 . A heat stable aqueous solution or gel according to  claim 2  wherein said pharmaceutically acceptable excipient is selected from the group consisting of antioxidants, preservatives and surface active agents.  
     
     
         12 . A heat stable aqueous solution or gel for use in an implantable drug delivery device comprising a pharmaceutically effective amount of a protein and a stabilizing effective amount of a polysaccharide gum material.  
     
     
         13 . A heat stable solution or gel according to  claim 12  wherein said stabilized solution or gel contains one or more minor amounts of a pharmaceutically acceptable excipient.  
     
     
         14 . A heat stable aqueous solution or gel according to  claim 13  wherein said pharmaceutically acceptable excipient is selected from the group consisting of antioxidants, preservatives and surface active agents.  
     
     
         15 . A heat stable aqueous solution or gel according to  claim 12  wherein said protein is selected from the group consisting of an antibody, a hormone, a growth factor, and a cytokine.  
     
     
         16 . A heat stable aqueous solution or gel according to  claim 15  wherein said protein is a hormone or a growth factor.  
     
     
         17 . A heat stable aqueous solution or gel according to  claim 15  wherein said protein is a cytokine.  
     
     
         18 . A heat stable aqueous solution or gel according to  claim 12  wherein said gum is selected from the group consisting of gum arabic, guar gum, xanthan gum, locust bean gum, tragacanth gum, gum karaya, and gum ghatti.  
     
     
         19 . A heat stable aqueous solution or gel according to  claim 18  wherein said gum is gum arabic.  
     
     
         20 . A heat stable aqueous solution or gel according to  claim 18  wherein said gum is present at from about 5% (w/v) to about 50% (w/v) or the gum's solubility limit.  
     
     
         21 . A heat stable aqueous solution or gel according to  claim 20  wherein said gum is present at from about 10% (w/v) to about 50% (w/v) or the gum's solubility limit.  
     
     
         22 . A heat stable aqueous solution or gel according to  claim 21  wherein said gum is present at from about 20% (w/v) to about 50% (w/v) or the gum's solubility limit  
     
     
         23 . A lyophilized composition having biological activity, wherein said lyophilized composition is formed by lyophilizing a heat stable solution or gel comprising a biologically effective amount of a protein and a stabilizing effective amount of a polysaccharide gum material.  
     
     
         24 . The lyophilized composition according to  claim 23 , wherein the lyophilized polysaccharide and protein dry particles are reconstituted in an aqueous buffer in a manner so as to get high concentration of gum that stabilizes the protein.  
     
     
         25 . A lyophilized composition according to  claim 23 , wherein the said lyophilized powder is added to an implantable device that controls the release of therapeutic protein.  
     
     
         26 . A lyophilized composition according to  claim 23 , wherein the lyophilized powder is reconstituted in an aqueous buffer to provide high concentrations of the polysaccharide that will stabilize the said therapeutic protein, and this reconstituted aqueous gum gel or solution is further added to an implantable device.  
     
     
         27 . A lyophilized composition according to  claim 23  wherein said protein is selected from the group consisting of an enzyme, an antibody, a hormone, a growth factor, and a cytokine.  
     
     
         28 . A lyophilized composition according to  claim 23  wherein said gum is selected from the group consisting of gum arabic, guar gum, xanthan gum, locust bean gum, tragacanth gum, gum karaya, and gum ghatti.  
     
     
         29 . A lyophilized composition according to  claim 28  wherein said gum is gum arabic.  
     
     
         30 . A lyophilized composition according to  claim 28  wherein said gum is present at from about 5% to about 50% (w/v) after reconstitution in aqueous buffer, or the solubility limit of the gum, and wherein when gum arabic is selected said gum is present at greater than 10% (w/v).  
     
     
         31 . A lyophilized composition according to  claim 30  wherein said gum is present at from about 10% (w/v) to from about 50% (w/v) after reconstitution in aqueous buffer.  
     
     
         32 . A lyophilized composition according to  claim 31  wherein said gum is present at from about 20% (w/v) to from about 50% (w/v) after reconstitution in aqueous buffer.  
     
     
         33 . A lyophilized composition according to  claim 23  optionally containing one or more pharmaceutically acceptable excipients.  
     
     
         34 . An implantable drug delivery device containing a heat stable aqueous solution or gel comprising a pharmaceutically effective amount of a protein and a stabilizing effective amount of a polysaccharide gum material.  
     
     
         35 . An implantable drug delivery device containing a lyophilized powder according to  claim 23 .  
     
     
         36 . An implantable drug delivery device that is filled with a lyophilized powder according to  claim 23  that has been reconstituted with an aqueous buffer to provide a thermally stabilizing amount of polysaccharide and pharmaceutically acceptable amount of therapeutic protein.  
     
     
         37 . An implantable drug delivery device according to  claim 32  wherein said stabilized solution or gel contains one or more minor amounts of a pharmaceutically acceptable excipient.  
     
     
         38 . An implantable drug delivery device according to  claim 33  wherein said pharmaceutically acceptable excipient is selected from the group consisting of antioxidants, preservatives and surface active agents.  
     
     
         39 . An implantable drug delivery device according to  claim 32  wherein said protein is selected from the group consisting of an antibody, a hormone, a growth factor, and a cytokine.  
     
     
         40 . An implantable drug delivery device according to  claim 35  wherein said protein is a hormone or a growth factor.  
     
     
         41 . An implantable drug delivery device according to  claim 32  wherein said gum is selected from the group consisting of gum arabic, guar gum, xanthan gum, locust bean gum, tragacanth gum, gum karaya, and gum ghatti.  
     
     
         42 . An implantable drug delivery device according to  claim 37  wherein said gum is gum arabic.  
     
     
         43 . An implantable drug delivery device according to  claim 37  wherein said gum is present at from about 5% (w/v) to from about 50% (w/v) or the gum's solubility limit.  
     
     
         44 . An implantable drug delivery device according to  claim 39  wherein said gum is present at from about 10% (w/v) to about 50% (w/v) or the gum's solubility limit.  
     
     
         45 . An implantable drug delivery device according to  claim 40  wherein said gum is present at from about 20% (w/v) to about 50% (w/v) or the gum's solubility limit.  
     
     
         46 . An implantable drug delivery device according to  claim 40  wherein said gum is present at from about 30% (w/v) to about 50% (w/v) or the gum's solubility limit.  
     
     
         47 . An implantable drug delivery device according to  claim 40  wherein said gum is present at from about 40% (w/v) to about 50% (w/v) or the gum's solubility limit.  
     
     
         48 . An aqueous solution or gel stable against metal catalized oxidation reactions comprising a biologically effective amount of a protein and a stabilizing effective amount of a polysaccharide gum material.  
     
     
         49 . The oxidation stable solution or gel according to  claim 48 , wherein when gum arabic is selected said gum is present above about 30%(w/v) to the gums solubility limit.