Pharmaceutical composition formulated for pre-gastric absorption of monoamine oxidase B inhibitors

Abstract

The invention described herein provides a fast dispersing oral solid dosage form containing monoamine oxidase B inhibitor (MAO-B inhibitor) as the active ingredient, and method of treating disease therewith, such as Parkinson's disease. In one embodiment, the monoamine oxidase B inhibitor selegiline or its analogue can be the sole active ingredient in the composition administered. The dosage form composition is formulated to promote absorption through the buccal, sublingual, pharyngeal and/or esophageal mucous membrane tissue, such that at least 5% of the active ingredient is absorbed within one minute of placement in the oral cavity, as determined by a buccal absorption test. Monoamine oxidase B inhibitor compounds administered in accordance with the invention decrease the amount of undesirable metabolites associated with first pass effect of selegiline, for example, such as amphetamine and methamphetamine. The invention provides a number of other advantages over conventional orally administered tablet forms, including administration of monoamine oxidase B inhibitor compounds to patients that have difficulty swallowing.

1 . A fast disintegrating oral solid dosage form formulated for pre-gastric absorption, said dosage form comprising a monoamine oxidase B inhibitor and carrier.  
     
     
         2 . The fast disintegrating oral solid dosage form according to  claim 1 , wherein the monoamine oxidase B inhibitor has the following formula:  
       
         
           
           
               
               
           
         
         or an acid addition salt thereof, wherein X represents hydrogen or methyl group, and Y represents hydrogen or fluorine.  
       
     
     
         3 . The fast disintegrating oral solid dosage form according to  claim 1 , wherein said monoamine oxidase inhibitor is selected from the group consisting of selegiline, para-fluoroselegiline, mofegiline, rasagiline, lazabemide, and combinations thereof.  
     
     
         4 . The fast disintegrating oral solid dosage form according to  claim 3 , wherein said monoamine oxidase B inhibitor is selegiline.  
     
     
         5 . The fast disintegrating oral solid dosage form according to  claim 4 , wherein selegiline is the only pharmacologically active ingredient present in said dosage form.  
     
     
         6 . The fast disintegrating oral solid dosage form according to  claim 1 , wherein said dosage form is formulated to promote absorption of said monoamine oxidase B inhibitor through the buccal, sublingual, pharyngeal or esophageal mucous membrane.  
     
     
         7 . The fast disintegrating oral solid dosage form according to  claim 1 , wherein said dosage form disintegrates within one minute after placement in the oral cavity.  
     
     
         8 . The fast disintegrating oral solid dosage form according to  claim 7 , wherein said dosage form disintegrates within 10 seconds after placement in the oral cavity.  
     
     
         9 . The fast disintegrating oral solid dosage form according to  claim 1 , wherein at least 5% of said monoamine oxidase B inhibitor is absorbed within one minute of placement in the oral cavity as measured by a buccal absorption test.  
     
     
         10 . The fast disintegrating oral solid dosage form according to  claim 9 , wherein at least 10% of said monoamine oxidase B inhibitor is absorbed within one minute of placement in the oral cavity as measured by a buccal absorption test.  
     
     
         11 . The fast disintegrating oral solid dosage form according to  claim 10 , wherein at least 15% of said monoamine oxidase B inhibitor is absorbed within one minute of placement in the oral cavity as measured by a buccal absorption test.  
     
     
         12 . The fast disintegrating oral solid dosage form according to  claim 4 , wherein said dosage form is formulated such that about 2.96 mg of selegiline hydrochloride is pre-gastrically absorbed within one minute of placement in the oral cavity.  
     
     
         13 . The fast disintegrating oral solid dosage form according to  claim 1 , wherein said dosage form comprises a network of the monoamine oxidase B inhibitor and water-soluble or water dispersible carrier which is inert toward said monoamine oxidase B inhibitor, said network is formed by subliming solvent from a solid state composition comprising the monoamine oxidase B inhibitor and a solution of the carrier in a solvent.  
     
     
         14 . The fast disintegrating oral solid dosage form according to  claim 13 , wherein said dosage form disintegrates within 1 to 10 seconds of being placed in the oral cavity.  
     
     
         15 . The fast disintegrating oral solid dosage form according to  claim 13 , wherein said monoamine oxidase B inhibitor is selegiline.  
     
     
         16 . The fast disintegrating oral solid dosage form according to  claim 1 , wherein the bioavailability of said monoamine oxidase B inhibitor is at least about 8 times that as compared to an orally swallowed solid tablet dosage form, wherein each of said dosage forms contain the same amount of monoamine oxidase B inhibitor.  
     
     
         17 . A method of treatment of Parkinson's disease comprising administering to a patient in need of treatment thereof, a fast disintegrating oral solid dosage form containing a pharmaceutically effective amount of monoamine oxidase B inhibitor, said dosage form being formulated for pre-gastric absorption and comprising monoamine oxidase B inhibitor and carrier.  
     
     
         18 . The method according to  claim 17 , wherein said dosage form is formulated to promote absorption of said monoamine oxidase B inhibitor through the buccal, sublingual, pharyngeal or esophageal mucous membrane.  
     
     
         19 . The method according to  claim 17 , wherein said dosage form disintegrates within one minute after placement in the oral cavity.  
     
     
         20 . The method according to  claim 19 , wherein said dosage form disintegrates within 1 to 10 seconds after placement in the oral cavity.  
     
     
         21 . The method according to  claim 17 , wherein at least 5% of said monoamine oxidase B inhibitor is absorbed within one minute of placement in the oral cavity as measured by a buccal absorption test.  
     
     
         22 . The method according to  claim 21 , wherein at least 10% of said monoamine oxidase B inhibitor is absorbed within one minute of placement in the oral cavity as measured by a buccal absorption test.  
     
     
         23 . The method according to  claim 22 , wherein at least 15% of said monoamine oxidase B inhibitor is absorbed within one minute of placement in the oral cavity as measured by a buccal absorption test.  
     
     
         24 . The method according to  claim 17 , wherein said dosage form is formulated such that about 2.96 mg of selegiline hydrochloride is pre-gastrically absorbed within one minute of placement in the oral cavity.  
     
     
         25 . The method according to  claim 17 , wherein said dosage form comprises a network of the monoamine oxidase B inhibitor and water-soluble or water dispersible carrier which is inert toward said monoamine oxidase B inhibitor, said network is formed by subliming solvent from a solid state composition comprising the monoamine oxidase B inhibitor and a solution of the carrier in a solvent.  
     
     
         26 . The method according to  claim 25 , wherein said dosage form disintegrates within 1 to 10 seconds of being placed in the oral cavity.  
     
     
         27 . The method according to  claim 17 , wherein said monoamine oxidase B inhibitor is selegiline.  
     
     
         28 . The method according to  claim 17 , wherein the bioavailability of said monoamine oxidase B inhibitor is at least about 8 times that as compared to an orally swallowed solid tablet dosage form, wherein each of said dosage forms contain the same amount of monoamine oxidase B inhibitor.  
     
     
         29 . A method of treatment of Alzheimer's disease comprising administering to a patient in need of treatment thereof, a fast disintegrating oral solid dosage form containing a pharmaceutically effective amount of monoamine oxidase B inhibitor, said dosage form being formulated for pre-gastric absorption and comprising monoamine oxidase B inhibitor and carrier.  
     
     
         30 . The method according to  claim 29 , wherein said monoamine oxidase B inhibitor is selegiline.  
     
     
         31 . A method of treatment of depression comprising administering to a patient in need of treatment thereof, a fast disintegrating oral solid dosage form containing a pharmaceutically effective amount of monoamine oxidase B inhibitor, said dosage form being formulated for pre-gastric absorption and comprising monoamine oxidase B inhibitor and carrier.  
     
     
         32 . The method according to  claim 31 , wherein said monoamine oxidase B inhibitor is selegiline.  
     
     
         33 . A method of increasing phenethylamine levels in the body comprising administering to a patient in need of treatment thereof, a fast disintegrating oral solid dosage form containing a pharmaceutically effective amount of monoamine oxidase B inhibitor, said dosage form being formulated for pre-gastric absorption and comprising monoamine oxidase B inhibitor and carrier.  
     
     
         34 . The method according to  claim 33 , wherein said monoamine oxidase B inhibitor is selegiline.