Drug delivery method

Abstract

The present invention relates to a new drug delivery strategy based on prodrug conversion, in which a water-soluble prodrug and its converting enzyme are co-delivered and at a point of administration such as the nasal or buccal mucosa. Enzymatic conversion of the prodrug produces drug in concentrations exceeding the drug's thermodynamic solubility, or saturation level. The supersaturated drug crosses the mucosal membrane quickly, as a result of its high thermodynamic activity, prior to crystallization. This strategy is particularly useful when fast action is required, for example in preventing or responding rapidly to Status Epilepticus (SE) or other central nervous system conditions such as migraine.

1 - 29 . (canceled) 
     
     
         30 . A pharmaceutical dosage form comprising a soluble precursor of a pharmaceutically active compound and a soluble enzyme that converts said precursor to said pharmaceutically active compound, wherein said enzyme is not in contact with said precursor. 
     
     
         31 . The dosage form of  claim 30  which comprises separate compartments for the precursor and enzyme whereby said enzyme cannot convert the precursor to the pharmaceutically active compound. 
     
     
         32 . (canceled) 
     
     
         33 . The pharmaceutical dosage form of  claim 30  which is a gelatin capsule. 
     
     
         34 . The pharmaceutical dosage form of  claim 31  which is a tablet comprising a layer containing the precursor and another layer containing the enzyme. 
     
     
         35 . The pharmaceutical dosage form of  claim 34 , wherein the tablet is enterically coated. 
     
     
         36 . (canceled) 
     
     
         37 . The pharmaceutical dosage form of  claim 30 , wherein the pharmaceutically active compound is phenytoin. 
     
     
         38 . The pharmaceutical dosage form of  claim 37 , wherein the precursor is fosphenytoin and the enzyme is alkaline phosphatase. 
     
     
         39 - 46 . (canceled) 
     
     
         47 . The pharmaceutical dosage form of  claim 30 , wherein the pharmaceutically active compound is an antiepileptic drug. 
     
     
         48 . The pharmaceutical dosage form of  claim 30 , wherein the pharmaceutically active compound is an antiseizure drug. 
     
     
         49 . The pharmaceutical dosage form of  claim 31 , wherein the separate compartments are part of a spray device and the precursor and enzyme are mixed at the same time or mixed just prior to spraying. 
     
     
         50 . The pharmaceutical dosage form of  claim 31 , wherein the separate compartments are part of an aerosolizing device and the precursor and enzyme are aerosolized at the same time or mixed just prior to aerosolization. 
     
     
         51 . The pharmaceutical dosage form of  claim 31 , wherein the separate compartments are part of a nebulizer thereby preventing the enzyme from substantially converting the precursor prior to inhalation and are inhaled at the same time. 
     
     
         52 . The pharmaceutical dosage form of  claim 30 , wherein the pharmaceutical dosage form can include sterile powders comprising of the precursor and/or enzyme plus any additional desired ingredient. 
     
     
         53 . The pharmaceutical dosage form of  claim 30 , wherein the pharmaceutical dosage form includes an injectable composition. 
     
     
         54 . The pharmaceutical dosage form of  claim 53 , wherein the injectable composition may include agents delaying absorption. 
     
     
         55 . The pharmaceutical dosage form of  claim 30 , wherein the pharmaceutical dosage form is an aqueous solution. 
     
     
         56 . The pharmaceutical dosage form of  claim 30 , wherein the pharmaceutically active compound is diazepam. 
     
     
         57 . The pharmaceutical dosage form of  claim 30 , wherein the water soluble precursor is avizafone. 
     
     
         58 . The pharmaceutical dosage form of  claim 30 , wherein the converting enzyme is a protease or exopeptidase. 
     
     
         59 . The pharmaceutical dosage form of  claim 30 , wherein the precursor is fosphenytoin and the enzyme is alkaline phosphatase. 
     
     
         60 . The pharmaceutical dosage form of  claim 30 , wherein the precursor and enzyme are mixed together immediately prior to administration. 
     
     
         61 . A pharmaceutical dosage form comprising:
 (a) a composition comprising a therapeutically effective amount of a soluble precursor of a pharmaceutically active compound and an effective amount of an enzyme that converts said precursor to said pharmaceutically active compound or   (b) a first composition comprising a therapeutically effective amount of a soluble precursor of the compound and a second composition comprising an effective amount of an enzyme that converts said soluble precursor to said compound,   wherein said enzyme is not in contact with said precursor.   
     
     
         62 . The pharmaceutical dosage form of  claim 61  which comprises separate compartments for the precursor and enzyme whereby said enzyme cannot convert the precursor to the pharmaceutically active compound. 
     
     
         63 . The pharmaceutical dosage form of  claim 62 , wherein the separate compartments are part of a spray device and the precursor and enzyme are mixed at the same time or mixed just prior to spraying. 
     
     
         64 . The pharmaceutical dosage form of  claim 62 , wherein the separate compartments are part of an aerosolizing device and the precursor and enzyme are aerosolized at the same time or mixed just prior to aerosolization. 
     
     
         65 . The pharmaceutical dosage form of  claim 62 , wherein the separate compartments are part of a nebulizer thereby preventing the enzyme from substantially converting the precursor prior to inhalation and are inhaled at the same time 
     
     
         66 . The pharmaceutical dosage form of  claim 61 , wherein the pharmaceutically active compound is an antiepileptic drug. 
     
     
         67 . The pharmaceutical dosage form of  claim 61 , wherein the pharmaceutically active compound is an antiseizure drug. 
     
     
         68 . The pharmaceutical dosage form of  claim 61 , wherein the pharmaceutically active compound is diazepam. 
     
     
         69 . The pharmaceutical dosage form of  claim 61 , wherein the soluble precursor is avizafone. 
     
     
         70 . The pharmaceutical dosage form of  claim 61 , wherein the converting enzyme is a protease or exopeptidase. 
     
     
         71 . The pharmaceutical dosage form of  claim 61 , wherein the pharmaceutically active compound is phenytoin. 
     
     
         72 . The pharmaceutical dosage form of  claim 61 , wherein the precursor is fosphenytoin and the enzyme is alkaline phosphatase. 
     
     
         73 . The pharmaceutical dosage form of  claim 61 , wherein the pharmaceutical dosage form can include sterile powders comprising of the precursor and/or enzyme plus any additional desired ingredient. 
     
     
         74 . The pharmaceutical dosage form of  claim 61 , wherein the pharmaceutical dosage form includes an injectable composition. 
     
     
         75 . The pharmaceutical dosage form of  claim 74 , wherein the injectable composition may include agents delaying absorption. 
     
     
         76 . A method for transporting and administering a compound to a mammal in need thereof, comprising:
 (a) a composition comprising a therapeutically effective amount of a water-soluble precursor of the compound and an effective amount of an enzyme that converts said water-soluble precursor to said compound or   (b) a first composition comprising a therapeutically effective amount of a water-soluble precursor of the compound and a second composition comprising an effective amount of an enzyme that converts said water-soluble precursor to said compound   wherein said enzyme is not in contact with said precursor prior to administration and the precursor is converted to the compound at administration and   wherein the compound is administered to the mammal.   
     
     
         77 . The method of  claim 76  which comprises separate compartments for the precursor and enzyme whereby said enzyme cannot convert the precursor to the pharmaceutically active compound. 
     
     
         78 . The method of  claim 77 , wherein the separate compartments are part of an aerosolizing device and are mixed for aerosolization. 
     
     
         79 . The method of  claim 77 , wherein the separate compartments are part of a spray device and the precursor and enzyme are mixed at the same time or mixed just prior to spraying. 
     
     
         80 . The method of  claim 77 , wherein the separate compartments are part of an aerosolizing device and the precursor and enzyme are aerosolized at the same time or mixed just prior to aerosolization. 
     
     
         81 . The method of  claim 77 , wherein the separate compartments are part of a nebulizer thereby preventing the enzyme from substantially converting the precursor prior to inhalation and are inhaled at the same time 
     
     
         82 . The method of  claim 76 , wherein either or both of the precursor and enzyme are administered as a spray. 
     
     
         83 . The method of  claim 76 , wherein the precursor and enzyme are administered intranasally. 
     
     
         84 . The method of  claim 76 , wherein the precursor and enzyme are administered as aerosol sprays. 
     
     
         85 . The method of  claim 76 , wherein the precursor and enzyme are both administered as solutions. 
     
     
         86 . The method of  claim 76 , wherein the precursor and enzyme are mixed upon administration. 
     
     
         87 . The method of  claim 76 , wherein the precursor and enzyme are administered intramuscularly. 
     
     
         88 . The method of  claim 76 , wherein the precursor and enzyme are administered subcutaneously. 
     
     
         89 . The method of  claim 76 , wherein the precursor and enzyme are administered in a capsule. 
     
     
         90 . The method of  claim 76 , wherein the composition is an injectable composition. 
     
     
         91 . The method of  claim 76 , wherein the compound is diazepam. 
     
     
         92 . The method of  claim 76 , wherein the precursor is avizafone and the enzyme is a protease or exopeptidase. 
     
     
         93 . The method of  claim 76 , wherein the compound is phenytoin. 
     
     
         94 . The method of  claim 76 , wherein the precursor is fosphenytoin and the enzyme is alkaline phosphatase.