Methods and Compositions for the Delivery of a Therapeutic Agent

Abstract

The present invention provides a liquid pharmaceutical composition comprising a therapeutic agent and an alkoxy-polyethylene glycol, for example, methoxy-polyethylene glycol, for administration of the therapeutic agent to the mammal. The compositions can be applied to a membrane, for example, a nasal membrane during intranasal administration. The invention also provides methods of administering such compositions to a mammal.

1 . A liquid pharmaceutical composition comprising a therapeutic agent and an alkoxy-polyethylene glycol represented by Formula I:
   R—O—(CH 2 CH 2 O) n —H  (I)   
       wherein:
 R is methyl, ethyl, n-propyl, isopropyl, or cyclopropyl; and 
 n is a number in the range of from about 1 to about 25. 
 
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the therapeutic agent is an organic compound having a molecular weight of less than 1500 g/mol. 
     
     
         3 . A liquid pharmaceutical composition comprising a poorly soluble therapeutic agent and an alkoxy-polyethylene glycol represented by Formula I:
   R—O—(CH 2 CH 2 O) n —H  (I)   
       wherein:
 R is (C 1 -C 6 )alkyl; and 
 n is a number in the range of from about 1 to about 25. 
 
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein the alkoxy-polyethylene glycol comprises from about 0.5% (v/v) to about 70% (v/v) of the composition. 
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein the alkoxy-polyethylene glycol comprises about 1% (v/v) to about 60% (v/v) of the composition. 
     
     
         6 . The pharmaceutical composition of  claim 1 , wherein the alkoxy-polyethylene glycol comprises about 5% (v/v) to about 50% (v/v) of the composition. 
     
     
         7 . The pharmaceutical composition of  claim 1 , wherein the therapeutic agent comprises about 0.001% (w/v) to about 20% (w/v) of the composition. 
     
     
         8 . The pharmaceutical composition of  claim 1 , wherein the therapeutic agent comprises about 0.1% (w/v) to about 10% (w/v) of the composition. 
     
     
         9 . The pharmaceutical composition of  claim 1 , further comprising water. 
     
     
         10 . The pharmaceutical composition of  claim 9 , wherein the water comprises about 10% (v/v) to about 95% (v/v) of the composition. 
     
     
         11 . The pharmaceutical composition of  claim 1 , further comprising a buffer. 
     
     
         12 . The pharmaceutical composition of  claim 1 , further comprising a preservative. 
     
     
         13 . The pharmaceutical composition of  claim 1 , wherein the composition at a temperature of 20° C. has a viscosity in the range of from about 1.5 cP to about 60 cP. 
     
     
         14 . The pharmaceutical composition of  claim 1 , wherein the composition at a temperature of 20° C. has a viscosity in the range of from about 5 cP to about 25 cP. 
     
     
         15 . The pharmaceutical composition of  claim 1 , wherein the composition has a pH in the range of from about 4.5 to about 8.5. 
     
     
         16 . The pharmaceutical composition of  claim 1 , wherein the composition has a pH in the range of from about 5.5 to about 7.5. 
     
     
         17 . The pharmaceutical composition of  claim 1 , wherein the composition is sterile. 
     
     
         18 . The pharmaceutical composition of  claim 1 , wherein the composition has a sterility assurance level of at least about 10 3 . 
     
     
         19 . The pharmaceutical composition of  claim 1 , wherein less than 1% by weight of the therapeutic agent degrades after storage for 30 days at 20° C. 
     
     
         20 . The pharmaceutical composition of  claim 1 , wherein less than 1% by weight of the therapeutic agent degrades after storage for 6 months at 20° C. 
     
     
         21 . The pharmaceutical composition of  claim 1 , wherein the composition is formulated so that upon intranasal administration to a subject, the therapeutic agent has a peak concentration (t max ) in the blood of the subject within 30 minutes after administration of the therapeutic agent. 
     
     
         22 . The pharmaceutical composition of  claim 1 , wherein the composition is formulated so that upon intranasal administration to a subject, the therapeutic agent has a peak concentration (t max ) in the blood of the subject within 10 minutes after administration of the therapeutic agent. 
     
     
         23 . The pharmaceutical composition of  claim 1 , wherein R is methyl. 
     
     
         24 . The pharmaceutical composition of  claim 1 , wherein n is 3-15. 
     
     
         25 . The pharmaceutical composition of  claim 1 , wherein the alkoxy-polyethylene glycol is mPEG 350, mPEG 550, or a combination thereof. 
     
     
         26 . The pharmaceutical composition of  claim 1 , wherein the alkoxy-polyethylene glycol is methoxy-triethylene glycol (m3EG), methoxy-tetraethylene glycol (m4EG), methoxy-pentaethylene glycol (m5EG), methoxy-hexaethylene glycol (m6EG), methoxy-heptaethylene glycol (m7EG), methoxy-octaethylene glycol (m8EG), methoxy-nonaethylene glycol (m9EG), methoxy-decaethylene glycol (m10EG), methoxy-undecaethylene glycol (m11EG), methoxy-dodecaethylene glycol (m12EG), methoxy-tridecaethylene glycol (m13EG), or methoxy-tetradecaethylene glycol (m14EG). 
     
     
         27 . The pharmaceutical composition of  claim 1 , wherein the therapeutic agent has a molecular weight of less than 500 g/mol. 
     
     
         28 . The pharmaceutical composition of  claim 1 , wherein the therapeutic agent has an aqueous solubility of less than about 0.3 mg/mL at pH 7 and 20° C. 
     
     
         29 . The pharmaceutical composition of  claim 1 , wherein the therapeutic agent has an aqueous solubility of less than about 0.1 mg/mL at pH 7 and 20° C. 
     
     
         30 . The pharmaceutical composition of  claim 1 , wherein the therapeutic agent is a benzodiazepine. 
     
     
         31 . The pharmaceutical composition of  claim 30 , wherein the therapeutic agent is midazolam. 
     
     
         32 . (canceled) 
     
     
         33 . A method of administering a therapeutic agent to a mammal, the method comprising administering a pharmaceutical composition of  claim 1  to a mucosal surface of the mammal. 
     
     
         34 . The method of  claim 33 , wherein the mucosal surface is a nasal membrane, sublingual membrane, buccal membrane, pulmonal membrane, ocular membrane, or rectal membrane. 
     
     
         35 . The method of  claim 33 , wherein the mucosal surface is a nasal membrane. 
     
     
         36 . The method of  claim 33 , wherein the therapeutic agent has a peak concentration (T max ) in the blood of the mammal within 30 minutes after administration of the therapeutic agent. 
     
     
         37 . The method of  claim 33 , wherein the therapeutic agent has a peak concentration (T max ) in the blood of the mammal within 10 minutes after administration of the therapeutic agent. 
     
     
         38 . The method of  claim 33 , wherein the pharmaceutical composition is administered in a volume of from about 1 μL to about 1000 μL. 
     
     
         39 . The method of  claim 38 , wherein the pharmaceutical composition is administered in a volume from about 50 μL to about 300 μL. 
     
     
         40 . The method of  claim 33 , wherein the mammal is a human.