Pharmaceutical composition for controlled release of weak acid drugs and uses thereof

Abstract

Provided herein are pharmaceutical compositions containing at least one liposome, said liposome comprise an external lipid bilayer including at least one vesicle-forming phospholipid and less than 15 mole % of sterol; and an internal aqueous medium including a weak acid drug and weak acid salt. The pharmaceutical compositions reduce the burst release of the weak acid drug. Also provided is the use of the pharmaceutical composition disclosed herein to treat respiratory diseases and reduce the side effect of the weak acid drug.

What is claimed is: 
     
         1 . A pharmaceutical composition, comprising:
 one or more liposome suspended in an external medium, said liposome comprising:   (a) an external lipid bilayer, comprising at least one vesicle-forming phospholipid and less than 15 mole % of sterol and   (b) an internal aqueous medium, comprising a weak acid drug and a weak acid salt, wherein less than 65% of the weak acid drug is released into the external medium within 1 hour after the administration of the pharmaceutical composition.   
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the external lipid bilayer comprises less than 10 mole % of sterol. 
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein the external lipid bilayer is substantially free of sterol. 
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein the sterol is selected from the group consisting of cholesterol, cholesterol hexasuccinate, ergosterol, lanosterol, and combination thereof. 
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein the vesicle-forming lipid is a mixture of a first phospholipid and a second phospholipid or a mixture of a first phospholipid and a charged lipid. 
     
     
         6 . The pharmaceutical composition of  claim 1 , wherein the weak acid salt is carboxylic acid salt or bicarbonate salt. 
     
     
         7 . The pharmaceutical composition of  claim 6 , wherein the carboxylic acid salt is selected from the group consisting of formate, acetate, propionate, butyrate, isobutyrate, valerate, isovalerate, benzoate and a combination thereof. 
     
     
         8 . The pharmaceutical composition of  claim 6 , wherein the bicarbonate salt is selected from the group consisting of potassium bicarbonate, sodium bicarbonate, calcium bicarbonate, magnesium bicarbonate, cesium bicarbonate, lithium bicarbonate, nickel bicarbonate, ferrous iron bicarbonate or combination thereof. 
     
     
         9 . The pharmaceutical composition of  claim 1 , wherein the internal aqueous medium further comprising cyclodextrin. 
     
     
         10 . The pharmaceutical composition of  claim 9 , wherein the molar ratio of the weak acid drug to cyclodextrin (drug/CD ratio) is less than or equal to 0.06. 
     
     
         11 . The pharmaceutical composition of  claim 9 , wherein the molar ratio of the weak acid drug to cyclodextrin (drug/CD ratio) is less than or equal to 0.03. 
     
     
         12 . The pharmaceutical composition of  claim 1 , wherein the weak acid drug is prostaglandin, prostacyclin receptor agonist, steroid, non-steroidal anti-inflammatory drug (NSAID), anticoagulant, endothelin (ET) receptor antagonist or the combination thereof. 
     
     
         13 . The pharmaceutical composition of claim of  claim 12 , wherein the prostaglandin is iloprost. 
     
     
         14 . The pharmaceutical composition of claim of  claim 12 , wherein the ET receptor antagonist is ambrisentan. 
     
     
         15 . A method of treating a respiratory disease, comprising the steps of administering the pharmaceutical composition of  claim 1   
     
     
         16 . A method for reducing the side effect of a weak acid drug, comprising the step of administering to a subject in need thereof an effective amount of a pharmaceutical composition of  claim 1 . 
     
     
         17 . The method of  claim 16 , wherein the weak acid is inhaled to reduce the side effect of the weak acid drug in the upper respiratory tract.