Parenteral sustained-release delivery of carvedilol disperse systems

Abstract

Carvedilol parenteral sustained release systems by IV infusion, injection, or subcutaneous routes are disclosed. Preparation of carvedilol disperse systems such as liposomes, biodegradable microparticles or nanparticles, and polymeric microparticles or nanparticles have been presented in the present invention. Compositions containing carvedilol encapsulated in liposomes showed higher bioavailability and lower clearance rate than that of the free solution after intravenous administration. In vitro release of those liposomes in buffer solutions shows drug extended release over 48 hours, and correspondingly the in vivo animal data shows that parenteral administration of carvedilol encapsulated in liposomal materials has sustained release PK profile.

What is claimed: 
     
         1 . A parenteral drug delivery composition for sustained release, comprising a non-selective β-adrenergic receptor blocker, an α-adrenergic receptor blocker, or an α-β adrenergic receptor blocker, wherein the adrenergic receptor blocker is encapsulated inside microparticles or nanoparticles. 
     
     
         2 . The composition of  claim 1 , wherein the non-selective β-, α-, or α-β adrenergic receptor blocker is carvedilol or its metabolites. 
     
     
         3 . The composition of  claim 1 , wherein the composition is a liposome formulation. 
     
     
         4 . The composition of  claim 1 , wherein the microparticles or nanoparticles are biodegradable. 
     
     
         5 . The composition of  claim 1 , wherein the microparticles or nanoparticles are polymeric. 
     
     
         6 . The composition of  claim 3 , wherein (i) the liposome formulation contains 0.001 to 10% percent (m/m) carvedilol or a pharmacologically acceptable salt thereof, (ii) the liposome formulation is in a size range of 0.02 microns to 0.9 microns in diameter, and (iii) the liposome formulation provides a longer residence time of the carvedilol in vivo, as compared to a free-carvedilol solution administered parenterally. 
     
     
         7 . The composition of  claim 6 , wherein the liposome formulation before dosing includes between about 0.01 to 90 mole percent phospholipid(s), 0.01 to 70 mole percent cholesterol, and between about 0.01 to 90 mole percent of a negatively charged phospholipid. 
     
     
         8 . The composition of  claim 6 , wherein a Z-average of a liposome mean diameter is less than 500 nm, preferably less than 300 nm, more preferably less than 200 nm, or even more preferably less than 100 nm. 
     
     
         9 . The composition of  claim 6 , wherein the liposome exhibits an in vitro release of 80% of total drug for a minimum of 2 hours, preferably an in vitro release of 80% of total drug for a minimum of 6 hours. 
     
     
         10 . The composition of  claim 4 , wherein (i) the biodegradable formulation contains 0.001 to 30.0 percent (m/m) of carvedilol or a pharmacologically acceptable salt thereof, (ii) the microparticles or nanoparticles are in the size range of 0.02 to 20 microns in diameter, and (iii) the biodegradable formulation provides a longer residence time of the carvedilol in vivo, as compared to a free-carvedilol solution administered parenterally. 
     
     
         11 . The composition of  claim 10 , wherein the biodegradable formulation includes about 0.001% to 30% m/m of carvedilol or a pharmacologically acceptable salt thereof, and the drug loading in the microparticles or nanoparticles is in the range of 0.1% to 90%, preferably 1% to 50%, and more preferably 10% to 30% (m/m). 
     
     
         12 . The composition of  claim 10 , wherein a Z-average of a mean diameter of the microparticles or nanoparticles is less than 20 micron, preferably less than 1000 nm, more preferably less than 500 nm, still more preferably less than 300 nm, even more preferably less than 200 nm, or much more preferably less than 100 nm. 
     
     
         13 . The composition of  claim 10 , wherein the microparticles or nanoparticles exhibits an in vitro release of 80% of total drug for a minimum of 2 hours, preferably an in vitro release of 80% of total drug for a minimum of 6 hours. 
     
     
         14 . The composition of  claim 5 , wherein (i) the polymeric microparticles or nanoparticles suspension contains 0.001% to 50% (m/m) carvedilol or a pharmacologically acceptable salt thereof, (ii) the polymeric microparticles or nanoparticles are in a size range of 0.02 microns to 50 microns in diameter, and (iii) the polymeric microparticles or nanoparticles provide a longer residence time of the carvedilol in vivo as compared to a free-carvedilol solution administered parenterally. 
     
     
         15 . The composition of  claim 14 , wherein the microparticles or nanoparticles contain 0.001 to 50% m/m of carvedilol, and a weight ratio of carvedilol to the polymer(s) is 1:1 to 1:100, preferably 1:20 to 1:1000, and more preferably 1:10 to 1:100. 
     
     
         16 . The composition of  claim 14 , wherein a Z-average of a mean diameter of the microparticles or nanoparticles is less than 50 micron, preferably less than 10 micron, more preferably less than 1 micron, still more preferably less than 500 nm, even more preferably less than 300 nm, much more preferably less than 200 nm, or even much more preferably less than 100 nm. 
     
     
         17 . A pharmaceutical composition for use in a parenteral drug delivery system for sustained release of carvedilol according to  claim 1 , wherein the composition being administered is for treating mild to severe congestive heart failure (CHF), left ventricular dysfunction (LVD) following heart attack in human or animals who are otherwise stable, and for treating high blood pressure for human or animals under emergence and intense care or who cannot swallow an oral dosage form.