System and Method for Multiphasic Release of Growth Factors

Abstract

A system for multiphasic delivery of at least one growth factor at a treatment site comprises a delivery vehicle for releasing at least one growth factor in an initial release profile and a carrier for releasing at least one growth factor in a sustained release profile. The initial release profile releases at least one growth factor over a period of hours to days, wherein the growth factor is released in a large amount initially, with the remainder being released in progressively lower amounts. The sustained release profile releases at least one growth factor over a period of days to weeks, wherein the growth factor is released at a generally constant amount over such period. The system of the invention is particularly suited for applications on bioimplants. The invention also comprises methods and kits for multiphasic delivery of at least one growth factor. The invention also comprises calcium sulphate as a carrier for releasing at least one growth factor in both single and multiphasic systems for delivering at least one growth factor at a treatment site.

We claim: 
     
         1 . A system for multiphasic release of growth factors at a treatment site, the system comprising:
 a) a delivery vehicle comprising at least one first growth factor, the delivery vehicle being adapted to release the at least one first growth factor in an initial release profile over a first time period; and,   b) a carrier comprising a plurality of particles having at least one second growth factor on the surfaces thereof, the carrier being adapted to release the at least one second growth factor over a second time period, wherein the second time period is of a longer duration than the first time period, and wherein the carrier comprises calcium sulphate dihydrate particles.   
     
     
         2 . The system according to  1 , wherein the carrier further comprises calcium phosphate particles. 
     
     
         3 . The system according to  1 , wherein the delivery vehicle comprises a polymer. 
     
     
         4 . The system according to  3 , wherein the polymer is poloxamer 407. 
     
     
         5 . The system according to  3 , wherein the particles of the carrier are dispersed within the delivery vehicle. 
     
     
         6 . The system according to  1 , wherein the first time period ranges from hours to days and wherein the second time period ranges from days to weeks. 
     
     
         7 . The system according to  1 , wherein the carrier releases the at least one second growth factor in a sustained release profile over the second time period. 
     
     
         8 . The system according to  claim 1 , wherein the first and second growth factors are bone morphogenetic protein 2, BMP-2. 
     
     
         9 . The system according to  claim 1 , wherein the delivery vehicle is adapted to release at least about 10% of the total amount of the growth factor during the first time period and the carrier is adapted to release at least about 50% of the total amount of the growth factor during the second time period. 
     
     
         10 . The system according to 1, wherein the delivery vehicle to carrier ratio is from about 0.5:1 to about 4:1 (v/v). 
     
     
         11 . A method of multiphasic release of growth factors, the method comprising:
 delivering at least one first growth factor in an initial release profile over a first time period by means of a delivery vehicle; and,   delivering at least one second growth factor over a second time period by means of a carrier, the second time period being of a longer duration than the first time period;   wherein the carrier comprises a plurality of particles having the at least one second growth factor on the surfaces thereof, and wherein the carrier comprises calcium sulphate dihydrate particles or a mixture of calcium sulphate dihydrate particles and calcium phosphate particles.   
     
     
         12 . The method according to  claim 11 , wherein the particles of the carrier are dispersed within the delivery vehicle. 
     
     
         13 . The method according to  claim 11 , wherein the delivery vehicle comprises a polymer and wherein the polymer is poloxamer 407. 
     
     
         14 . The method according to  claim 11 , wherein one or more of the first and second growth factors is bone morphogenetic protein 2, BMP-2. 
     
     
         15 . The method according to  claim 11 , wherein the first time period ranges from hours to days and wherein the second time period ranges from days to weeks. 
     
     
         16 . The method according to  claim 11 , wherein the carrier releases the at least one second growth factor in a sustained release profile over the second time period. 
     
     
         17 . The method according to  claim 11 , wherein the at least one first growth factor and the at least one second growth factor are the same and wherein at least about 10% of the total amount of the growth factor is released during the first time period and at least about 50% of the total amount of the growth factor is released during the second time period. 
     
     
         18 . A method of forming the system according to  claim 1 , the method comprising:
 providing a solution comprising the at least one growth factor;   applying the solution to the surfaces of the carrier particles;   lyophilizing the at least one growth factor onto the carrier particles to result in: (i) carrier particles having provided thereon the at least one growth factor; and, (ii) free powder comprising the at least one growth factor;   adding the delivery vehicle in the form of a polymer gel, whereby the free powder comprising the at least one growth factor is incorporated into the delivery vehicle.   
     
     
         19 . The method according to  claim 18 , wherein the growth factor is bone morphogenetic protein 2, BMP-2. 
     
     
         20 . The method according to  claim 18 , wherein the polymer gel is poloxamer 407.