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.

What is claimed is: 
     
         1 . A composition for multiphasic release of growth factors at a treatment site, the composition comprising:
 a delivery vehicle comprising at least one first growth factor; and   a carrier comprising at least one second growth factor;   wherein:   the delivery vehicle is a polymer liquid or gel that is in a flowable form to be applied on the carrier and adapted to release about 80% of the at least one first growth factor within a first time period of 72 hours; and,   the carrier consists of a plurality of particles that are adapted to release the at least one second growth factor in a sustained release profile over a second time period.   
     
     
         2 . The composition according to  claim 1 , wherein the polymer gel is formed from poloxamer 407. 
     
     
         3 . The composition according to  claim 1 , wherein the second time period comprises several days or weeks. 
     
     
         4 . The composition according to  claim 1 , wherein the at least one first growth factor and the at least one second growth factor are the same or different and at least one of the first and second growth factors is chosen from: growth factors of the transforming growth factor beta superfamily; insulin-like growth factors (IGFs); fibroblast growth factors (FGFs); platelet derived growth factors (PDGFs); and vascular endothelial growth factors (VEGFs). 
     
     
         5 . The composition according to  claim 1 , wherein the at least one first growth factor and the at least one second growth factor are, independently, BMP-2 or BMP-7. 
     
     
         6 . The composition according to  claim 1 , wherein the delivery vehicle delivers at least 10% of the total amount of the at least one first growth factor and the carrier delivers at least 50% of the total amount of the at least one second growth factor. 
     
     
         7 . The composition according to  claim 1 , wherein the plurality of particles is dispersed within a polymeric matrix. 
     
     
         8 . The composition according to  claim 7 , wherein the polymeric matrix comprises polylactic acid (PLA) or polylactic-co-glycolic acid (PLGA). 
     
     
         9 . The composition according to  claim 1 , wherein the at least one second growth factor of the carrier is provided on the surfaces of the particles or is mixed within the particles. 
     
     
         10 . The composition according to  claim 1 , wherein the at least one first growth factor comprises at least 10% of the total amount of growth factors provided in the composition and the at least one second growth factor comprises at least 50% of the total amount of growth factors provided in the composition. 
     
     
         11 . The composition according to  claim 1 , wherein the delivery vehicle comprises a reverse phase polymer. 
     
     
         12 . The composition according to  claim 1 , wherein the composition comprising the delivery vehicle and the carrier is in the form of a gel or putty when the carrier is mixed within the delivery vehicle. 
     
     
         13 . The composition according to  claim 1 , wherein the ratio of the carrier to the delivery vehicle is from 1:1 to 2:1 (v/v). 
     
     
         14 . A kit for multiphasic delivery of growth factors, the kit comprising:
 a delivery vehicle component;   at least one first growth factor associated with the delivery vehicle and adapted to be delivered by the delivery vehicle;   a carrier component; and   at least one second growth factor associated with the carrier and adapted to be delivered by the carrier;   
       wherein:
 the delivery vehicle is a polymer liquid or gel that is in a flowable form to be applied on the carrier and adapted to release about 80% of the at least one first growth factor within a first time period of 72 hours; and 
 the carrier consists of a plurality of particles that are adapted to release the at least one second growth factor in a sustained release profile over a second time period. 
 
     
     
         15 . The kit according to  claim 14 , wherein:
 the at least one first growth factor and the at least one second growth factor are the same or different and at least one of the first and second growth factors is chosen from: growth factors of the transforming growth factor beta superfamily; insulin-like growth factors (IGFs); fibroblast growth factors (FGFs); platelet derived growth factors (PDGFs); and vascular endothelial growth factors (VEGFs).   
     
     
         16 . The kit according to  claim 14 , wherein the at least one first growth factor and the at least one second growth factor are, independently, BMP-2 or BMP-7. 
     
     
         17 . The kit according to  claim 14 , wherein the plurality of particles is dispersed within a polymeric matrix. 
     
     
         18 . The kit according to  claim 14 , wherein the at least one second growth factor of the carrier is provided on the surfaces of the particles or is mixed within the particles. 
     
     
         19 . The kit according to  claim 14 , wherein the at least one first growth factor comprises at least 10% of the total amount of growth factors provided in the kit and the at least one second growth factor comprises at least 50% of the total amount of growth factors provided in the kit. 
     
     
         20 . The kit according to  claim 14 , wherein the delivery vehicle comprises a reverse phase polymer. 
     
     
         21 . The kit according to  claim 14 , wherein the delivery vehicle and the carrier are adapted to form a gel or putty when the carrier is mixed with the delivery vehicle. 
     
     
         22 . The kit according to  claim 14 , wherein the ratio of the carrier to the delivery vehicle is from 1:1 to 2:1 (v/v). 
     
     
         23 . 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 with a delivery vehicle, wherein the delivery vehicle is adapted to release about 80% of the at least one first growth factor within a first time period of 72 hours;   delivering at least one second growth factor in a sustained release profile over a second time period with a carrier, wherein the carrier consists of a plurality of particles that are adapted to release the at least one second growth factor in a sustained release profile over a second time period.   
     
     
         24 . The method according to  claim 23 , wherein the second time period comprises several days or weeks. 
     
     
         25 . The method according to  claim 23 , wherein the at least one first growth factor and the at least one second growth factor are the same or different and at least one of the first and second growth factors is chosen from: growth factors of the transforming growth factor beta superfamily; insulin-like growth factors (IGFs); fibroblast growth factors (FGFs); platelet derived growth factors (PDGFs); and vascular endothelial growth factors (VEGFs). 
     
     
         26 . The method according to  claim 23 , wherein the at least one first growth factor and the at least one second growth factor are, independently, BMP-2 or BMP-7. 
     
     
         27 . The method according to  claim 23 , wherein the delivery vehicle delivers at least 10% of the total amount of the growth factors and the carrier delivers at least 50% of the total amount of the growth factors. 
     
     
         28 . The method according to  claim 23 , wherein the carrier comprises a plurality of calcium phosphate particles. 
     
     
         29 . The method according to  claim 23 , wherein the carrier comprises a plurality of calcium phosphate particles dispersed within a polymeric matrix.