Delivery of biologic therapeutics

Abstract

Formulations and methods are disclosed which provide controlled, sustained release of a biologic therapeutic to a space within the body. More specifically, formulations comprising a plurality of hydrophilic polymer strands, and methods of forming and administering such formulations, are disclosed. In some embodiments, the formulations exhibit a burst release, an initial release, a triphasic release, and release over thirty to ninety days of the biologic therapeutic. In some embodiments, the formulations exhibit reversible precipitation of the biologic therapeutic into precipitates having a diameter of about 50 nm to about 10 μm.

1 . A formulation comprising:
 (a) a biologic therapeutic; and   (b) a plurality of hydrophilic polymer strands comprising a functional group capable of inter-polymer cross-linking;   wherein said formulation, when cross-linked, forms a hydrogel that exhibits reversible precipitation of the biologic therapeutic into precipitates having a size of about 50 nm to about 10 μm in diameter, and exhibits a triphasic release profile of the biologic therapeutic;   wherein the weight ratio of the biologic therapeutic to the plurality of hydrophilic polymer strands is between 1:1 and 1:125.   
     
     
         2 . The formulation of  claim 1 , wherein the biologic therapeutic is a protein. 
     
     
         3 . The formulation of  claim 2 , wherein the protein is an antibody. 
     
     
         4 . (canceled) 
     
     
         5 . The formulation of  claim 3 , wherein the antibody is selected from the group consisting of: trastuzumab, bevacizumab, adalimumab, ranibizumab aflibercept, etanercept, rituximab, pegfilgrastim, interferon beta-1a, interfereon beta 1-a, and infliximab. 
     
     
         6 . The formulation of  claim 3 , wherein the antibody is adalimumab. 
     
     
         7 . The formulation of  claim 1 , wherein the plurality of hydrophilic polymer strands is selected from the group consisting of: polyethylene glycol (PEG); dextran; hyaluronic acid; pectin; collagen; fibrinogen; alginate; PLLA-PEG-PLLA copolymers; PLDA-PEG-PLDA copolymers, PLGA-PEG-PLGA copolymers, PEG-PLLA copolymers, PEG-PLDA copolymers and PEG-PLGA copolymers. 
     
     
         8 . The formulation of  claim 7 , wherein the plurality of hydrophilic polymer strands includes functional groups selected from the group consisting of acrylate, thiol, vinyl, amino, hydroxyl, CO—NH—NH 2 , aldehyde, vinylsulfone, succinimidyl, nitrophenolate, and hydroxysuccinimidyl. 
     
     
         9 . The formulation of  claim 8 , wherein each hydrophilic polymer strand of said plurality of hydrophilic polymer strands has a structure selected from the group consisting of: linear; branched; star; and comb. 
     
     
         10 . The formulation of  claim 9 , wherein the hydrophilic polymer strand structure is branched, star, or comb and has 2 to 16 arms. 
     
     
         11 . The formulation of  claim 10 , wherein the molecular weight of each of the hydrophilic polymer strands is between about 2 and 30 kDa. 
     
     
         12 . The formulation of  claim 11 , wherein the plurality of hydrophilic polymer strands comprises a first type of hydrophilic polymer and a second type of hydrophilic polymer. 
     
     
         13 . (canceled) 
     
     
         14 . The formulation of  claim 12 , wherein the first type of hydrophilic polymer strand has 4 or 8 or 16 arms and the second type of hydrophilic polymer strand has 4 or 8 or 16 arms. 
     
     
         15 . The formulation of  claim 14 , wherein each arm of the hydrophilic polymer strands comprises a functional group. 
     
     
         16 . The formulation of  claim 15 , wherein the ratio of the first type of hydrophilic polymer strand and the second type of hydrophilic polymer strand is between 9:10 to about 10:9. 
     
     
         17 . The formulation of  claim 15 , wherein the first type of hydrophilic polymer strand has 8 arms and the second type of hydrophilic polymer strand has 8 arms, or the first type of hydrophilic polymer strand has 16 arms and the second type of hydrophilic polymer strand has 16 arms. 
     
     
         18 . (canceled) 
     
     
         19 . (canceled) 
     
     
         20 . (canceled) 
     
     
         21 . (canceled) 
     
     
         22 . The formulation of  claim 15 , wherein the formulation is provided in lyophilized form. 
     
     
         23 . The formulation of  claim 22 , further comprising a buffer solution. 
     
     
         24 . The formulation of  claim 23 , wherein said buffer solution has a pH of about 3.5 to about 6. 
     
     
         25 . The formulation of  claim 24 , wherein the weight to volume ratio of the hydrophilic polymer strands to buffer is between about 5% and about 30%. 
     
     
         26 . (canceled) 
     
     
         27 . A kit comprising:
 (a) a formulation comprising a biologic therapeutic and a plurality of hydrophilic polymer strands; wherein the weight ratio of the biologic therapeutic to the plurality of hydrophilic polymer strands is between 1:1 and 1:125; and   (b) an activation buffer to induce cross-linking;   wherein said formulation, when cross-linked, forms a hydrogel that exhibits:   (i) a burst effect of <5% of cumulative biologic therapeutic release at 24 hours post administration to a space within the body of a patient;   (ii) an initial release of <10% of cumulative biologic therapeutic release at 7 days post administration to the space within the body of the patient;   (iii) a triphasic release profile where the rate of release post administration to a space within the body of the patient is approximately constant for a first phase of about 0-30 days, for a second phase of about 0-30 days, and for a third phase of about 0-30 days; and   (iv) a release duration of 1-3 months post administration to the space within the body of the patient for complete release of the biologic therapeutic.   
     
     
         28 . The kit of  claim 27 , further comprising a delivery device for delivery of the formulation mixed with the activation buffer, wherein the delivery device is selected from a single-bore syringe, a dual-bore syringe or a multichannel delivery device comprising a mixing head. 
     
     
         29 . A kit comprising:
 (a) a formulation comprising a biologic therapeutic and a plurality of hydrophilic polymer strands; wherein the weight ratio of the biologic therapeutic to the plurality of hydrophilic polymer strands is between 1:1 and 1:125; and   (b) an activation buffer to induce cross-linking;   wherein said formulation, when cross-linked, forms a hydrogel that exhibits reversible precipitation of the biologic therapeutic into precipitates having a size of about 50 nm to about 10 μm in diameter, and exhibits a triphasic release profile of the biologic therapeutic.   
     
     
         30 . The kit of  claim 29 , further comprising a delivery device for delivery of the formulation mixed with the activation buffer, wherein the delivery device is selected from a single-bore syringe, a dual-bore syringe or a multichannel delivery device comprising a mixing head.