Sustained release thermosetting gels comprising sodium channel blockers and the methods of making same
The present disclosure provides compositions comprising a thermosensitive hydrogel formulation of funapide and a tri-block polymer, and methods of use and manufacture of the compositions for management of acute pain or pain associated with surgical procedure.
1. A composition of funapide formulated in a PLGA-PEG-PLGA tri-block copolymer, wherein the composition comprises:
a) funapide at a concentration of 0.2 to 2% w/w;
b) a PLGA-PEG-PLGA tri-block copolymer at a concentration of 5% to 35% w/w:
(i) wherein each Poly-Lactic-co-Glycolic acid (PLGA) polymer block has a molecular weight (MW) of 400 to 2550 Da and wherein the Polyethylene Glycol (PEG) polymer block has a MW of 1000-3000 Da; and
(ii) wherein the PLGA comprises 40% to 100% of lactic acid (LA) and 60% to 0% of glycolic acid (GA);
c) a polar organic solvent at a concentration of 1% to 20% w/w; and
d) a solubility enhancer at a concentration of 1% to 20% w/w.
2. The composition of claim 1 , wherein each PLGA polymer block has a MW of 1000-2450 Da.
3. The composition of claim 1 , wherein each PLGA polymer block has a MW of 1400-2450 Da.
4. The composition of claim 1 , wherein the PEG polymer block has a MW of 1000-1600 Da.
5. The composition of claim 1 , wherein the funapide concentration is 0.2% to 1.8% w/w.
6. The composition of claim 1 , wherein the polar organic solvent concentration is 1.5% to 20% w/w.
7. The composition of claim 1 , wherein the polar organic solvent concentration is 1% to 10.5% w/w.
8. The composition of claim 1 , wherein the polar organic solvent is Dimethyl acetamide (DMA), Dimethyl sulfoxide (DMSO), Glycofurol, N-Methyl-2-Pyrrolidone (NMP), or any combination thereof.
9. The composition of claim 1 , wherein the solubility enhancer concentration is 5% to 20% w/w.
10. The composition of claim 1 , wherein the solubility enhancer concentration is 10% to 11% w/w.
11. The composition of claim 1 , wherein the solubility enhancer is Propylene Glycol (PG), Cremophor EL, Cremophor RH 60, Ethanol, Glycerin, PEG 300, PEG 400, polysorbates, Vitamin E-TPGS, PLGA-PEG diblock copolymers, hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, poloxamer 188, poloxomer 407, polyvinyl pyrrolidone (PVP), glycerol formal, Solutol HS, or any combination thereof.
12. The composition of claim 1 , wherein the PLGA comprises any one of:
a) 40% of lactic acid (LA) and 60% of glycolic acid (GA) (LA:GA ratio of 40:60);
b) 50% of lactic acid (LA) and 50% of glycolic acid (GA) (LA:GA ratio of 50:50); and
c) 100% of lactic acid (LA) and 0% of glycolic acid (GA) (LA:GA ratio of 100:0.
13. The composition of claim 1 , wherein the PLGA-PEG-PLGA tri-block copolymer concentration is 8% to 25% w/w.
14. The composition of claim 1 , wherein the total molecular weight of the total tri-block polymer system is 2500-7000 Da.
15. The composition of claim 1 , wherein the total molecular weight of the total tri-block polymer system is 4000-7000 Da.
16. The composition of claim 1 , wherein the PLGA-PEG-PLGA tri-block copolymer is any one of:
a) 1000 Da-1000 Da-1000 Da of PLGA-PEG-PLGA;
b) 1500 Da-1500 Da-1500 Da of PLGA-PEG-PLGA; and
c) 2450 Da-1500 Da-2450 Da of PLGA-PEG-PLGA.
17. The composition of claim 1 , wherein the formulation comprises:
a) funapide at a concentration of 1.3% w/w;
b) a PLGA-PEG-PLGA tri-block copolymer at a concentration of 19% to 19.5% w/w:
(i) wherein each PLGA polymer block has a MW of 1500-2250 Da, and wherein the PEG polymer block has a MW of 1500 Da; and
(ii) wherein the PLGA comprises 50% of lactic acid (LA) and 50% of glycolic acid (GA) (LA:GA ratio of 50:50);
c) DMA at a concentration of 1.7% w/w; and
d) PEG 400 at a concentration of 10.5% w/w.
18. The composition of claim 1 , wherein the formulation comprises:
a) funapide at a concentration of 0.65% w/w;
b) a PLGA-PEG-PLGA tri-block copolymer at a concentration of 19% to 19.5% w/w:
(i) wherein each PLGA polymer block has a MW of 1500-2250 Da, and wherein the PEG polymer block has a MW of 1500 Da; and
(ii) wherein the PLGA comprises 50% of lactic acid (LA) and 50% of glycolic acid (GA) (LA:GA ratio of 50:50);
c) DMA at a concentration of 1.7% w/w; and
d) PEG 400 at a concentration of 10.5% w/w.
19. The composition of claim 1 , wherein the composition has a dose volume of 5 ml to 40 ml.
20. A method of prevention or treatment for post-surgical pain in a subject in need thereof, wherein the method comprises administering an effective amount of the composition of claim 1 .
21. A method of prevention or treatment for pain in a subject in need thereof, wherein the method comprises administering an effective amount of the composition of claim 1 .
22. A method of manufacturing a composition of claim 1 , the method comprising:
i) combining and dissolving:
a) an amount of the PLGA-PEG-PLGA tri-block polymer;
b) an amount of water;
c) an amount of the funapide;
d) an amount of the polar organic solvent; and
e) an amount of the solubility enhancer;
to form a mixture;
ii) stirring the mixture of (i) at 1-30° C.;
iii) filtering the clear solution of (ii) through a sterile filter; and
iv) collecting and freezing the filtered solution of (iii) at ≤−20° C.
23. The method of claim 22 , wherein step i) comprises:
1) compounding and dissolving the amount of the PLGA-PEG-PLGA tri-block polymer of (a) in the amount of water of (b) at 1-30° C., to form a polymer solution;
2) dissolving the amount of the funapide of (c) in the amount of the polar organic solvent of (d) and the amount of the solubility enhancer of (e), in a separate vessel to form a funapide solution; and
3) combining the dissolved funapide solution of (1) with the polymer solution of (2) to form a mixture.
24. The method of claim 23 , wherein the combining of (3) is done at a temperature of 8-12° C.