	US 11,731,099 B2
	Method for controlling encapsulation efficiency and burst release of water soluble molecules from nanoparticles and microparticles produced by inverse flash nanoprecipitation
Robert K. Prud'homme, Princeton, NJ (US); Robert F. Pagels, Princeton, NJ (US); and Chester E. Markwalter, Princeton, NJ (US)
Assigned to The Trustees of Princeton University, Princeton, NJ (US)
Filed by The Trustees of Princeton University, Princeton, NJ (US)
Filed on Jul. 19, 2019, as Appl. No. 16/517,510.
Claims priority of provisional application 62/700,934, filed on Jul. 20, 2018.
Prior Publication US 2020/0023332 A1, Jan. 23, 2020
Int. Cl. B01J 13/02 (2006.01); C08J 3/21 (2006.01); B01J 13/22 (2006.01); C08J 3/215 (2006.01); C08J 3/22 (2006.01); C08G 81/02 (2006.01); B01J 13/14 (2006.01); B82Y 40/00 (2011.01); B82Y 30/00 (2011.01); B82Y 35/00 (2011.01)

CPC B01J 13/025 (2013.01) [B01J 13/14 (2013.01); B01J 13/22 (2013.01); C08G 81/025 (2013.01); C08G 81/027 (2013.01); C08J 3/212 (2013.01); C08J 3/215 (2013.01); C08J 3/226 (2013.01); B82Y 30/00 (2013.01); B82Y 35/00 (2013.01); B82Y 40/00 (2013.01)]

19 Claims

1. A method of forming a polymer inverse nanoparticle that encapsulates a water soluble active to maximize or optimize encapsulation efficiency and/or to mimimize or optimize burst fraction, comprising:

dissolving the water soluble active at a concentration and a block copolymer at a concentration in an amount of a process solvent to form a process solution; and

continuously mixing the process solution with an amount of a nonprocess solvent at a process temperature to form a first nanoparticle solution comprising polymer inverse nanoparticles having a core and a shell and a first nanoparticle solvent;

adding a second block copolymer to the first nanoparticle solution to form a second stage process solution; and

continuously mixing the second stage process solution with a finishing solvent to form a second nanoparticle solution comprising the polymer inverse nanoparticles coated with the second block copolymer,

wherein the block copolymer comprises a hydrophilic block and a hydrophobic block having a glass transition temperature (Tg),

wherein the hydrophilic block is soluble in the process solvent and is insoluble in the nonprocess solvent,

wherein the hydrophobic block is insoluble in the process solvent and is soluble in the nonprocess solvent,

wherein the process solution is more polar than the nonprocess solvent,

wherein the water soluble active and the hydrophilic block are in the core and the hydrophobic block is in the shell, and

wherein the encapsulation efficiency is maximized or optimized by

(a) selecting the process solvent, so that the hydrophilic block is close to a solubility limit in the process solution for the concentration of the block copolymer, and/or

(b) crosslinking the hydrophilic block in the core, and/or

(d) selecting the hydrophobic block to have a molecular weight of at least 10 kDa, 20 kDa, 30 kDa, 40 kDa, 50 kDa, 70 kDa, or 100 kDa, and/or

(e) selecting the process temperature and/or the hydrophobic block, so that the process temperature is less than the hydrophobic block glass transition temperature (Tg), and/or

(f) selecting the process solvent to have high osmolarity, and/or

(g) adding a supplemental hydrophobic compound to the process solvent and/or to the nonprocess solvent to increase the bulk of hydrophobic material in the shell,

and/or

wherein the burst fraction is minimized or optimized by

(aa) crosslinking the hydrophilic block in the core, and/or

(bb) increasing the hydrophobic block glass transition temperature (Tg), and/or

(cc) adding the supplemental hydrophobic compound to the process solvent and/or to the nonprocess solvent to increase the bulk of hydrophobic material in the shell, and

wherein the second block copolymer comprises a second hydrophilic block and a second hydrophobic block.