US 2020/0268679 Al  2  Aug. 27, 2020  [0023]  The nanoparticles can include a polyethylene gly› col coating.  [0016]  The solution of the hydrophobic salt dissolved in  the organic solvent can be continuously mixed with a polar  solvent to form a mixed solution from which the nanopar› ticles assemble and precipitate.  [0015]  The dissolved water-insoluble precipitate can be  used in an organic stream to form the nanoparticles by flash  nanoprecipitation.  [0022]  The polymer can be self-assembling. The polymer  can be hydroxypropyl methylcellulose acetate succinate  (HPMCAS), polystyrene-block-polyethylene glycol (PS-b› PEG),  or  polycaprolactone-block-polyethylene  glycol  (PCL-b-PEG). For example, the polymer can be 1.6 kDa  polystyrene-block-5 kDa polyethylene glycol or 5 kDa poly› caprolactone-block-5 kDa polyethylene glycol.  [0021]  The counterion can have a log P value of 2 or  greater at a pH of 7. The counterion can have a log P value  of greater than 5. The release profile of the API can exhibit  a plateau in the release rate ( or fraction released) with time.  The counterion can have 1, 2, or more ionic sites. The  counterion can be an anionic counterion that has a pKa value  of from -2 to 5. The counterion can have a pKb value of  greater than 3. The counterion can be a quaternized cationic  species, for example, a quaternized cationic species that is  permanently cationic. The counterion can have an ionic site  selected from the group consisting of a carboxylic acid,  sulfate, sulfonate, or amine. The IP reagent can be sodium  hexanoate, sodium decanoate, sodium myristate (MA),  sodium oleate (OA), pamoic acid disodium salt (PA), ben› zenesulfonic acid monohydrate, sodium 2-naphthalenesul› fonate, (1 R)-(-)-10-camphorsulfonic acid, sodium 1,2-eth› anesulfonate,  sodium  1-heptanesulfonate,  sodium  1-octanesulfonate monohydrate, sodium 1-decanesulfonate,  sodium dodecyl sulfate (SDS), sodium dodecylbenzene sul› fonate (DBS), sodium deoxycholate, or sodium decyl sulfate  (DS). The counterion can be dodecyl hydrogen sulfate, decyl  hydrogen sulfate, dodecylbenzene sulfonic acid, or myristic  acid. The counterion can be oleic acid or pamoic acid.  [0014]  A method of the invention for encapsulating an  active pharmaceutical ingredient (API) includes producing a  hydrophobic salt by ion pairing charged functional groups  on a water soluble API with an ion pairing (IP) reagent and  forming nanoparticles that are carriers of the hydrophobic  salt to encapsulate the API, with the IP reagent including a  counterion for the APL Producing a hydrophobic salt can  include mixing the API and the IP in water to form a  water-insoluble precipitate as the hydrophobic salt, remov› ing the water, and dissolving the water-insoluble precipitate  into an organic solvent. A polymer can be dissolved into the  organic solvent. The organic solvent can be water-miscible.  [0020]  The API can be an antibacterial and/or a biologic.  The API can be an antimicrobial small molecule, a peptide,  a cationic peptide, an anionic peptide, a protein, a cationic  protein, an anionic protein, or an aminoglycoside. The API  can have an aqueous solubility of greater than 10 mg/ml, can  have a log P value less than -2 in an aqueous solution at pH  of 7, and/or can have 1, 2, 3, 4, 5, 6, or more ionic groups.  The API can be other than an oligonucleotide. The API can  be gentamycin, polymyxin B, mastoparan 7, sub5, LL37,  colistin, ecumicin, OZ439, ovalbumin, or lysozyme. The  API can be gentamycin, polymyxin B, mastoparan 7, sub5,  colistin, or ovalbumin.  [0019]  The nanoparticles can be formed by an emulsion/  stripping process.  pharmaceutical ingredient is mastoporan 7, the ion pairing  reagent is sodium dodecyl sulfate (SDS), and the nanopar› ticle encapsulation material is polycaprolactone-block-poly› ethylene glycol block copolymer. In an embodiment the  active pharmaceutical ingredient is sub5, the ion pairing  reagent is sodium dodecyl sulfate (SD S), and the nanopar› ticle encapsulation material is polycaprolactone-block-poly› ethylene glycol block copolymer. In an embodiment, the  active pharmaceutical ingredient is LL37, the ion pairing  reagent is sodium dodecyl sulfate (SDS), and the nanopar› ticle encapsulation material is polycaprolactone-block-poly› ethylene glycol block copolymer. In an embodiment, the  active pharmaceutical ingredient is colistin, the ion pairing  reagent is sodium oleate, and the nanoparticle encapsulation  material  is  polycaprolactone-block-polyethylene  glycol  block copolymer. In an embodiment, the active pharmaceu› tical ingredient is ecumicin, the ion pairing reagent is  vitamin E succinate, and the nanoparticle encapsulation  material  is  polycaprolactone-block-polyethylene  glycol  block copolymer. In an embodiment, the active pharmaceu› tical ingredient is OZ439, the ion pairing reagent is sodium  oleate, and the nanoparticle encapsulation material is  hydroxypropyl methylcellulose acetate succinate (HPM› CAS). In an embodiment, the active pharmaceutical ingre› dient is ovalbumin, the ion pairing reagent is a quaternary  ammonium surfactant, and the nanoparticle encapsulation  material  is  polycaprolactone-block-polyethylene  glycol  block copolymer. In an embodiment, the active pharmaceu› tical ingredient is ovalbumin, the ion pairing reagent is cetyl  trimethylammonium bromide, and the nanoparticle encap› sulation material is polycaprolactone-block-polyethylene  glycol block copolymer. In an embodiment, the active  pharmaceutical ingredient is lysozyme, the ion pairing  reagent is sodium oleate, and the nanoparticle encapsulation  material  is  polycaprolactone-block-polyethylene  glycol  block copolymer. In an embodiment, the active pharmaceu› tical ingredient is lysozyme, the ion pairing reagent is  sodium dodecyl sulfate (SDS), and the nanoparticle encap› sulation material is polycaprolactone-block-polyethylene  glycol block copolymer. In an embodiment, the active  pharmaceutical ingredient is lysozyme, the ion pairing  reagent is dextran sulfate (DXS) polymer, and the nanopar› ticle encapsulation material is polycaprolactone-block-poly› ethylene glycol block copolymer.  [0018]  The nanoparticles can be formed by dissolving the  API in a polar solvent to form a polar solution stream,  dissolving the IP in an organic solvent to form an organic  solution stream, and continuously mixing the polar solution  stream against the organic solution stream to form a mixed  solution from which the nanoparticles that encapsulate the  API assemble and precipitate, and the organic solvent can be  less polar than the polar solvent. A polymer can be dissolved  into the organic solvent. The organic solvent can be water› miscible.  [0017]  Producing a hydrophobic salt can include dissolv› ing the API in a water stream, dissolving the IP in an organic  stream, and forming a water-insoluble precipitate as the  hydrophobic salt through micro-mixing the organic stream  against the water stream in a Flash NanoPrecipitation (FNP)  process. A polymer can be dissolved into the organic stream.  The organic stream can be water-miscible. 