Aug. 27, 2020  1  US 2020/0268679 Al  HYDROPHOBIC ION PAIRING AND FLASH  NANOPRECIPITATION FOR FORMATION  OF CONTROLLED-RELEASE  NANOCARRIER FORMULATIONS  [0001]  This International Application claims the benefit of  the filing date of U.S. Provisional Application 62/581,394,  filed Nov. 3, 2017, which is incorporated by reference in its  entirety herein.  [0002]  This invention was made with government support  under Grant No. GM-066134 awarded by the National  Institutes of Health and Grant No. CNS-0612345 awarded  by the National Science Foundation. The government has  certain rights in the invention.  [0003]  Sequestration of active pharmaceutical ingredients  (APis) into drug carriers has been considered for producing  formulations with biological efficacy.  [0004]  In an embodiment of the invention, a nanoparticle  includes a modified salt including a water-soluble active  pharmaceutical ingredient (API) ion paired with a hydro› phobic counterion of an ion pairing (IP) reagent and a  nanoparticle encapsulant material substantially surrounding  the modified salt. The API can be an antibacterial and/or a  biologic. The API can be an antimicrobial small molecule, a  peptide, a protein, or an aminoglycoside. The API can have  an aqueous solubility of greater than 10 mg/ml, a log P value  less than -2 in an aqueous solution at pH of 7, and/or 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.  [0005]  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, and the release profile of the API can  exhibit a plateau in the release rate 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 quatemized cationic species. The coun› terion 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,  benzenesulfonic acid monohydrate, sodium 2-naphthalene› sulfonate, (lR)-(-)-10-camphorsulfonic acid, sodium 1,2- ethanesulfonate, sodium 1-heptanesulfonate, sodium 1-oc› tanesulfonate monohydrate, sodium 1-decanesulfonate, or  sodium deoxycholate. The IP reagent can be sodium dodecyl  sulfate (SDS), sodium decyl sulfate (DS), sodium dodecyl› benzene sulfonate (DBS), sodium myristate (MA), sodium  oleate (OA), or pamoic acid disodium salt (PA). The coun› terion can be dodecyl hydrogen sulfate, decyl hydrogen  sulfate, dodecylbenzene sulfonic acid, or myristic acid. The  counterion can be oleic acid or pamoic acid.  [0006]  The nanoparticle encapsulant material can be a  self-assembling material. The nanoparticle encapsulant  material can be hydroxypropyl methylcellulose acetate suc› cinate (HPMCAS), polystyrene-block-polyethylene glycol  (PS-b-PEG), or polycaprolactone-block-polyethylene glycol  (PCL-b-PEG). For example, the nanoparticle encapsulant  material can be 1.6 kDa polystyrene-block-5 kDa polyeth› ylene glycol or 5 kDa polycaprolactone-block-5 kDa poly› ethylene glycol.  [0007]  The nanoparticle can include a polyethylene glycol  coating on the nanoparticle.  [0008]  The nanoparticle can have a particle size of from  10 nm to 1000 nm, from 10 nm to 1200 nm, from 25 nm to  1000 nm, from 50 nm to 500 nm, from 75 nm to 400 nm,  from 100 nm to 350 nm, from 100 nm to 250 nm, or from  100 nm to 150 nm.  [0009]  The API and a supplemental hydrophobic com› pound can be co-encapsulated within the nanoparticle. For  example, the supplemental hydrophobic compound can be a  therapeutic, imaging agent, or agrochemical compound.  [0010]  The API can include gentamycin, polymyxin B,  mastoporan 7, sub5, LL37, colistin, ecumicin, OZ439, oval› bumin, or lysozyme. The API can include an antimicrobial  small molecule, for example, an antimicrobial small mol› ecule having a molecular weight of less than 1000 Da. The  API can include an aminoglycoside, for example, a 4,6- disubstituted deoxystreptamine trisaccharide. The API can  include an oligopeptide, such as a linear oligopeptide or a  cyclic oligopeptide, which can have a molecular weight of  from 1000 Da to 2000 Da. The API can include a protein,  such as an anionic protein or a cationic protein, which can  have a molecular weight of greater than 2000 Da.  [0011]  The IP reagent can include sodium dodecyl sulfate  (SDS), sodium decyl sulfate (DS), sodium dodecylbenzene  sulfonate (DBS), sodium myristate (MA), sodium oleate  (OA), pamoic acid disodium salt (PA), vitamin E succinate,  or sodium dextran sulfate (DXS). The counterion can  include dodecyl hydrogen sulfate, decyl hydrogen sulfate,  dodecylbenzene sulfonic acid, myristic acid, oleic acid,  pamoic acid, vitamin E succinic acid, or dextran hydrogen  sulfate, or a salt, such as an alkali metal ( e.g., lithium (Li),  sodium (Na), potassium (K), rubidium (Rb), or caesium  (Cs)) salt, of any of these. The counterion can include a fatty  acid, an alkyl hydrogen sulfate, an alkylsulfonic acid, an  alkyl quaternary ammonium cation, or a salt, such as an  alkali metal salt, of any of these.  BACKGROUND OF THE INVENTION  SUMMARY OF THE INVENTION  [0012]  The nanoparticle encapsulant material can include  hydroxypropyl methylcellulose acetate succinate (HPM› CAS), polystyrene-block-polyethylene glycol (PS-b-PEG),  or polycaprolactone-block-polyethylene glycol (PCL-b› PEG). The nanoparticle encapsulant material can include a  block copolymer, such as an amphiphilic block copolymer,  which can have a molecular weight of about 10 kDa or less.  [0013]  In an embodiment the active pharmaceutical ingre› dient is gentamycin, the ion pairing reagent is sodium  dodecyl sulfate (SDS), and the nanoparticle encapsulation  material  is  polycaprolactone-block-polyethylene  glycol  block copolymer. In an embodiment the active pharmaceu› tical ingredient is polymyxin B, 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 polymyxin B, the ion pairing  reagent is sodium dodecylbenzene sulfonate (DBS), and the  nanoparticle encapsulation material is polycaprolactone› block-polyethylene glycol block copolymer. In an embodi› ment the active pharmaceutical ingredient is polymyxin B,  the ion pairing reagent is sodium oleate, and the nanoparticle  encapsulation material is polycaprolactone-block-polyethyl› ene glycol block copolymer. In an embodiment, the active 