Granted Patent
B2
US 12,357,582 · App. 16/761,140 · Granted Jul 15, 2025
Hydrophobic ion pairing and flash nanoprecipitation for formation of controlled-release nanocarrier formulations
Inventors:
Robert K. Prud'homme (Princeton, NJ); Kurt D. Ristroph (Princeton, NJ); Nathalie M. Pinkerton (Princeton, NJ); Hoang D. Lu (Princeton, NJ); Paradorn Rummaneethorn (Princeton, NJ)
Assignee:
The Trustees of Princeton University
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Abstract
Methods for encapsulating water-soluble biologic and small molecule active pharmaceutical ingredients (APIs) into nanoparticles by applying nanoprecipitation techniques and ion-pairing the nanoparticles with hydrophobic counterions to produce new API salts that exhibit altered solubilities are presented.
Claims (42)
1. A set of nanoparticles, comprising:
nanoparticles comprising
a modified salt comprising an active pharmaceutical ingredient (API) ion paired with a hydrophobic counterion; and
a nanoparticle encapsulant material substantially surrounding the modified salt,
wherein the nanoparticle encapsulant material comprises polycaprolactone-block-polyethylene glycol block copolymer (PCL-b-PEG),
wherein the active pharmaceutical ingredient (API) is a water-soluble linear cationic peptide of a molecular weight of from 1,422 Da to 2,000 Da and of at least 14% basic amino acids of amino acids,
wherein the hydrophobic counterion is an alkyl sulfate, and
wherein the set of nanoparticles has a Z-average diameter of at least 120 nm.
2. The set of nanoparticles according to claim 1 , wherein the API is selected from the group consisting of mastoparan 7 (amino acid sequence INLKALAALAKALL-NH 2 [SEQ ID NO: 1), Sub5 (amino acid sequence RRWKIVVIRWRR-NH 2 [SEQ ID NO: 2]), LL37 (amino acid sequence FKRIVQRIKDFLR [SEQ ID NO: 3]), and combinations thereof.
3. The set of nanoparticles according to claim 1 , wherein the hydrophobic counterion has a logP value of greater than 5 at a pH of 7 and wherein the release profile of the API displays a plateau in the release rate with time.
4. The set of nanoparticles according to claim 1 , wherein the hydrophobic counterion is selected from the group consisting of dodecyl sulfate, decyl sulfate and combinations thereof.
5. The set of nanoparticles according to claim 1 ,
wherein the API is selected from the group consisting of mastoparan 7 (amino acid sequence INLKALAALAKALL-NH 2 [SEQ ID NO: 1), Sub5 (amino acid sequence RRWKIVVIRWRR-NH 2 [SEQ ID NO: 2]), LL37 (amino acid sequence FKRIVQRIKDFLR [SEQ ID NO: 3]), and combinations thereof, and
wherein the hydrophobic counterion is dodecyl sulfate.
6. The set of nanoparticles according to claim 1 , wherein the API is mastoparan 7 (amino acid sequence INLKALAALAKALL-NH 2 [SEQ ID NO: 1]).
7. The set of nanoparticles according to claim 1 , wherein the API is Sub5 (amino acid sequence RRWKIVVIRWRR-NH 2 [SEQ ID NO: 2]).
8. The set of nanoparticles according to claim 1 , wherein the API is LL37 (amino acid sequence FKRIVQRIKDFLR [SEQ ID NO: 3]).
9. The set of nanoparticles according to claim 1 , wherein the hydrophobic counterion is dodecyl sulfate.
10. The set of nanoparticles according to claim 1 , wherein the hydrophobic counterion is decyl sulfate.
11. A method for producing the set of nanoparticles according to claim 1 , comprising:
providing the active pharmaceutical ingredient (API),
providing an ion-pairing (IP) reagent which comprises a hydrophobic counterion wherein said hydrophobic counter-ion is an alkyl sulfate,
mixing the API and IP reagent in water to from a water-insoluble precipitate of the API and hydrophobic counterion;
removing the water;
dissolving the water-insoluble precipitate into an organic solvent to form an organic solution comprising the API and hydrophobic counterion together;
combining the organic solution comprising the API and hydrophobic counterion together with polycaprolactone-block-polyethylene glycol (PCL-b-PEG); and
combining the organic solution comprising the API, the hydrophobic counterion, and the PCL-b-PEG with a polar solvent to form nanoparticles via precipitation.
12. The method according to claim 11 , wherein
the polar solvent is water.
13. The method according to claim 12 , wherein the combining of the organic solution comprising the API, the hydrophobic counterion, and the PCL-b-PEG with water as the polar solvent is by continuous mixing.
14. A method for producing the set of nanoparticles according to claim 1 , comprising:
providing the active pharmaceutical ingredient (API);
providing an ion-pairing (IP) reagent which comprises a hydrophobic counterion wherein the hydrophobic counterion is an alkyl sulfate;
dissolving the API in a polar solvent to form a polar solution comprising the API;
dissolving the IP reagent and polycaprolactone-block-polyethylene glycol (PCL-b-PEG) in an organic solvent to form an organic solution comprising the hydrophobic counterion and the PCL-b-PEG; and
combining the polar solution comprising the API with the organic solution comprising the hydrophobic counterion and the PCL-b-PEG to form the nanoparticles via precipitation.
15. The method according to claim 14 ,
wherein the combining of the polar solution comprising the API with the organic solution comprising the hydrophobic counterion and the PCL-b-PEG is by continuous mixing and
wherein the organic solvent is less polar than the polar solvent.
16. The method according to claim 15 ,
wherein the organic solvent is water-miscible and
wherein the polar solvent is water.
Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded May 28, 2020
From: PRUD'HOMME, ROBERT K.; RISTROPH, KURT D.; PINKERTON, NATHALIE M.; LU, HOANG D.; RUMMANEETHORN, PARADORN
To: THE TRUSTEES OF PRINCETON UNIVERSITY
Reel/Frame 052770/0507 →
Continuity (2)
Provisional Application
62581394
· Nov 3, 2017
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