Cellulosic polymer nanoparticles and methods of forming them

Patent metadata

Field	Value
Publication number	US-11737981-B2
Application number	US-202016816241-A
Country	US
Kind code	B2
Filing date	Mar 11, 2020
Priority date	Sep 12, 2017
Publication date	Aug 29, 2023
Grant date	Aug 29, 2023

Abstract

Nanoparticles including a cellulosic polymer and a hydrophobic material and methods for forming them.

First claim

The invention claimed is:

1. A nanoparticle comprising
a cellulosic polymer substituted with hydrophilic groups; and
a hydrophobic material,
wherein the cellulosic polymer has a molecular weight from 10,000 to 2,000,000 g/mol and,
wherein the nanoparticle has a size from 10 nm to 5000 nm,
wherein the cellulosic polymer comprises a hydroxypropyl substitution level of from 5 to 10% wt, a methoxyl substitution level of from 20 to 26% wt, an acetyl substitution level of from 5 to 14% wt or from 10 to 14% wt, and a succinyl substitution level of from 4 to 18% wt or from 4 to 8% wt, and
wherein the cellulosic polymer is a surface stabilizer around a core formed by the hydrophobic material.

2. The nanoparticle of claim 1 , wherein the nanoparticle size does not change by more than 50% over 4 hours in aqueous solution.

3. The nanoparticle of claim 1 , wherein the hydrophobic material has a molecular weight of from 800 to 5000 g/mol.

4. The nanoparticle of claim 1 , wherein the hydrophobic material has a solubility in water of from 0.001 to 2 mg/L and a log P of from 7.5 to 12.

5. The nanoparticle of claim 1 , wherein the hydrophobic material is selected from the group consisting of clofazimine, lumefantrine, cyclosporine A, artefenomel, artefenomel mesylate, and combinations.

6. A dispersion of nanoparticles of claim 1 , wherein the dispersion is not an emulsion.

7. A process for forming a nanoparticle, comprising
dissolving a cellulosic polymer substituted with hydrophilic groups and a hydrophobic material in a less polar solvent to form a process solution, and
combining the process solution with a more polar solvent to rapidly precipitate the nanoparticle,
wherein the formed nanoparticle comprises the cellulosic polymer and the hydrophobic material,
wherein the cellulosic polymer is a surface stabilizer around a core formed by the hydrophobic material,
wherein the cellulosic polymer comprises a hydroxypropyl substitution level of from 5 to 10% wt, a methoxyl substitution level of from 20 to 26% wt, an acetyl substitution level of from 5 to 14% wt or from 10 to 14% wt, and a succinyl substitution level of from 4 to 18% wt or from 4 to 8% wt, and
wherein the cellulosic polymer has a molecular weight of from 10,000 to 2,000,000 g/mol.

8. The process of claim 7 ,
wherein the cellulosic polymer comprises a hydroxypropyl substitution level of from 5 to 10% wt, a methoxyl substitution level of from 20 to 26% wt, an acetyl substitution level of from 5 to 14% wt or from 10 to 14% wt, and a succinyl substitution level of from 4 to 18% wt or from 4 to 8% wt, and
wherein the cellulosic polymer has a molecular weight of from 20,000 to 2,000,000 g/mol.

9. The process of claim 8 ,
wherein the nanoparticle comprises an exterior hydrophilic shell,
wherein the exterior hydrophilic shell comprises the cellulosic polymer,
wherein the exterior hydrophilic shell surrounds the hydrophobic material.

10. The process of any one of claim 8 ,
wherein the process solution is in a process stream,
wherein the more polar solvent is in a more polar solvent stream,
wherein the process stream is continuously combined with the more polar solvent stream in a confined mixing volume, and
wherein the formed nanoparticle exits the confined mixing volume in an exit stream.

11. The process of claim 8 ,
wherein the less polar solvent is selected from the group consisting of acetone, an alcohol, methanol, ethanol, tetrahydrofuran, and combinations and
wherein the more polar solvent is water, an alcohol, or a water/alcohol combination.

12. The process of claim 8 , further comprising
combining the formed nanoparticle with a water-soluble cellulosic polymer of hydroxypropyl and/or methyl substitution to form a further mixture, and
spray drying the further mixture to form a powder.

13. The process of claim 12 , wherein the formed nanoparticle in the powder can be redispersed to within 20%, 30%, 50%, or 100% of its original size.

14. A process for forming a nanoparticle, comprising
dissolving a hydrophobic material in an organic solvent to form an organic solution,
dissolving a cellulosic polymer substituted with hydrophilic groups in an aqueous solvent to form an aqueous solution,
emulsifying the organic solution with the aqueous solution to form an emulsion, and
removing the organic solvent from the emulsion to form the nanoparticle by emulsion stripping,
wherein the formed nanoparticle comprises the cellulosic polymer as a surface stabilizer around a core formed by the hydrophobic material,
wherein the cellulosic polymer comprises a hydroxypropyl substitution level of from 5 to 10% wt, a methoxyl substitution level of from 20 to 26% wt, an acetyl substitution level of from 5 to 14% wt or from 10 to 14% wt, and a succinyl substitution level of from 4 to 18% wt or from 4 to 8% wt, and
wherein the cellulosic polymer has a molecular weight of from 10,000 to 2,000,000 g/mol.

15. The process of claim 14 , further comprising
prior to dissolving the hydrophobic material in the organic solvent to form the organic solution, dissolving a block copolymer and a hydrophilic molecule in a preliminary polar solvent to form a preliminary polar solution, and
combining the preliminary polar solution with a preliminary less polar solvent to rapidly form a hydrophobic nanoparticle and a preliminary nanoparticle solvent,
wherein the hydrophobic nanoparticle is the hydrophobic material,
wherein the block copolymer comprises a hydrophobic block and a hydrophilic block,
wherein the hydrophobic nanoparticle comprises a surface that is hydrophobic,
wherein a hydrophilic core of the hydrophobic nanoparticle comprises the hydrophilic block,
wherein the hydrophilic core comprises the hydrophilic molecule,
wherein a preliminary nanoparticle solution comprises the hydrophobic nanoparticle and the preliminary nanoparticle solvent, and
wherein the preliminary less polar solvent is less polar than the preliminary polar solvent.

16. The process of claim 15 , wherein the block copolymer comprises a triblock copolymer of a hydrophobic center block and two hydrophilic outer blocks.

17. The process of claim 15 ,
wherein the hydrophobic block is selected from the group consisting of poly(lactic acid), poly(lactic-co-glycolic acid), poly(caprolactone), and combinations and
wherein the hydrophilic block is selected from the group consisting of poly(aspartic acid), poly(glutamic acid), and combinations.

18. The process of claim 15 , wherein the block copolymer comprises poly(aspartic acid)-b-poly(lactic acid)-b-poly(aspartic acid).

19. The process of claim 15 ,
wherein the preliminary polar solvent is selected from the group consisting of water, dimethyl sulfoxide (DMSO), and combinations and
wherein the preliminary less polar solvent is selected from the group consisting of dichloromethane, chloroform, and combinations.

20. The process of claim 15 , further comprising adding a crosslinking agent to the preliminary nanoparticle solution to crosslink the hydrophilic block in the hydrophilic core.

21. The process of claim 15 , further comprising exchanging the preliminary nanoparticle solvent with the less polar solvent.

22. The process of claim 15 , wherein the hydrophilic molecule is of a molecular weight ranging from 100 g/mol to 40,000 g/mol, from 200 g/mol to 1500 g/mol, from 1000 g/mol to 40,000 g/mol, from 5000 g/mol to 40,000 g/mol, or from 5000 g/mol to 25,000 g/mol.

23. Th

Assignees

• Univ Princeton

Inventors

• Prud'Homme Robert K
• Feng Jie
• Ristroph Kurt D
• Lu Hoang (Jack)
• Zhang Yingyue
• Mcmanus Simon A
• Pagels Robert F

Classifications

• A61K9/167 Primary

  with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface (with further drug-free outer coating A61K9/5073) · CPC title

• A61K9/1652

  Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin (homeopathic globules A61K9/1623) · CPC title

• A61K31/135

  having aromatic rings {, e.g. ketamine, nortriptyline (methadone A61K31/137)} · CPC title

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title

• A61K31/498

  Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine · CPC title