Shear-thinning self-healing networks

Patent metadata

Field	Value
Publication number	US-11517538-B2
Application number	US-202117342368-A
Country	US
Kind code	B2
Filing date	Jun 8, 2021
Priority date	Sep 24, 2014
Publication date	Dec 6, 2022
Grant date	Dec 6, 2022

Abstract

Network materials which exhibit both shear thinning and self-healing properties are disclosed. The networks contain particles and gel-forming compounds. The networks are useful for a variety of biomedical uses, including drug delivery.

First claim

We claim:

1. A method for treating a patient in need thereof, the method comprising administering to the patient a shear-thinning injectable hydrogel comprising:
one or more therapeutic, prophylactic or diagnostic agents,
one or more biocompatible gel-forming polymers selected from the group consisting of polysaccharides and proteins, optionally modified with one or more ester, carbonate, amide, carbamate, urea, ether or amine-linked capping groups, and
nanoparticles having a diameter between 10 nm and 1000 nm formed of one or more biocompatible amphiphilic polymers comprising one or more hydrophobic polymers selected from the group consisting of polyanhydrides, poly(ortho)esters, polyesters, polyurethanes, and copolymers comprising the monomers of these polymers and one or more hydrophilic polymers selected from the group consisting of polysaccharides, proteins polyamino acids, polyalkylene oxides,
optionally including an electrostatic charge enhancing agent,
wherein the nanoparticles are non-covalently bound to multiple biocompatible gel-forming polymers to form the shear-thinning injectable hydrogel comprising between about 1 and 15 wt % nanoparticles in the shear-thinning injectable hydrogel,
the hydrogel comprising one or more therapeutic, prophylactic or diagnostic agents encapsulated within the nanoparticles, associated with the surface of the particles and/or dispersed through the hydrogel,
wherein the dynamic shear viscosity of the shear-thinning injectable hydrogel at a shear rate within the range between 0.1 s −1 and 100 s −1 , inclusive, is greater than the sum of the dynamic shear viscosity of a suspension of the nanoparticles and a solution of the one or more biocompatible gel-forming polymers at the shear rate within the range between 0.1 s −1 and 100 s −1 , inclusive.

2. The method of claim 1 , wherein the dynamic shear viscosity of the shear-thinning injectable hydrogel at a shear rate within the range between 0.1 s −1 and 100 s −1 is a multiplicative factor of between 2 and 100,000 times, inclusive, greater than the sum of the dynamic shear viscosity of the suspension of nanoparticles and the solution of the one or more biocompatible gel-forming polymers at the shear rate within the range between 0.1 s −1 and 100 s −1 , inclusive.

3. The method of claim 2 , wherein the dynamic shear viscosity of the hydrogel at a shear rate within the range between 0.1 s −1 and 100 s −1 is a multiplicative factor of between 2 and 1,000 times, inclusive, greater than the sum of the dynamic shear viscosity of the suspension of nanoparticles and the solution of the one or more biocompatible gel-forming polymers at the shear rate within the range between 0.1 s −1 and 100 s −1 , inclusive.

4. The method of claim 3 , wherein the dynamic shear viscosity of the hydrogel at a shear rate within the range between 0.1 s −1 and 100 s −1 is a multiplicative factor of between 10 and 1000 times, inclusive, greater than the sum of the dynamic shear viscosity of the suspension of nanoparticles and the solution of the one or more biocompatible gel-forming polymers at the shear rate within the range between 0.1 s −1 and 100 s −1 , inclusive.

5. The method of claim 4 , wherein the dynamic shear viscosity of the shear-thinning injectable hydrogel at a shear rate within the range between 0.1 s −1 and 100 s −1 is a multiplicative factor of between 100 and 1000 times, inclusive, greater than the sum of the dynamic shear viscosity of the suspension of nanoparticles and the solution of the one or more biocompatible gel-forming polymers at the shear rate within the range between 0.1 s −1 and 100 s −1 , inclusive.

6. The method of claim 1 , wherein at least one of the one or more biocompatible gel-forming polymers is a polysaccharide selected from the group consisting of celluloses, hyaluronic acids, dextrans, xanthans and combinations thereof.

7. The method of claim 6 , wherein the polysaccharide is a cellulose or a modified cellulose.

8. The method of claim 7 , wherein the cellulose is hydroxypropyl methylcellulose or carboxymethyl cellulose.

9. The method of claim 1 , wherein the one or more biocompatible gel-forming polymers are modified with one or more ester, carbonate, amide, carbamate, urea, ether or amine-linked capping groups.

10. The method of claim 9 , wherein the one or more capping groups are selected from the group consisting of C 1 -C 20 alkyl groups, C 3 -C 18 cycloalkyl groups, and C 6 -C 18 aryl, wherein any of the C 1 -C 20 alkyl groups, C 3 -C 18 cycloalkyl groups, and C 6 -C 18 aryl groups may be unsubstituted or substituted one or more times.

11. The method of claim 1 , wherein the one or more biocompatible gel-forming polymers are at a concentration of between about 0.1 wt. % and about 10 wt. % prior to mixing with the nanoparticles.

12. The method of claim 1 , wherein the one or more biocompatible amphiphilic polymers comprise one or more hydrophobic polymers selected from the group consisting of polymers of lactic acid and glycolic acid, poly(butic acid), poly(valeric acid), poly(caprolactone), poly(hydroxybutyrate), poly(ethylene-co-maleic anhydride), poly(ethylene maleic anhydride-co-L-dopamine), poly(ethylene maleic anhydride-co-phenylalanine), poly(ethylene maleic anhydride-co-tyrosine), poly(butadiene-co-maleic anhydride), poly(butadiene maleic anhydride-co-L-dopamine), poly(butadiene maleic anhydride-co-phenylalanine), poly(butadiene maleic anhydride-co-tyrosine), and copolymers comprising the monomers of these polymers.

13. The method of claim 1 , wherein the nanoparticles comprise a core-shell nanoparticle.

14. The method of claim 1 , wherein the one or more biocompatible amphiphilic polymers are a poly(alkylene oxide)-block-(polyester).

15. The method of claim 1 , wherein the one or more biocompatible amphiphilic polymers are a poly(ethylene glycol)-block-poly(lactic acid).

16. The method of claim 1 , wherein the one or more biocompatible gel-forming polymers are charged at physiological conditions.

17. The method of claim 1 , wherein the one or more biocompatible gel-forming polymers are selected from the group consisting of hyaluronic acid, xanthan, and guar.

18. The method of claim 17 , wherein at least one of the one or more biocompatible gel-forming polymers is hyaluronic acid.

19. The method of claim 1 , wherein the one or more biocompatible gel-forming polymers are selected from the group consisting of aminopolysaccharides and positively charged proteins.

20. The method of claim 1 , further comprising an ionic surfactant.

21. The method of claim 20 , wherein the ionic surfactant is a cationic surfactant when the one or more biocompatible gel-forming polymers are negatively charged at physiological conditions.

22. The method of claim 21 , wherein the cationic surfactant is selected from the group consisting of cetyltrimethylammonium bromide, cetyltrimethylammonium iodide, cetyltrimethylammonium fluoride, and cetyltrimethylammonium chloride.

23. The method of claim 22 , wherein the cationic surfactant is cetyltrimethylammonium bromide.

24. The method of claim 20 , wherein the ionic surfactant is an anionic surfactant when the one or more biocompatible gel-forming polymers are positively charged at physiological conditions.

25. The method of claim 24 , wherein the anionic surfactant is selected from the group consisting of sodium dodecyl sulfate, sodium stearate, and charged fatty acid surfactan

Assignees

• Massachusetts Inst Technology

Inventors

• Appel Eric A
• Tibbitt Mark W
• Langer Robert S

Classifications

• A61K47/34

  Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers (A61K47/10 takes precedence) · CPC title

• A61K9/06 Primary

  Ointments; Bases therefor; {Other semi-solid forms, e.g. creams, sticks, gels (composition of ointments, creams or gels A61K47/00)} · CPC title

• A61K47/38

  Cellulose; Derivatives thereof · CPC title

• A61K9/5153

  Polyesters, e.g. poly(lactide-co-glycolide) · CPC title

• A61K9/5146

  obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides · CPC title