Nitric oxide releasing PLGA microspheres for biomedical applications

Patent metadata

Field	Value
Publication number	US-11439609-B2
Application number	US-201615735122-A
Country	US
Kind code	B2
Filing date	Jun 10, 2016
Priority date	Jun 11, 2015
Publication date	Sep 13, 2022
Grant date	Sep 13, 2022

Abstract

A polymeric composition includes poly(lactide-co-glycolide) (PLGA) microspheres; and at least one of a discrete RSNO adduct or a polymeric RSNO encapsulated within the microspheres, with the at least one of the discrete RSNO adduct or the polymeric RSNO adduct capable of releasing nitric oxide (NO). The polymeric composition exhibits stability under dry conditions at 37° C. and prolonged and controllable NO release rates, when exposed to light capable of photolyzing an RSNO bond, or when exposed to moisture, for a predetermined amount of time from the at least one of the discrete RSNO adduct or the polymeric RSNO adduct.

First claim

What is claimed is:

1. A polymeric composition, consisting of:
poly(lactide-co-glycolide) microspheres or poly(lactic-co-glycolic acid) microspheres; and
S-nitroso-N-acetylpenicillamine (SNAP) or a biodegradable polymer possessing an appended SNAP encapsulated within the poly(lactide-co-glycolide) microspheres or poly(lactic-co-glycolic acid) microspheres by a solid-in-oil-in-water emulsion and solvent evaporation method, wherein the SNAP or the biodegradable polymer possessing the appended SNAP is capable of spontaneously releasing nitric oxide (NO) when exposed to light capable of photolyzing an S-nitrosothiol (RSNO) bond or when exposed to moisture;
the polymeric composition to exhibit stability under dry conditions at 37° C., and prolonged and controllable NO release rates, when exposed to the light or the moisture, for a predetermined amount of time.

2. The polymeric composition as defined in claim 1 wherein the poly(lactide-co-glycolide) microspheres consist of at least one of: ester capped poly(lactide-co-glycolide) having a 50:50 ratio of lactic acid monomer to glycolic acid monomer; and acid terminated poly(lactide-co-glycolide) having a 50:50 ratio of lactic acid monomer to glycolic acid monomer.

3. The polymeric composition as defined in claim 2 wherein the polymeric composition exhibits sustained NO release under physiological conditions for an amount of time ranging from about 10 days to about 4 weeks.

4. The polymeric composition as defined in claim 1 wherein the poly(lactide-co-glycolide) microspheres or poly(lactic-co-glycolic acid) microspheres each have an average diameter ranging from about 20 μm to about 125 μm.

5. A method for making an NO-releasing polymeric composition, comprising:
encapsulating S-nitroso-N-acetylpenicillamine (SNAP) or a biodegradable polymer possessing an appended SNAP within poly(lactide-co-glycolide) microspheres or poly(lactic-co-glycolic acid) microspheres by a solid-in-oil-in-water emulsion and solvent evaporation method, wherein the SNAP or the biodegradable polymer possessing the appended SNAP is capable of spontaneously releasing nitric oxide (NO) when exposed to light capable of photolyzing an S-nitrosothiol (RSNO) bond or when exposed to moisture;
the polymeric composition to exhibit stability under dry conditions at 37° C., and prolonged and controllable NO release rates, when exposed to the light or the moisture, for a predetermined amount of time.

6. The method as defined in claim 5 wherein:
the SNAP is encapsulated in the poly(lactide-co-glycolide) microspheres; and
the poly(lactide-co-glycolide) microspheres comprise at least one of: ester capped poly(lactide-co-glycolide) having a 50:50 ratio of lactic acid monomer to glycolic acid monomer; and acid terminated poly(lactide-co-glycolide having a 50:50 ratio of lactic acid monomer to glycolic acid monomer.

7. The method as defined in claim 6 wherein the polymeric composition exhibits sustained NO release under physiological conditions for an amount of time ranging from about 10 days to about 4 weeks.

8. An NO releasing wound dressing, comprising:
a hydrogel film; and
the polymeric composition of claim 1 incorporated into the hydrogel film.

9. An NO releasing ointment, comprising:
a hydrophobic ointment; and
the polymeric composition of claim 1 dispersed within the hydrophobic ointment.

10. An NO releasing fluid, comprising:
the fluid including a vehicle, the fluid to be incorporated into a depot injection; and
the polymeric composition of claim 1 incorporated into the vehicle.

11. A method for making an NO releasing wound dressing, comprising:
dispersing the polymeric composition of claim 1 in an alginate solution to form a dispersion;
casting the dispersion into a mold; and
drying the cast dispersion to form a layer of a polymer microsphere-alginate composite film; and
crosslinking the composite film to form a hydrogel wound dressing material.

12. The polymeric composition as defined in claim 1 wherein the SNAP is encapsulated within the poly(lactide-co-glycolide) microspheres or poly(lactic-co-glycolic acid) microspheres, and wherein an amount of encapsulated SNAP ranges from about 0.3 μmol per mg microsphere to about 0.6 μmol per mg microsphere.

13. The polymeric composition as defined in claim 1 wherein the SNAP is encapsulated within the poly(lactide-co-glycolide) microspheres or poly(lactic-co-glycolic acid) microspheres.

14. The polymeric composition as defined in claim 1 wherein the biodegradable polymer possessing the appended SNAP is encapsulated within the poly(lactide-co-glycolide) microspheres or poly(lactic-co-glycolic acid) microspheres, and wherein the biodegradable polymer is selected from the group consisting of polylactide, polyglycolide (PGA), polycaprolactone, copolymers thereof, and mixtures thereof.

15. The polymeric composition as defined in claim 13 wherein the SNAP is non-dissolved, crystalline SNAP.

16. The polymeric composition as defined in claim 15 wherein a loading of the SNAP does not decrease below 90% after a one-month storage period in dark conditions at room temperature.

17. The polymeric composition as defined in claim 15 wherein a loading of the SNAP does not decrease below 70% after a one year storage period in dark conditions at 37° C.

Assignees

• Univ Michigan Regents

Inventors

• Lautner Gergely
• Schwendeman Steven P
• Meyerhoff Mark E

Classifications

• A61K9/0014

  Skin, i.e. galenical aspects of topical compositions (non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00) · CPC title

• A61L15/28

  Polysaccharides or their derivatives {(A61L15/225 takes precedence)} · CPC title

• A61K9/0024

  Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue (compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L) · CPC title

• A61K9/1647

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

• A61K47/36

  Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin · CPC title