Compositions and methods utilizing poly(vinyl alcohol) and/or other polymers that aid particle transport in mucus

• US 10,688,041 B2
• Filed: 05/03/2013
• Issued: 06/23/2020
• Est. Priority Date: 05/03/2012
• Status: Active Grant

• Current Assignee: Alcon Incorporated
• Original Assignee: Kala Pharmaceuticals, Inc.
• Inventors: Popov, Alexey
• Primary Examiner(s): Sasan, Aradhana
• Assistant Examiner(s): Truong, Quanglong N
• Application Number:
  US13/886,514
• Publication Number:
  US 20130316009A1
• Time in Patent Office: 2,608 Days
• CPC Class Codes: A61K 31/56 Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 47/32 Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers , poly(meth)acrylates, or polyvinyl pyrrolidone
• CPC Class Codes: A61K 9/0012 Galenical forms characterised by the site of application
• CPC Class Codes: A61K 9/10 Dispersions; Emulsions A61K9/06 takes precedence; composition of dispersions, emulsions A61K47/00
• CPC Class Codes: A61K 9/5026 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/5138 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Abstract

Particles, compositions, and methods that aid particle transport in mucus are provided. The compositions and methods may include, in some embodiments, modifying the surface coatings of particles including pharmaceutical agents that have a low water/aqueous solubility. In some embodiments, a surface coating includes a synthetic polymer having pendant hydroxyl groups on the backbone of the polymer, such as poly(vinyl alcohol) (PVA). Such compositions and methods can be used to achieve efficient transport of particles of pharmaceutical agents though mucus barriers in the body for a wide spectrum of applications, including drug delivery, imaging, and diagnostic applications. In certain embodiments, a pharmaceutical composition including such particles is well-suited for administration routes involving the particles passing through a mucosal barrier.

Claims

1. An ophthalmic composition comprising:

(a) a plurality of mucus-penetrating coated particles,

wherein each of the coated particles comprises;

(i) a core particle comprising a pharmaceutical agent or a salt thereof, wherein the pharmaceutical agent constitutes at least about 80 wt % of the core particle; and

(ii) a mucus penetration-enhancing coating comprising a surface-altering agent surrounding the core particle, wherein the surface-altering agent comprises a poly(vinyl alcohol) (PVA) polymer having pendant hydroxyl groups on the backbone of the PVA polymer, the PVA polymer having a molecular weight of at least about 1 kDa and less than or equal to about 1000 kDa, wherein the hydrolysis level of the PVA polymer is at least about 30% and less than about 95%, and

(b) one or more pharmaceutically acceptable excipients or carriers;

wherein the coated particles have an increased mobility in human mucus relative to uncoated particles;

wherein the coated particles have an average size of less than 1 μ

m; and

wherein the ophthalmic composition is configured for delivery to an eye.

2. The ophthalmic composition of claim 1, wherein the surface-altering agent is non-covalently adsorbed to the core particles.

3. The ophthalmic composition of claim 1, wherein the polymer has a molecular weight of at least about 2 kDa.

4. The ophthalmic composition of claim 3, wherein the polymer has a molecular weight of less than or equal to about 200 kDa.

5. The ophthalmic composition of claim 1, wherein the hydrolysis level is at least about 40%.

6. The ophthalmic composition of claim 1, wherein the hydrolysis level is less than about 90%.

7. The ophthalmic composition of claim 1, wherein each of the core particles comprises a solid crystalline pharmaceutical agent or a salt thereof.

8. The ophthalmic composition of claim 1, wherein each of the core particles comprises a solid amorphous pharmaceutical agent or a salt thereof.

9. The ophthalmic composition of claim 1, wherein each of the core particles comprises a salt of the solid pharmaceutical agent.

10. The ophthalmic composition of claim 1, wherein each of the core particles comprises a pharmaceutical agent or a salt thereof that is encapsulated in a polymer, a lipid, a protein, or a combination thereof.

11. The ophthalmic composition of claim 1, wherein the pharmaceutical agent is at least one of a therapeutic agent or a diagnostic agent.

12. The ophthalmic composition of claim 1, wherein the pharmaceutical agent is at least one of a small molecule, a peptide, a peptidomimetic, a protein, a nucleic acid, or a lipid.

13. The ophthalmic composition of claim 1, wherein the pharmaceutical agent or a salt thereof has an aqueous solubility of less than or equal to about 1mg/mL at 25°

C.

14. The ophthalmic composition of claim 1, wherein the pharmaceutical agent constitutes at least about 80 wt % of the core particle.

15. The ophthalmic composition of claim 1, wherein the core particle has an average size of at least 20 nm and less than 500 nm.

16. The ophthalmic composition of claim 1, wherein the coated particles have an average size of at least 20 nm and less than 1 μ

m.

17. The ophthalmic composition of claim 1, wherein the coated particles have a relative velocity of greater than 0.5 in mucus.

18. The ophthalmic composition of claim 17, wherein the mucus is human cervicovaginal mucus.

19. A pharmaceutical preparation suitable for injection or topical administration to a mucus membrane comprising the ophthalmic composition of claim 1.

20. The ophthalmic composition of claim 17, wherein the coated particles have a relative velocity of greater than 0.8 in mucus.

21. The ophthalmic composition of claim 1, wherein the liquid carrier is aqueous.

23. The ophthalmic composition of claim 1, wherein the coated particles have a zeta potential of between −

10 mV and +10 mV.

24. The ophthalmic composition of claim 1, wherein the ratio of the total weight of the pharmaceutical agent to the total weight of the PVA comprised in the composition is about 1:

1 to about 10;

1.

28. The composition of claim 17, wherein the plurality of coated particles have the surface-altering agent present on the core particle at an average density of at least about 0.1 molecules/nm².

33. The composition of claim 1, wherein the core particle is substantially free of a polymeric component.

22. A composition comprising:

(a) a plurality of mucus-penetrating coated particles,

wherein each of the coated particles comprises;

(i) a core particle of a pharmaceutical agent or a salt thereof; and

(ii) a mucus penetration-enhancing coating comprising a surface-altering agent surrounding the core particle, wherein the surface-altering agent consists of a poly(vinyl alcohol) (PVA) polymer having pendant hydroxyl groups on the backbone of the PVA polymer, the PVA polymer having a molecular weight of at least about 1 kDa and less than or equal to about 1000 kDa, wherein the hydrolysis level of the PVA polymer is at least about 30% and less than about 95%; and

(b) one or more pharmaceutically acceptable excipients or carriers;

wherein the coated particles have an increased mobility in human mucus relative to uncoated particles; and

wherein the coated particles have an average size of less than 800 nm.

25. The composition of claim 22, wherein the coated particles have a zeta potential of between −

10 mV and +10 mV.

26. The composition of claim 22, wherein the ratio of the total weight of the pharmaceutical agent to the total weight of the PVA comprised in the composition is about 1:

1 to about 10;

1.

27. The composition of claim 25, wherein the plurality of coated particles have the surface-altering agent present on the core particle at an average density of at least about 0.01 molecules/nm².

29. The composition of claim 22, wherein the coated particles have a relative velocity in mucus of greater than 0.5.

30. The composition of claim 29, wherein the mucus is human cervicovaginal mucus.

31. The composition of claim 22, wherein the plurality of coated particles have the surface-altering agent present on the core particle at an average density of at least about 0.01 molecules/nm².

32. The composition of claim 22, wherein the core particle is a nanocrystal of the pharmaceutical agent.