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EP-4739302-A2 - HYALURONIC ACID BASED DRUG DELIVERY SYSTEMS

EP4739302A2EP 4739302 A2EP4739302 A2EP 4739302A2EP-4739302-A2

Abstract

The present disclosure provides a hyaluronic acid-based drug delivery system comprising a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein X, R 1 , and R 2 are as defined herein. The present disclosure also provides compositions comprising the hyaluronic acid-based drug delivery system described herein and one or more active pharmaceutical ingredient(s). The present disclosure also provides methods of delivering one or more active pharmaceutical ingredient(s) to the eye of a subject in need thereof and methods of treating ophthalmic diseases, disorders, or conditions in a subject in need thereof, comprising administering a composition disclosed herein to the subject.

Inventors

  • HUGHES, PATRICK
  • SCHIFFMAN, RHETT

Assignees

  • Cella Therapeutics, LLC

Dates

Publication Date
20260513
Application Date
20240702

Claims (20)

  1. 1. Hyaluronic acid comprising a compound of Formula (I): or a salt or solvate thereof, wherein: n is an integer from 500 to 25,000; X at each occurrence is selected from the group consisting of -NH- and -O-; R 1 and R 2 at each occurrence are independently selected from the group consisting of hydrogen, a hydrophobic group, -L J -L 2 -A, and -A; each L 1 is an amino acid or absent; each L 2 is a linker; and each A is independently a covalently bonded active pharmaceutical ingredient, wherein each instance of -A can be the same or different.
  2. 2. The hyaluronic acid of claim 1, wherein n is from 1,200 to 5,000.
  3. 3. The hyaluronic acid of claim 1 or 2, wherein X is -NH-.
  4. 4. The hyaluronic acid of claim 1 or 2, wherein X is -O-.
  5. 5. The hyaluronic acid of any one of claims 1-4, wherein the hydrophobic group is selected from the group consisting of optionally substituted Ci-Cis alkyl and an amino acid.
  6. 6. The hyaluronic acid of claim 5, wherein the hydrophobic group is Ci-Cis alkyl that is substituted with a phenyl group.
  7. 7. The hyaluronic acid of claim 5 or 6, wherein the hydrophobic group is a Ci-Cis alkyl that is selected from the group consisting of:
  8. 8. The hyaluronic acid of claim 5, wherein the hydrophobic group is an amino acid that is selected from the group consisting of:
  9. 9. The hyaluronic acid of any one of claims 1-8, wherein L 1 is selected from the group consisting of:
  10. 10. The hyaluronic acid of any one of claims 1-9, wherein L 2 is selected from the group consisting of:
  11. 11. The hyaluronic acid of any one of claims 1-10, wherein each A is independently selected from the group consisting of an intraocular pressure (IOP) lowering agent, a CNTF analog, a FAS inhibitor or FAS ligand inhibitor, a HIF-1 alpha inhibitor, a HIF-2 alpha inhibitor, a VEGF inhibitor, a VIP analog, a histatin analog, an alpha crystallin aggregation inhibitor, a reducing agent, a mitochondrial stabilizer, and a TNF-alpha inhibitor.
  12. 12. The hyaluronic acid of claim 11, wherein the IOP lowering agent is a prostaglandin, a beta blocker, an alpha agonist, a carbonic anhydrase inhibitor, a cholinergic agent, a rho kinase inhibitor, or a cannabinoid receptor agonist.
  13. 13. The hyaluronic acid of claim 12, wherein the prostaglandin is a prostaglandin compound, a prostaglandin EP2 agonist, a prostaglandin EP3 agonist, a nitric oxide donating prostaglandin compound, or a combination thereof.
  14. 14. The hyaluronic acid of claim 13, wherein the prostaglandin compound is bimatoprost, bimatoprost acid, travoprost, travoprost acid, latanoprost, latanoprost acid, latanoprostene, tafluprost, or tafluprost acid.
  15. 15. The hyaluronic acid of claim 13, wherein the prostaglandin EP2 agonist is taprenepag or omidenepag isopropyl.
  16. 16. The hyaluronic acid of claim 13, wherein the prostaglandin EP3 agonist is dinoprostone, misoprostol, limaprost, gemeprost, alprostadil, or rivenprost.
  17. 17. The hyaluronic acid of claim 13, wherein the nitric oxide donating prostaglandin compound is latanoprostene bunod.
  18. 18. The hyaluronic acid of claim 12, wherein the beta blocker is timolol, betaxolol, levobunolol, or metipranolol.
  19. 19. The hyaluronic acid of claim 12, wherein the alpha agonist is brimonidine or apraclonidine.
  20. 20. The hyaluronic acid of claim 12, wherein the carbonic anhydrase inhibitor is brinzolamide, acetazolamide, dorzolamide, or methazolamide.

Description

HYALURONIC ACID BASED DRUG DELIVERY SYSTEMS FIELD OF THE INVENTION [0001] The present disclosure relates to hyaluronic acid modified by cross-linking, the covalent addition of hydrophobic groups, and/or the covalent addition of one or more active pharmaceutical ingredients. The present disclosure also relates to compositions comprising the hyaluronic acid described herein and one or more active pharmaceutical ingredients. The present disclosure also relates to methods of delivering one or more active pharmaceutical ingredients to one or both eyes of a subject in need thereof and methods of treating ophthalmic diseases, disorders, or conditions in a subject in need thereof, comprising administering a composition disclosed herein to the subject. BACKGROUND OF THE INVENTION [0002] Active pharmaceutical ingredients must achieve therapeutic concentrations at the target tissue for the appropriate duration to have a beneficial effect. This can be extremely challenging for ocular drugs, as not every active pharmaceutical ingredient can be formulated topically. For those active pharmaceutical ingredients that can be formulated topically, the bioavailability of those in the aqueous humor is usually only 1 to 5 percent. [0003] Injectable formulations can potentially be provided by in situ gelling depots and hydrogels or sustained delivery particulates sequestered by in situ gelling depots or hydrogels. Injectable depots are attractive for delivery to the posterior segment of the eye because they can potentially deliver a high payload through a small gauge needle. The materials are often hydrophilic and hydrated, conferring a degree of biocompatibility. [0004] Hyaluronic acid (HA) and collagen (Col) are attractive polymers for the design of intraocular drug delivery systems as both are naturally present in the vitreous. HA has a history of clinical use as a viscosupplement or surgical aid with an extensive positive safety profile. Non-crosslinked HA is known to clear from the posterior segment quickly relative to a desired 3 to 12 month, or longer, delivery profile. [0005] Therefore, there remains a need to develop drug delivery systems and compositions thereof that are capable of sustained release of one or more active pharmaceutical ingredient(s) over a controlled time period. BRIEF SUMMARY OF THE INVENTION [0006] The present disclosure provides hyaluronic acid comprising a compound of Formula (I): or a salt or solvate thereof, wherein: n is an integer from 500 to 25,000; X at each occurrence is selected from the group consisting of -NH- and -O-; R1 and R2 at each occurrence are independently selected from the group consisting of hydrogen, a hydrophobic group, -LJ-L2-A, and -A; each L1 is an amino acid or absent; each L2 is a linker; and each A is independently a covalently bonded active pharmaceutical ingredient, wherein each instance of -A can be the same or different. [0007] In some aspects, n is from 1,200 to 5,000. [0008] In some aspects, X is -NH-. [0009] In some aspects, X is -O-. [0010] In some aspects, the hydrophobic group is selected from the group consisting of optionally substituted Ci-Cis alkyl and an amino acid. [0011] In some aspects, the hydrophobic group is Ci-Cis alkyl that is substituted with a phenyl group. [0012] In some aspects, the hydrophobic group is a Ci-Cis alkyl that is selected from the group consisting of: [0013] In some aspects, the hydrophobic group is an amino acid that is selected from the group consisting of: [0014] In some aspects, L1 is selected from the group consisting of: [0015] In some aspects, L2 is selected from the group consisting of: [0016] In some aspects, each A is independently selected from the group consisting of an intraocular pressure (IOP) lowering agent, a CNTF analog, a FAS inhibitor or FAS ligand inhibitor, a HIF-1 alpha inhibitor, a HIF-2 alpha inhibitor, a VEGF inhibitor, a VIP analog, a histatin analog, an alpha crystallin aggregation inhibitor, a reducing agent, a mitochondrial stabilizer, and a TNF-alpha inhibitor. [0017] In some aspects, the IOP lowering agent is a prostaglandin, a beta blocker, an alpha agonist, a carbonic anhydrase inhibitor, a cholinergic agent, a rho kinase inhibitor, or a cannabinoid receptor agonist. [0018] In some aspects, the prostaglandin is a prostaglandin compound, a prostaglandin EP2 agonist, a prostaglandin EP3 agonist, a nitric oxide donating prostaglandin compound, or a combination thereof. [0019] In some aspects, the prostaglandin compound is bimatoprost, bimatoprost acid, travoprost, travoprost acid, latanoprost, latanoprost acid, latanoprostene, tafluprost, or tafluprost acid. [0020] In some aspects, the prostaglandin EP2 agonist is taprenepag or omidenepag isopropyl. [0021] In some aspects, the prostaglandin EP3 agonist is dinoprostone, misoprostol, limaprost, gemeprost, alprostadil, or rivenprost. [0022] In some aspects, the nitric oxide donating prostaglandin compound is latanoprostene bunod. [0023] In some as