Intracameral drug delivery depots

Patent metadata

Field	Value
Publication number	US-2018085307-A1
Application number	US-201715714633-A
Country	US
Kind code	A1
Filing date	Sep 25, 2017
Priority date	Sep 23, 2016
Publication date	Mar 29, 2018
Grant date	—

Abstract

Methods of treating an eye for an ocular condition such as placing a composite depot comprising a xerogel with embedded degradable particles into an anterior chamber of an eye to deliver a therapeutic agent. The xerogel is a hydrogel after exposure to intraocular fluid and is degradable. The degradable particles comprise the therapeutic agent and hydrolytically degrade in the anterior chamber to provide a controlled release of the therapeutic agent into the eye. Materials and processes for making depots are provided as well as alternative methods of their use.

First claim

1 . A method of treating an eye for an ocular condition, the method comprising
placing a composite depot comprising a xerogel with embedded hydrolytically degradable particles into an anterior chamber of an eye to deliver a therapeutic agent, with the xerogel being a hydrogel after exposure to intraocular fluid, with the hydrogel being hydrolytically degradable, wherein the hydrolytically degradable particles comprise the therapeutic agent and hydrolytically degrade in the anterior chamber to provide a controlled release of the therapeutic agent into the eye, wherein an index of depot residue retention (IRR) is from 0.5 to 2.0, with IRR being a time to full dissolution of the depot divided by a time to release of 100% of the therapeutic agent.

2 . The method of claim 1 wherein the hydrogel provides a coefficient of increased delivery time of at least 2, said coefficient being measured in vitro under agitation conditions sufficient to suspend the hydrolytically degradable particles in phosphate buffered saline and being a time for 100% release of the agents in a presence of the hydrogel divided by a time for 100% release of the agents from the particles in an absence of the hydrogel.

3 . The method claim 1 wherein a matrix of the xerogel has a dry weight that is at least 20% of a sum of the dry weight of the xerogel matrix and a dry weight of the embedded hydrolytically degradable particles.

4 . The method of claim 1 wherein a matrix of the hydrogel is formed by covalently crosslinking one or more multiple-arm polyethylene glycol precursors that comprise hydrolytically degradable linkages on each of the multiple arms so that hydrolysis products of the hydrogel are non-toxic and the matrix formed of the polyethylene glycol precursors is hydrolytically degraded to be multiple-arm polyethylene glycol molecules with arms that terminate in hydroxyl or carboxyl end groups.

5 . The method of claim 4 wherein at least one of the multi-arm polyethylene glycol precursors has a molecular weight that is no more than 50 kDa (Mn) and a number of the multiple arms is at least four.

6 . The method of claim 5 wherein the xerogel and/or the at least one multi-arm polyethylene glycol precursors are sterilized by irradiation.

7 . The method of claim 1 wherein the hydrolytically degradable particles are sterilized by irradiation.

8 . The method of claim 1 wherein the composite is sterilized by irradiation.

9 . The method of 1 wherein the composite depot is placed into the anterior chamber using a needle smaller than, or equal to, 25 gauge.

10 . The method of claim 1 wherein the controlled release of the agent takes place in a period of time between 10 days and 2 years.

11 . The method of claim 1 wherein the hydrogel is formed by at least one hydrophilic precursor covalently crosslinked to form the hydrogel.

12 . The method of claim 11 wherein the hydrophilic precursor comprises a plurality of arms that are each from 500 to 10,000 Daltons (Mn).

13 . The method of claim 1 wherein the hydrolytically degradable particles comprise the therapeutic agent and a hydrolytically degradable material.

14 . The method of claim 13 wherein the hydrolytically degradable material comprises one or more of polylactic acid (PLA), polyglycolic acid (PGA), and a copolymer of PLA and PGA.

15 . The method of claim 1 wherein the ocular condition comprises glaucoma, ocular hypertension, hyphema, macular degeneration, cystoid macular edema (CME), diabetic macular edema (DME), posterior uveitis, diabetic retinopathy, presbyopia, cataract, retinal vein occlusion, or uveitis.

16 . The method of claim 1 wherein the therapeutic agent comprises travoprost, a prostaglandin analogue, a low-soluble prostaglandin analogue, an anti-angiogenic agent, an intraocular pressure-lowering agent, an anti inflammatory, an anti infective, a mydriatic agent, an anti-cancer agent, anti-VEGF, blocks VEGFR1, blocks VEGFR2, blocks VEGFR3, anti-PDGF, anti-PDGF-R blocks PDGFRβ, anti-angiogenesis, sunitinib, E7080, takeda-6d, tivozanib, regorafenib, sorafenib, pazopanib, axitinib, nintedanib, cediranib, vatalanib, motesanib, macrolides, sirolimus, everolimus, a tyrosine kinase inhibitor, imatinib, gefinitib, toceranib, erlotinib, lapatinib, nilotinib bosutinib neratinib, lapatinib, vatalanib, a steroid, a nonsteroidal anti-inflammatory drug, an antibiotic, a pain killer, travoprost, dexamethasone, moxifloxacin, nepafenac, a macrolide, rapamycin, sirolimus, tacrolimus, lipoic acid and derivatives, or sterols, oxysterols and related compounds.

17 . The method of claim 1 wherein the depot has a volume from 0.1 to 1000 μl.

18 . The method of claim 1 wherein the depot is a rod.

19 . A composite depot comprising a xerogel with embedded hydrolytically degradable particles, with the xerogel being a biocompatible hydrogel after exposure to intraocular fluid, with the hydrogel being hydrolytically degradable, wherein the hydrolytically degradable particles comprise the therapeutic agent and hydrolytically degrade in a physiological fluid to provide a controlled release of the therapeutic agent.

20 . The depot of claim 19 wherein a matrix of the xerogel has a dry weight that is at least 20% of a sum of the dry weight of the xerogel matrix and a dry weight of the embedded hydrolytically degradable particles.

21 . The depot of claim 20 wherein a matrix of the hydrogel is formed by covalently crosslinking one or more multiple-arm polyethylene glycol precursors that comprise hydrolytically degradable linkages on each of the multiple arms so that hydrolysis products of the hydrogel are non-toxic and the one or more multiple-arm polyethylene glycol precursors are hydrolytically degradable to be multiple-arm polyethylene glycol molecules with arms that terminate in hydroxyl or carboxyl end groups.

22 . The depot of claim 20 wherein at least one of the multi-arm polyethylene glycol precursors has a molecular weight that is no more than 50 kDa (Mn) and a number of the multiple arms is at least four.

23 . The depot of claim 19 wherein the controlled release of the agent takes place in a period of time between 10 days and 2 years.

24 . The depot of claim 19 wherein the hydrogel is formed by at least one hydrophilic precursor covalently crosslinked to form the hydrogel.

25 . The depot of claim 19 wherein the hydrolytically degradable particles comprise the therapeutic agent and a hydrolytically degradable material.

26 . The depot of claim 25 wherein the hydrolytically degradable material comprises one or more of polylactic acid (PLA), polyglycolic acid (PGA), and a copolymer of PLA and PGA.

27 . The depot of claim 25 wherein the therapeutic agent comprises travoprost, a prostaglandin analogue, a low-soluble prostaglandin analogue, an anti-angiogenic agent, an intraocular pressure-lowering agent, an anti inflammatory, an anti infective, a mydriatic agent, an anti-cancer agent, anti-VEGF, blocks VEGFR1, blocks VEGFR2, blocks VEGFR3, anti-PDGF, anti-PDGF-R blocks PDGFRβ, anti-angiogenesis, sunitinib, E7080, takeda-6d, tivozanib, regorafenib, sorafenib, pazopanib, axitinib, nintedanib, cediranib, vatalanib, motesanib, macrolides, sirolimus, everolimus, a tyrosine kinase inhibitor, imatinib, gefinitib, toceranib, erlotinib, lapatinib, nilotinib bosutinib neratinib, lapatinib, vatalanib, a steroid, a nonsteroidal anti-inflammatory drug, an an

Assignees

• Incept Llc

Inventors

• Sawhney Amarpreet S
• Driscoll Arthur
• Blizzard Charles D
• Desai Ankita D
• Jarrett Peter

Classifications

• A61P27/12

  for cataracts · CPC title

• A61P27/06

  Antiglaucoma agents or miotics · CPC title

• A61P27/02

  Ophthalmic agents · CPC title

• A61K31/382

  having six-membered rings, e.g. thioxanthenes (thiothixene A61K31/496) · CPC title

• A61F9/0017

  implantable in, or in contact with, the eye, e.g. ocular inserts · CPC title