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(12) Patent Application Publication (10) Pub. No.: US 2015/0374633 A1 Fedorchak Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2015/0374633 A1 Fedorchak Et Al US 20150374633A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0374633 A1 Fedorchak et al. (43) Pub. Date: Dec. 31, 2015 (54) THERMORESPONSIVE HYDROGEL Related U.S. Application Data CONTAINING POLYMERMICROPARTICLES FOR NONINVASIVE OCULAR DRUG (60) Eyinal application No. 61/773,076, filed on Mar. DELIVERY s (71) Applicants: Morgan V. FEDORCHAK, Wexford, O O PA (US); Steven R. LITTLE, Allison Publication Classification Par, PA (US); Joel S. SCHUMAN, E.- EA SS Anthony CUGINI, (51) A6IK9/50Int. Cl. (2006.01) s A6IK47/34 (2006.01) (72) Inventors: Morgan Virginia Fedorchak, Wexford, A6IX 9/06 (2006.01) PA (US); Steven R. Little, Allison Park, A6IX3 L/498 (2006.01) PA (US); Joel Steven Schuman, A6IK9/00 (2006.01) Pittsburgh, PA (US); Anthony Cugini, (52) U.S. Cl. Pittsburgh, PA (US) CPC ............. A61K 9/5021 (2013.01); A61 K9/5031 (2013.01); A61 K3I/498 (2013.01); A61 K (73) Assignee: University of Pittsburgh - of the 9/0048 (2013.01); A61K 9/06 (2013.01); A6IK Commonwealth System of Higher 47/34 (2013.01) Education, Pittsburgh, PA (US) (21) Appl. No.: 14/772,758 (57) ABSTRACT (22) PCT Filed: Mar. 4, 2014 A method for Sustained delivery of an agent to an ocular organ in a subject, comprising topically delivering to the ocular (86). PCT No.: PCT/US2014/020355 Surface a liquid thermoresponsive hydrogel comprising S371 (c)(1), agent-loaded polymer microparticles, wherein the agent is (2) Date: Sep. 3, 2015 sustainably released for a period of at least five days. Patent Application Publication Dec. 31, 2015 Sheet 1 of 9 US 2015/0374633 A1 F.G. 1 FG. 2 Patent Application Publication Dec. 31, 2015 Sheet 2 of 9 US 2015/0374633 A1 FG. 3 Patent Application Publication Dec. 31, 2015 Sheet 3 of 9 US 2015/0374633 A1 irriga B 8:::::::: FG. 4B Patent Application Publication Dec. 31, 2015 Sheet 4 of 9 US 2015/0374633 A1 e s KE Ex s : s: R388 88 fix: s F.G. 5B Patent Application Publication Dec. 31, 2015 Sheet 5 of 9 US 2015/0374633 A1 Patent Application Publication Dec. 31, 2015 Sheet 6 of 9 US 2015/0374633 A1 - - -opica B minimian P. 4 3.4 w Topica B maximum 8 Bioaded Microparticies 8 Gelt BT-loaded Microparticles. 8 4. Time (days) FG. 8 Patent Application Publication Dec. 31, 2015 Sheet 8 of 9 US 2015/0374633 A1 FG. FG 2A FG 2B Day 7 lay 4 Ray 2 Day 28 Patent Application Publication Dec. 31, 2015 Sheet 9 of 9 US 2015/0374633 A1 FG. A A freatinent Eye 8 gags 3e 38sseine M in days a s 4.ii. 34.8 "pigs torpaed ; kaik is got iggG,35, ix8.93 at ared to 3 disast 4. ite days) G. 43 US 2015/0374633 A1 Dec. 31, 2015 THERMORESPONSIVE HYDROGEL BRIEF DESCRIPTION OF THE DRAWINGS CONTAINING POLYMERMCROPARTICLES FOR NONINVASIVE OCULAR DRUG 0009 FIG. 1: SEM images of brimonidine tartrate-loaded DELIVERY PLGA microparticles (BTMPs). These images confirm the desired size and morphology of the BTMPs, consistent with PRIORITY CLAIM Volume impedance measurements (average Volume diam eter–7.46+2.86 um). 0001. This claims the benefit of U.S. Patent Application 0010 FIG. 2: In vitro release of brimonidinefrom PLGA No. 61/773,076, filed Mar. 5, 2013, which is incorporated by MPs (n=3). Also shown are the theoretical maximum and reference in its entirety. minimum amounts of brimonidine absorbed, based on 2 drops per day of 0.2% BT solution and 1-7% absorption BACKGROUND (Ghate and Edelhauser, 2008) as well as 0.66 mg brimonidine per mg BT. 0002. It is estimated that nearly 4 million adults will be diagnosed with open angle glaucoma by the year 2020, the (0011 FIG. 3: BTMP bleb in subconjunctival space of majority of which will be treated with a daily regimen of Dutch belted rabbit on Day 1 of study. ocular hypotensive medication (Friedman et al., 2004). These 0012 FIG. 4: Actual IOP measurements in each of the IOP-reducing drugs are given as eye drops, which must be three groups taken from A) the right eye (treated eye) and B) administered frequently by the patient to reduce the risk of the left eye (untreated eye). N=3 for BTMP and topical BT irreversible vision loss. The rigorous dosing schedule, initial groups; n=2 for blank MP group. lack of symptoms, and difficult drop administration lead to (0013 FIG. 5: Delta IOP values (baseline minus current extremely low patient compliance rates (Hermann et al., day) for each of the three groups in A) the right eye (treated 2010). Additionally, eye drop administration requires high eye) and B) the left eye (untreated eye). N=3 for BTMP and concentrations of drug to overcome the many absorption bar topical BT groups; n=2 for blank MP group. riers in the eye (Ghate and Edelhauser, 2008). (0014 FIG. 6: Partially degraded BTMPs in the subcon 0003. One of the main risk factors for glaucoma, the sec junctival space (stained with Masson’s trichrome) following ond leading cause ofblindness worldwide, is Sustained ocular hypertension. Intraocular pressure (IOP) reduction in glau sacrifice on Day 28 of the study. coma patients is typically accomplished through the admin (0015 FIGS. 7A, 7B and 7C: A representation of an istration of eye drops several times daily, the difficult and embodiment for administering an embodiment of the micro frequent nature of which contributes to compliance rates as particle/hydrogel delivery system disclosed herein. low as 50%. Brimonidine tartrate (BT), a common glaucoma 0016 FIG. 8: Agent release is not affected when micro medication which requires dosing every 8-12 hours, has yet to particles are loaded into hydrogel. Inset: SEM of hydrogel be adapted into a controlled-release formulation that could containing BT-loaded microparticles (scale bar-10 um). drastically improve compliance. 0017 FIG. 9: Theoretical and actual release of Gd-DOTA and brimonidine from polymer microparticles (brimonidine SUMMARY release data from FIGS. 2 and 8 with y-axis modified to 0004 One embodiment disclosed herein is a method for represent % of total release). Sustained delivery of an agent to an ocular organ in a subject, (0018 FIG. 10: Whole brain T1-weighted MR images of comprising topically delivering to the ocular Surface a liquid NZW at 24 h after intravitreal injection of thermoresponsive thermoresponsive hydrogel comprising agent-loaded poly gel containing A) Gd-DOTA-loaded MPs and b) soluble Gd mer microparticles, wherein the agent is Sustainably released DOTA only. Injections were in the right eye only; scans for a period of at least five days. performed within 1 h of sacrifice. 0005. A further embodiment disclosed herein is a method 0019 FIG. 11: A photo image of surgical resection of for ocular delivery of an agent comprising administering the rabbit nictating membrane prior to drop administration. agent at the lower fornix of an eye in a Subject, wherein the 0020 FIGS. 12A and 12B: A photo image showing gel/ method comprises topically delivering to an eye a liquid microparticle drop administration (FIG. 12A). No restraint or hydrogel comprising agent-loaded polymer microparticles, sedation was used during this time for any of the rabbits. The and permitting the liquid hydrogel to form in situ a gelled, presence of the gel drop in the inferior fornix was visually sustained release structure residing in the lower fornix of the confirmed immediately following instillation (FIG. 12 B). eye. 0021 FIG. 13: Photo images showing the presence of 0006. Also disclosed herein is a composition comprising gel/microparticle drop in inferior fornix from days 7-28. Note agent-loaded polymer microparticles dispersed within a ther that visibility of the gels was greatly decreased from Day moresponsive hydrogel, wherein the agent is an agent for 21-28. Gels were stained with fluorescein to confirm pres treating an ocular condition and the composition is config CCC. ured for Sustained topical ocular release of the agent. 0022 FIGS. 14A and 14B: Intraocular pressure data for 0007 Additionally disclosed herein is a drug depot posi BT drops (positive control), BT-loaded microparticles tioned in the lower fornix of an eye of a subject, wherein the (BTMP prior experimental treatment), gel/BTMP (GelMP. drug depot comprises a gelled hydrogel comprising drug current experimental treatment), and blank microparticles loaded polymer microparticles. (blank MP, negative control). These results were reported for 0008. The foregoing will become more apparent from the the treated eye (FIG. 14A) and the untreated contralateral eye following detailed description, which proceeds with refer (FIG. 14B). The legend indicating statistic significance ence to the accompanying figures. applies to both FIG. 14A and FIG. 14B. US 2015/0374633 A1 Dec. 31, 2015 DETAILED DESCRIPTION 0029 “Ocular condition” means a disease, ailment or con dition which affects or involves the eye or one of the parts or Terminology regions of the eye. Broadly speaking the eye includes the 0023 The following explanations of terms and methods eyeball and the tissues and fluids which constitute the eyeball, are provided to better describe the present compounds, com the periocular muscles (such as the oblique and rectus positions and methods, and to guide those of ordinary skill in muscles) and the portion of the optic nerve which is within or the art in the practice of the present disclosure. It is also to be adjacent to the eyeball. understood that the terminology used in the disclosure is for 0030. A “therapeutically effective amount” refers to a the purpose of describing particular embodiments and quantity of a specified agent sufficient to achieve a desired examples only and is not intended to be limiting.
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