Implants and methods for treating inflammation-mediated conditions of the eye

Abstract

Methods for treating inflammation-mediated conditions of the eye are described, comprising: implanting into the vitreous of the eye of an individual a bioerodible implant comprising a steroidal anti-inflammatory agent and a bioerodible polymer, wherein the implant delivers the agent to the vitreous in an amount sufficient to reach a concentration equivalent to at least about 0.05 μg/ml dexamethasone within about 48 hours and maintains a concentration equivalent to at least about 0.03 μg/ml dexamethasone for at least about three weeks.

Claims

1. A method for treating an inflammation-mediated condition of the eye comprising: implanting into the vitreous of the eye a bioerodible implant consisting of a steroidal anti-inflammatory agent and a bioerodible polymer, wherein the implant is produced by an extrusion method, wherein the total weight of the implant is about 500-1000 μg, and wherein the inflammation-mediated condition of the eye is macular edema, acute macular degeneration, retinal detachment, or proliferative vitreoretinopathy (PVR).

2. The method of claim 1, wherein the bioerodible polymer is a polylactic acid polyglycolic acid (PLGA) copolymer.

3. The method of claim 2, wherein the PLGA copolymer is a 50/50 PLGA copolymer.

4. The method of claim 2, wherein the steroidal anti-inflammatory agent comprises about 10% to 90% by weight of the implant.

5. The method of claim 4, wherein the steroidal anti-inflammatory agent comprises about 50% to about 80% by weight of the implant.

6. The method of claim 5, wherein the steroidal anti-inflammatory agent is dexamethasone.

Description

EXAMPLES

Example 1: Manufacture and In Vitro Testing of Bioerodible Dexamethasone Posterior Segment Drug Delivery System (DEX PS DDS®)

(1) 2100 mg of dexamethasone powder (Upjohn) (particle sizes less than 10 μm in diameter) were mixed with 900 mg of 50/50 polylactic acid polyglycolic acid (PLGA) (particle sizes approximately 9-12 μm in diameter) at ambient temperature. A small Teflon® tube was filled with 900-1100 μg of the above mixture, and placed directly on the die cavity. The powder was pushed out of the tubing into the die cavity with a stainless steel wire and the tube and wire were removed from the die. The powder was pressed using a tablet press (approximately 76 psi), ejected with the ejector switch, and removed with tweezers. The resulting pellet was approximately 2 mm×0.75 mm.

(2) Release of dexamethasone from the DEX PS DDS® system was measured. One DDS was placed in a glass vial filled with receptor medium (0.9% NaCl in water). To allow for “infinite sink” conditions, the receptor medium volume was chosen so that the concentration would never exceed 5% of saturation. To minimize secondary transport phenomena, e.g. concentration polarization in the stagnant boundary layer, the glass vial was placed into a shaking water bath at 37° C. Samples were taken for HPLC analysis from the vial at defined time points. The HPLC method was as described in USP 23 (1995) pp. 1791-1798. The concentration values were used to calculate the cumulative release data, as shown in Table 1.

(3) TABLE-US-00001 TABLE 1 DEX PS DDS ® In vitro Release Day % Total Release 1 10.1 2 16.4 7 39.4 14 55.5 21 69.3 28 80.7 35 88.1

(4) Table 1 shows an almost linear in vitro release of dexamethasone over a one month period of time.

Example 2: In Vivo Testing of DEX PS DDS® in Rabbits

(5) One DEX PS DDS® per eye was implanted into the vitreous of four rabbits with forceps. The in vivo vitreous concentrations of dexamethasone in each of the four eyes were monitored by vitreous sampling. For example, at day 2 the concentrations measured were 0.03 μg/ml, 0.1 μg/ml, 0.33 μg/ml and 0.19 μg/ml. The concentrations in each of the four eyes were measured on days 2, 7, 21, 28 and 35; the average results are summarized in Table 2. The volume of rabbit eyes is approximately 60-70% percent that of human eyes.

(6) TABLE-US-00002 TABLE 2 In vivo concentrations of dexamethasone (DDS placed with forceps) Day μg/ml 2 0.16 ± 0.13 7 0.15 ± 0.16 21 0.08 ± 0.07 28 0.005 ± 0.01  35 0.037 ± 0.03 

(7) The same DDS was tested in vivo in rabbits, wherein the DDS was placed to a depth of about 5-10 mm in the vitreous with trocar. The levels of dexamethasone in the vitreous are shown in Table 3.

(8) TABLE-US-00003 TABLE 3 In vivo concentrations of dexamethasone (DDS placed with trocar) Sample ID 5293-D 5295 = D 5293-S 5295-S 5304-D 5306-D 5304-S 5306-S Hours Sample Conc., ug/ml Avg SD  2 0.56 3.07 1.82 1.77  4 5.48 6.95 6.22 1.04  6 2.08 5.15 3.62 2.17 24 2.33 2.69 2.51 0.25 DDS wt. Dex wt. Dex ug/mL Animal#\day ug ug 2 7 14 21 28 35 21427-D 990 693 2.29 21427-S 1023 715.1 1.56 21433-D 804 562.8 1.2 21433-S 1057 739.9 0.77 21428-D 1003 702.1 9.26 21428-S 1025 717.5 0.35 21434-D 863 604.1 3.31 21434-S 1106 774.2 0.84 21429-D 1013 709.1 n/a 21429-S 927 648.9 0.19 21435-D 1104 772.8 0.43 21435-S 941 658.7 0.11 21432-D 860 692 0.43 21432-S 941 685.7 1.72 21436-D 1010 707 0.31 21436-S 1054 737.8 0.13 21431-D 996 697.2 0.52 21431-S 918 642.6 1.15 21437-D 1049 732.9 0.19 21437-D 1075 752.5 0.48 21430-D 994 695.8 0.06 21430-S 1086 760.2 0.18 21438-D 974 681.8 0.03 21438-S 831 581.7 8.35 Ave. 985.17 694.43 1.46 3.44 0.24 0.65 0.59 2.16 * Unable to determine due to insufficient sample

(9) The data indicate that the DEX PS DDS® releases dexamethasone to the vitreous in concentrations above 0.01 μg/ml for an extended period of time. Further, the data indicate that placement of the device with trocar results in much higher levels of drug release than with placement with forceps, most likely due to placement of the device deeper within the vitreous. The data at two, four, six, and 24 hours in Table 3 shows an initial spike of drug release.

Example 3: Treatment of Severe Uveitis in Human Patients with DEX PS DDS®

(10) Three eyes of two patients (ages 5 and 55 years) with severe progressive uveitis were treated with the DEX PS DDS®. The use of the DEX PS DDS® in compassionate and emergency use situations was conducted under an investigative new drug application (IND) with the U.S. F.D.A. A written informed consent was obtained from the participating patients.

(11) Subjects in this study underwent pars plana vitrectomy Immediately after the vitrectomy, the DEX PS DDS® was inserted into the vitreous cavity through the pars plana. The DDS pellet appeared to remain in the location where it was placed, and released the drug over at least approximately 4-5 weeks.

(12) Patient #1 was a 55-year-old female who initially presented with optic neuritis in 1990. This patient subsequently developed recurrent posterior uveitis secondary to inflammatory polyarthritis. Response to systemic and periocular steroid treatment was intermittent. Methotrexate and cyclosporine were found to be effective; however, these drugs induced severe side effects. Methotrexate caused elevated liver enzymes and pancreatitis. The patient developed pustular dermatitis with cyclosporine treatment. Cytoxan was subsequently used, both intravenously and orally, with satisfactory initial results. Later, the inflammatory polyarthritis was controlled with Gold injections. The patient's Type I diabetes was well controlled and the pancreatitis resolved.

(13) The patient was referred to us in September 1998 for further evaluation and treatment of uveitis due to progressive visual loss and lack of response to conventional medications. A vitrectomy had been performed on her left eye several years earlier for treatment of uveitis. Visual acuity in both eyes was counting fingers. Intraocular pressure in both eyes was 20 mm Hg. Slit lamp exam of the right anterior chamber revealed trace flare and 1-5 cells. Examination of the left anterior chamber revealed no flare and 8-9 cells. A mild nuclear sclerotic cataract was present in the right eye and a moderate one was noted in the left eye. In the anterior vitreous of the right eye, 50-100 fine cells were present. There were 6-7 cells in the left anterior vitreous.

(14) On ophthalmoscopy of the right eye, the vitreous was hazy and a poor view was obtained. It was possible to see a peripapillary scar and numerous histoplasmosis type retinal scars 360° from the posterior pole out to the periphery. In the left eye, the vitreous was not as hazy and the retina appearance was very similar to that of the right eye. The right eye was selected for initial treatment due to its more acute involvement and the more severe inflammatory response.

(15) In October 1998, a standard three port system pars plana vitrectomy was performed and the DEX PS DDS® was inserted through the pars plana. At the end of surgery, the patient received periocular celestone suspension 1 cc (β-methasone sodium phosphate/β-methasone acetate, Schering-Plough) and periocular gentamicin 0.1 cc (Abbott Laboratories). Topical medications consisting of Tobradex® (tobramycin/dexamethasone, Alcon Labs) and Cyclogyl® 1% drops (cyclopentolate HCl, Alcon Labs) q.i.d. were prescribed. The retina was clearly seen for the first time during surgery after removal of the vitreous. There was a peripapillary scar and numerous healed histoplasmosis type scars 360° from the posterior pole to the periphery. In addition, there were several small retinal hemorrhages that appeared to be consistent with diabetic retinopathy. No active inflammatory retinitis or choroiditis was seen. A mild amount of epiretinal gliosis was present at six o'clock in the mid-periphery. There was no evidence of snowbanking or snowball opacities.

(16) The first (right) eye of patient #1 improved from counting fingers to 20/200 on the first day postoperatively. The best vision was 20/40 at six months. One year acuity was 20/50 and at the last visit (16 months) the vision was 20/60 (Table 3).

(17) TABLE-US-00004 TABLE 4 Patient 1: Right Eye Visual Acuity Visual Acuity PreOp CF Day 1 20/200 Month 1 20/200 Month 2 20/80 Month 3 20/60 Month 4 20/40 Month 5 20/50 Month 16 20/60

(18) Postoperatively, anterior chamber flare varied between 0 and trace and cells varied between 1 and 6. Vitreous flare varied between 0 and trace. Vitreous cells varied between 0 and 20.

(19) On ophthalmoscopy, the vitreous and retina were found to remain completely quiet. The DEX PS DDS® implant was resorbed at approximately five weeks. The retinal hemorrhages disappeared. There was no detectable increase in the patient's cataract. Fluorescein angiography did not reveal any evidence of macular edema. Present eye medications consist of Acular® (ketorolac tromethamine 0.5%, Allergan) drops q.i.d.

(20) After it was determined that favorable results were achieved in the right eye, the patient received the same treatment for the left eye in April 1999. The left eye presented very similarly to the right eye, other than a more significant cataract and the uveitis being more chronic in nature. Notably, a pars plana vitrectomy had been performed on this eye for this condition 3 years previously.

(21) The second (left) eye of patient #1 initially improved to a visual acuity of 20/400 (3 months postoperatively), but later returned to counting fingers (7.5 months). This decline in visual acuity appeared to be secondary to progression of the cataract. Postoperatively (first 10 months), on slit lamp examination, anterior chamber flare varied from 0 to moderate and cells varied from 0 to >30. Vitreous flare varied from 0 to severe and vitreous cells varied from 0 to >250. On the last visit (11 months), there was no AC flare or cells, and vitreous detail was not observed due to cataract. There had been no vitreous flare or cells detected on the previous visit (10 months). Visual acuity at 11 months was counting fingers. Present eye medications consist of Acular® drops q.i.d.

(22) Patient #2 is a 5-year-old male with an eight month history of bilateral pars planitis. The right eye was mild and stable, but the left eye was progressive and severe with only transient response to topical and subtenon steroids. This was an idiopathic uveitis. The patient developed complications in the left eye including decreased vision to 20/200, a posterior subcapsular cataract, band keratopathy, and glaucoma with intraocular pressures in the low 30's. There was mild flare and 20 cells in the anterior chamber.

(23) The anterior vitreous was very prominent and the cells were too numerous to count. On ophthalmoscopy, the patient was found to have snowball vitreous opacities, snowbanking, and peripheral retinoschisis or a low retinal detachment. Multiple uveitis consultations offered treatment choices of systemic steroids, systemic antimetabolites, and pars plana vitrectomy. Because of the patient's young age and potential side effects of systemic treatments, it was elected to perform a pars plana vitrectomy. The surgery was carried out uneventfully in September 1999. The treatment consisted of a pars plana vitrectomy, insertion of DEX PS DDS®, and transconjunctival cryopexy.

(24) Patient #2 had a one day postoperative visual acuity of 20/400 and the best vision was 20/70 (Table 4).

(25) TABLE-US-00005 TABLE 5 Patient 2: Left Eye Visual Acuity Visual Acuity PreOp 20/200 Month 1 20/70 Month 2 20/100 Month 3 20/70 Month 4 20/80 Month 5 20/100 Month 6 20/80

(26) Visual acuity at five months decreased to 20/100 secondary to progression of the posterior subcapsular cataract. On slit lamp examination, anterior chamber flare varied between 0 to mild and cells varied from 0 to 4. Vitreous flare was 0 and vitreous cells varied from 0 to 10. On ophthalmoscopy, a mild amount of residual snowballs and snowbanking was evident. The peripheral retinal detachment/schisis healed well and was flat. The eye responded very well with the exception of intraocular pressure. Pressures were in the teens up to the 20's in the immediate postoperative period, and after two months the pressure went up to 44 mm Hg. A glaucoma consultation was obtained and it was concluded that the intraocular pressure increase was due to the topical antibiotic steroid combination drops used postoperatively. The medications were terminated and the patient was prescribed topical anti-glaucoma medication. The last postoperative pressure measurement (6 months) was 13 mm Hg. There is no evidence of damage to the optic nerve. Present medications consist of Timoptic® 0.25% (timolol maleate, Falcon Pharmaceuticals), Acular®, and Vexol® 1% (rimexolone, Alcon Labs) all b.i.d.

(27) Outcomes for these two patients suggest that DEX PS DDS® may be very effective in the treatment of severe uveitis. It appears that the DEX PS DDS® is well tolerated, and that the one month drug delivery system can be effective over a much longer period of time in treating these chronic uveitis patients.

Example 4: Treatment of Severe and Recalcitrant Uveitis in Human Patients with DEX PS DDS®

(28) Four eyes of 4 patients who have had failed treatments for severe uveitis were treated with the DEX PS DDS®. Subjects in this study underwent a standard 3 port pars plana vitrectomy Immediately after the vitrectomy, the DEX PS DDS® was inserted into the vitreous cavity through the pars plana. The DDS pellet appeared to remain in the location where it was placed, and released the drug over approximately 1 month.

(29) Three patients had a single procedure with DEX PS DDS® insertion and 1 patient had a second DEX PS DDS® insertion when surgery was required from complications of the disease. All patients have shown a remarkable response to the medication and vision in all patients has improved. The beginning vision was as low as counting fingers only and the improvement has been as high as 20/30. With 2-22 months follow up all patients have responded positively and there have been no new recurrences. The patient who had 2 insertions has shown complete regression of the disease.

Example 5: Use of DEX PS DDS® in the Treatment of Recurrent Retinal Detachment

(30) The effect of DEX PS DDS® as an adjunct in the treatment of recurrent retinal detachments associated with PVR was evaluated. Six eyes of six patients with 2-4 previous retinal procedures and who had recurrence due to PVR were treated with DEX PS DDS®, which was inserted into the vitreous cavity after a standard 3 port pars plana vitrectomy with membrane peeling, endolaser, and air-fluid-gas or silicone oil exchange, with or without a scleral buckle.

(31) Four patients had surgery with reattachment with one operation. Two patients had a second procedure due to initial incomplete removal of the existing PVR. With the second procedure the retina of one patient has remained attached. The second patient has developed recurrent PVR and re-detachment and will undergo further surgery. With 3-13 months follow-up five retinas were attached with no new PVR.

(32) The DEX PS DDS® appeared to be very effective in the treatment of PVR related retinal detachments.

Example 6: Manufacture and In Vitro Testing of 50/50 Dexamethasone/PLGA Posterior Segment Drug Delivery System

(33) 2.5 g of PLGA (particle sizes approximately 9-12 μm in diameter) were placed in a mixing vessel. The vessel was placed in the oven (130° C.) for ten minutes. 2.5 g of dexamethasone (particle sizes less than approximately 10 μm in diameter) were added to the vessel, and the vessel was returned to the oven for 10 minutes. The PLGA/dexamethasone mixture was mixed well, the blend loaded into a barrel, and 650-790 μm diameter filaments extruded. The resulting filaments were cut into lengths of approximately 0.94 and 1.87 mm for the 500 μg and 1000 μg formulations, respectively.

(34) Release of dexamethasone from the 50/50 dexamethasone/PLGA DDS formulations were measured. One DDS was placed in a glass vial filled with receptor medium (0.9% NaCl in water). To allow for “infinite sink” conditions, the receptor medium volume was chosen so that the concentration would never exceed 5% of saturation. To minimize secondary transport phenomena, e.g. concentration polarization in the stagnant boundary layer, the glass vial was placed into a shaking water bath at 37° C. Samples were taken for HPLC analysis from the vial at defined time points. The HPLC method was as described in USP 23 (1995) pp. 1791-1798. The concentration values were used to calculate the cumulative release data, as shown in Table 6.

(35) TABLE-US-00006 TABLE 6 In vitro release of 50% Dex-PS (0.5 mg formulation) Dex ug Day Release/day % Total release 50% Dex PS 0.5 mg system replicate 1 1 3.00 1.41 7 1.99 7.93 13 0.90 13.43 20 1.79 30.21 27 1.54 49.77 34 1.93 80.52 41 0.24 85.05 48 0.24 90.38 55 0.10 93.00 62 0.15 97.44 69 0.07 99.84 76 0.07 102.25 50% Dex PS 0.5 mg system replicate 2 1 6.00 2.17 7 1.66 6.38 13 0.99 11.05 20 1.21 19.82 27 2.29 42.23 34 2.34 71.05 41 0.44 77.54 48 0.29 82.61 55 0.14 85.34 62 0.20 89.80 69 0.10 92.21 76 0.06 84.38 50% Dex PS 0.5 mg system replicate 3 1 5.70 3.27 7 1.11 7.71 13 0.83 13.83 20 0.05 14.47 27 1.63 39.63 34 1.52 69.26 41 0.21 74.10 48 0.19 79.23 55 0.08 81.69 62 0.14 86.58 69 0.07 89.46 76 0.06 92.26

(36) TABLE-US-00007 TABLE 7 In vitro release of 50% Dex-PS (1 mg formulation) Dex ug Day Release/day % Total release 50% Dex PS 1 mg system replicate 1 1 6.90 1.28 7 3.48 5.78 13 1.93 10.43 20 3.46 23.22 27 3.74 41.89 34 3.94 66.83 41 1.79 80.17 48 1.28 91.49 55 0.21 93.59 62 0.24 96.39 69 0.11 97.85 76 0.09 99.11 50% Dex PS 1 mg system replicate 2 1 3.90 0.71 7 2.26 3.62 13 1.66 7.57 20 3.14 19.09 27 4.32 40.48 34 4.06 65.77 41 1.61 77.90 48 1.34 89.70 55 0.19 91.60 62 0.23 94.18 69 0.10 95.50 76 0.09 96.78 50% Dex PS 1 mg system replicate 3 1 4.50 0.91 7 2.16 3.98 13 1.69 8.42 20 1.25 13.48 27 3.88 34.67 34 3.53 58.97 41 1.85 74.28 48 0.88 82.85 55 0.19 84.94 62 0.26 88.15 69 0.11 89.75 76 0.10 91.26

Example 7: In Vivo Testing of 50/50 Dexamethasone/PLGA 1 mg Formulations in Rabbits

(37) One 50/50 dexamethasone/PLGA 1 mg formulation DDS per eye was implanted into the vitreous of 6 rabbits using a trocar. The DDS was loaded into the trocar, a hole was punched through the sclera, the trocar inserted through the hole, and the trocar plunger depressed to insert the DDS into the vitreous. In vivo vitreous concentrations of dexamethasone were monitored, as shown in Table 8.

(38) TABLE-US-00008 TABLE 8 In vivo vitreous concentrations of dexamethasone Sample ID 5293-D 5295 = D 5293-S 5295-S 5304-D 5306-D 5304-S 5306-S Hours Sample Conc., ug/ml Avg SD  2 1.38 1.69 1.54 0.22  4 2.16 0.96 0.47 0.37  6 0.73 0.21 0.47 0.37 24 0.57 0.74 0.66 0.12 Dex ug/mL Animal#\day 7 21 35 49 63 2953-D 0.5 0.58 2953-S 0.11 0.69 2952-D 0.13 1.2 2952-S 0.12 0.55 2946-D  0.19 2.55 2946-S * 3   0.14 2949-D * 5.44 0.28 2949-S   0.0248 0.01 2982-D 1.087 2982-S 0.058 2983-D 0.018 2983-S 0.045 Ave. 0.22  2.16 0.30 0.76 0.75 * High level was due to the surgical artifact

(39) The data indicate that the 50/50 dexamethasone/PLGA DDS releases dexamethasone to the vitreous in concentrations above 0.01 μg/ml for an extended period of time. The data at two, four, six, and 24 hours in Table 8 shows an initial spike of drug release, due to drug which is unencapsulated by the delivery system.

(40) The 100-120 μg 50/50 PLGA/dexamethasone implant disclosed in U.S. Pat. No. 5,869,079 shows similar in vitro release kinetics to the 500 and 1000 μg 50/50 PLGA/dexamethasone implant disclosed herein. However, the previously disclosed implant would not provide drug concentrations in the vitreous at the levels described herein.

(41) Modifications of the above described modes for carrying out the invention that are obvious to those of ordinary skill in the surgical, pharmaceutical, or related arts are intended to be within the scope of the following claims.