US20230172948A1 - Ocular implant made by a double extrusion proces - Google Patents

Abstract

The invention provides biodegradable implants sized for implantation in an ocular region and methods for treating medical conditions of the eye. The implants are formed from a mixture of hydrophilic end and hydrophobic end PLGA, and deliver active agents into an ocular region without a high burst release.

Description

CROSS REFERENCE
• This application is continuation of U.S. Pat. Application Serial No. 16/915,017, filed Jun. 29, 2020, which is a continuation of U.S. Pat. Application Serial No. 16/132,857, filed Sep. 17, 2018, now U.S. Pat. No. 10,702,539, issued Jul. 7, 2020, which is a continuation of U.S. Pat. Application Serial No. 14/949,454, filed Nov. 23, 2015, now U.S. Pat. No. 10,076,526, issued Sep. 18, 2018, which is a continuation of U.S. Pat. Application Serial No. 13/922,482, filed Jun. 20, 2013, now U.S. Pat. No. 9,192,511, issued Nov. 24, 2015, which is a continuation of U.S. Pat. Application Serial No. 13/797,230, filed Mar. 12, 2013, now U.S. Pat. No. 8,778,381, issued Jul. 15, 2014, which is a continuation of U.S. Pat. Application Serial No. 13/213,473, filed Aug. 19, 2011, now U.S. Pat. No. 8,506,987, issued Aug. 13, 2013, which is a divisional of U.S. Pat. Application Serial No. 11/932,101, filed Oct. 31, 2007, now U.S. Pat. No. 8,034,366, issued Oct. 11, 2011, which is a continuation of U.S. Pat. Application Serial No. 10/918,597, filed Aug. 13, 2004, now abandoned, the entire contents of all seven applications are herein incorporated by reference in their entirety.
BACKGROUND
• This invention relates to implants and methods for treating an ocular condition. In particular the present invention relates to implants and methods for treating an ocular condition by implanting into an ocular region or site a bioerodible implant comprising an active agent and a bioerodible polymer matrix, wherein the implant is made by a double extrusion process. The bioerodible implants of this invention have varying and extended release rates to provide for improved kinetics of release of one or more active (therapeutic) agents over time.
• An ocular condition can include a disease, aliment or condition which affects or involves the eye or one of the parts or regions of the eye. Broadly speaking the eye includes the eyeball and the tissues and fluids which constitute the eyeball, the periocular muscles (such as the oblique and rectus muscles) and the portion of the optic nerve which is within or adjacent to the eyeball. An anterior ocular condition is a disease, ailment or condition which affects or which involves an anterior (i.e. front of the eye) ocular region or site, such as a periocular muscle, an eye lid or an eye ball tissue or fluid which is located anterior to the posterior wall of the lens capsule or ciliary muscles. Thus, an anterior ocular condition primarily affects or involves, the conjunctiva, the cornea, the conjunctiva, the anterior chamber, the iris, the posterior chamber (behind the retina but in front of the posterior wall of the lens capsule), the lens or the lens capsule and blood vessels and nerve which vascularize or innervate an anterior ocular region or site. A posterior ocular condition is a disease, ailment or condition which primarily affects or involves a posterior ocular region or site such as choroid or sclera (in a position posterior to a plane through the posterior wall of the lens capsule), vitreous, vitreous chamber, retina, optic nerve (i.e. the optic disc), and blood vessels and nerves which vascularize or innervate a posterior ocular region or site.
• Thus, a posterior ocular condition can include a disease, ailment or condition, such as for example, macular degeneration (such as non-exudative age related macular degeneration and exudative age related macular degeneration); choroidal neovascularization; acute macular neuroretinopathy; macular edema (such as cystoid macular edema and diabetic macular edema); Behcet’s disease, retinal disorders, diabetic retinopathy (including proliferative diabetic retinopathy); retinal arterial occlusive disease; central retinal vein occlusion; uveitic retinal disease; retinal detachment; ocular trauma which affects a posterior ocular site or location; a posterior ocular condition caused by or influenced by an ocular laser treatment; posterior ocular conditions caused by or influenced by a photodynamic therapy; photocoagulation; radiation retinopathy; epiretinal membrane disorders; branch retinal vein occlusion; anterior ischemic optic neuropathy; non-retinopathy diabetic retinal dysfunction, retinitis pigmentosa and glaucoma. Glaucoma can be considered a posterior ocular condition because the therapeutic goal is to prevent the loss of or reduce the occurrence of loss of vision due to damage to or loss of retinal cells or optic nerve cells (i.e. neuroprotection).
• An anterior ocular condition can include a disease, ailment or condition, such as for example, aphakia; pseudophakia; astigmatism; blepharospasm; cataract; conjunctival diseases; conjunctivitis; corneal diseases;, corneal ulcer; dry eye syndromes; eyelid diseases; lacrimal apparatus diseases; lacrimal duct obstruction; myopia; presbyopia; pupil disorders; refractive disorders and strabismus. Glaucoma can also be considered to be an anterior ocular condition because a clinical goal of glaucoma treatment can be to reduce a hypertension of aqueous fluid in the anterior chamber of the eye (i.e. reduce intraocular pressure).
• The present invention is concerned with and directed to an implant and methods for the treatment of an ocular condition, such as an anterior ocular condition or a posterior ocular condition or to an ocular condition which can be characterized as both an anterior ocular condition and a posterior ocular condition.
• Therapeutic compounds useful for the treatment of an ocular condition can include active agents with, for example, an anti-neoplastic, anti-angiogenesis, kinase inhibition, anticholinergic, anti-adrenergic and/or anti-inflammatory activity.
• Macular degeneration, such as age related macular degeneration (“AMD”) is a leading cause of blindness in the world. It is estimated that thirteen million Americans have evidence of macular degeneration. Macular degeneration results in a break down the macula, the light-sensitive part of the retina responsible for the sharp, direct vision needed to read or drive. Central vision is especially affected. Macular degeneration is diagnosed as either dry (atrophic) or wet (exudative). The dry form of macular degeneration is more common than the wet form of macular degeneration, with about 90% of AMD patients being diagnosed with dry AMD. The wet form of the disease usually leads to more serious vision loss. Macular degeneration can produce a slow or sudden painless loss of vision. The cause of macular degeneration is not clear. The dry form of AMD may result from the aging and thinning of macular tissues, depositing of pigment in the macula, or a combination of the two processes. With wet AMD, new blood vessels grow beneath the retina and leak blood and fluid. This leakage causes retinal cells to die and creates blind spots in central vision.
• Macular edema (“ME”) can result in a swelling of the macula. The edema is caused by fluid leaking from retinal blood vessels. Blood leaks out of the weak vessel walls into a very small area of the macula which is rich in cones, the nerve endings that detect color and from which daytime vision depends. Blurring then occurs in the middle or just to the side of the central visual field. Visual loss can progress over a period of months. Retinal blood vessel obstruction, eye inflammation, and age-related macular degeneration have all been associated with macular edema. The macula may also be affected by swelling following cataract extraction. Symptoms of ME include blurred central vision, distorted vision, vision tinted pink and light sensitivity. Causes of ME can include retinal vein occlusion, macular degeneration, diabetic macular leakage, eye inflammation, idiopathic central serous chorioretinopathy, anterior or posterior uveitis, pars planitis, retinitis pigmentosa, radiation retinopathy, posterior vitreous detachment, epiretinal membrane formation, idiopathic juxtafoveal retinal telangiectasia, Nd:YAG capsulotomy or iridotomy. Some patients with ME may have a history of use of topical epinephrine or prostaglandin analogs for glaucoma. The first line of treatment for ME is typically anti-inflammatory drops topically applied.
• Macular edema is a non-specific response of the retina to a variety of insults. It is associated with a number of diseases, including uveitis, retinal vascular abnormalities (diabetic retinopathy and retinal vein occlusive disease), a sequelae of cataract surgery (post-cataract cystoid macular oedema), macular epiretinal membranes, and inherited or acquired retinal degeneration. Macular edema involves the breakdown of the inner blood retinal barrier at the level of the capillary endothelium, resulting in abnormal retinal vascular permeability and leakage into the adjacent retinal tissues. The macula becomes thickened due to fluid accumulation resulting in significant disturbances in visual acuity (Ahmed I, Ai E. Macular disorders: cystoid macular oedema. In: Yanoff M, Duker JS, eds. Ophthalmology. London: Mosby; 1999:34; Dick J, Jampol LM, Haller JA. Macular edema. In: Ryan S, Schachat AP, eds. Retina. 3rd ed. St. Louis, MO: CVMosby; 2001, v2, Section 2 chap 57:967-979).
• Macular edema may occur in diseases causing cumulative injury over many years, such as diabetic retinopathy, or as a result of more acute events, such as central retinal vein occlusion or branch retinal vein occlusion.
• In some cases macular edema resolves spontaneously or with short-term treatment. Therapeutic choices for macular oedema depend on the cause and severity of the condition. Currently there are no approved pharmacological therapies for macular edema. Focal/grid laser photocoagulation has been shown to be efficacious in the prevention of moderate visual loss for macular oedema due to diabetic retinopathy (Akduman L, Olk RS. The early treatment diabetic retinopathy study. In: Kertes PS, Conway MD, eds. Clinical trials in ophthalmology: a summary and practice guide. Baltimore, MD: Lippincott Williams & Wilkins; 1998:15-35; Frank RN. Etiologic mechanisms in diabetic retinopathy. In: Ryan S, Schachat AP, eds. Retina. 3rd ed. St. Louis, MO: CV Mosby; 2001, v2, Section 2, chap 71:1259-1294). Argon laser photocoagulation increased the likelihood of vision improvement in patients with macular oedema due to branch retinal vein occlusion (BRVO) (Orth D. The branch vein occlusion study. In: Kertes P, Conway M, eds. Clinical trials in ophthalmology: a summary and practice guide. Baltimore, MD: Lippincott Williams & Wilkins; 1998:113-127; Fekrat S, Finkelstein D. The Central Vein Occlusion Study. In: Kertes PS, Conway MD, eds. Clinical trials in ophthalmology: a summary and practice guide. Baltimore, MD: Lippincott Williams & Wilkins; 1998:129-143), but not in patients with macular oedema due to central retinal vein occlusion (CRVO) (Fekrat and Finkelstein 1998, supra; Clarkson JG. Central retinal vein occlusion. In: Ryan S, Schachat AP, eds. Retina. 3rd ed. St. Louis, MO: CV Mosby; 2001, v2, chap 75:1368 -1375). For CRVO, there are no known effective therapies.
• An anti-inflammatory (i.e. immunosuppressive) agent can be used for the treatment of an ocular condition, such as a posterior ocular condition, which involves inflammation, such as an uveitis or macula edema. Thus, topical or oral glucocorticoids have been used to treat uveitis. A major problem with topical and oral drug administration is the inability of the drug to achieve an adequate (i.e. therapeutic) intraocular concentration. See e.g. Bloch-Michel E. (1992). Opening address: intermediate uveitis, In Intermediate Uveitis, Dev. Ophthalmol, W.R.F. Böke et al. editors., Basel: Karger, 23:1-2; Pinar, V., et al. (1997). “Intraocular inflammation and uveitis” In Basic and Clinical Science Course. Section 9 (1997-1998) San Francisco: American Academy of Ophthalmology, pp. 57-80, 102-103, 152-156; Böke, W. (1992). Clinical picture of intermediate uveitis, In Intermediate Uveitis, Dev. Ophthalmol. W.R.F. Böke et al. editors., Basel: Karger, 23:20-7; and Cheng C-K et al. (1995). Intravitreal sustained-release dexamethasone device in the treatment of experimental uveitis, Invest. Ophthalmol. Vis. Sci. 36:442-53.
• Systemic glucocorticoid administration can be used alone or in addition to topical glucocorticoids for the treatment of uveitis. However, prolonged exposure to high plasma concentrations (administration of 1 mg/kg/day for 2-3 weeks) of steroid is often necessary so that therapeutic levels can be achieved in the eye.
• Unfortunately, these high drug plasma levels commonly lead to systemic side effects such as hypertension, hyperglycemia, increased susceptibility to infection, peptic ulcers, psychosis, and other complications. Cheng C-K et al. (1995). Intravitreal sustained-release dexamethasone device in the treatment of experimental uveitis, Invest. Ophthalmol. Vis. Sci. 36:442-53; Schwartz, B. (1966). The response of ocular pressure to corticosteroids, Ophthalmol. Clin. North Am. 6:929-89; Skalka, H.W. et al. (1980). Effect of corticosteroids on cataract formation, Arch Ophthalmol 98:1773-7; and Renfro, L. et al. (1992). Ocular effects of topical and systemic steroids, Dermatologic Clinics 10:505-12.
• Additionally, delivery to the eye of a therapeutic amount of an active agent can be difficult, if not impossible, for drugs with short plasma half-lives since the exposure of the drug to intraocular tissues is limited. Therefore, a more efficient way of delivering a drug to treat a posterior ocular condition is to place the drug directly in the eye, such as directly into the vitreous. Maurice, D.M. (1983). Micropharmaceutics of the eye, Ocular Inflammation Ther. 1:97-102; Lee, V.H.L. et al. (1989). Drug delivery to the posterior segment” Chapter 25 In Retina. T.E. Ogden and A.P. Schachat eds., St. Louis: CV Mosby, Vol. 1, pp. 483-98; and Olsen, T.W. et al. (1995). Human scleral permeability: effects of age, cryotherapy, transscleral diode laser, and surgical thinning, Invest. Ophthalmol. Vis. Sci. 36:1893-1903.
• Techniques such as intravitreal injection of a drug have shown promising results, but due to the short intraocular half-life of active agent, such as glucocorticoids (approximately 3 hours), intravitreal injections must be frequently repeated to maintain a therapeutic drug level. In turn, this repetitive process increases the potential for side effects such as retinal detachment, endophthalmitis, and cataracts. Maurice, D.M. (1983). Micropharmaceutics of the eye, Ocular Inflammation Ther. 1:97-102; Olsen, T.W. et al. (1995). Human scleral permeability: effects of age, cryotherapy, transscleral diode laser, and surgical thinning, Invest. Ophthalmol. Vis. Sci. 36:1893-1903; and Kwak, H.W. and D’Amico, D. J. (1992). Evaluation of the retinal toxicity and pharmacokinetics of dexamethasone after intravitreal injection, Arch. Ophthalmol. 110:259-66.
• Additionally, topical, systemic, and periocular glucocorticoid treatment must be monitored closely due to toxicity and the long-term side effects associated with chronic systemic drug exposure sequelae. Rao, N.A. et al. (1997). Intraocular inflammation and uveitis, In Basic and Clinical Science Course. Section 9 (1997-1998) San Francisco: American Academy of Ophthalmology, pp. 57-80, 102-103, 152-156; Schwartz, B. (1966). The response of ocular pressure to corticosteroids, Ophthalmol Clin North Am 6:929-89; Skalka, H.W. and Pichal, J.T. (1980). Effect of corticosteroids on cataract formation, Arch Ophthalmol 98:1773-7; Renfro, L and Snow, J.S. (1992). Ocular effects of topical and systemic steroids, Dermatologic Clinics 10:505-12; Bodor, N. et al. (1992). A comparison of intraocular pressure elevating activity of loteprednol etabonate and dexamethasone in rabbits, Current Eye Research 11:525-30.
• U.S. Pat. 6,217,895 discusses a method of administering a corticosteroid to the posterior segment of the eye, but does not disclose a bioerodible implant.
• U.S. Pat. 5,501,856 discloses controlled release pharmaceutical preparations for intraocular implants to be applied to the interior of the eye after a surgical operation for disorders in retina/vitreous body or for glaucoma.
• U.S. Pat. 5,869,079 discloses combinations of hydrophilic and hydrophobic entities in a biodegradable sustained release implant, and describes a polylactic acid polyglycolic acid (PLGA) copolymer implant comprising dexamethasone. As shown by in vitro testing of the drug release kinetics, the 100-120 µg 50/50 PLGA/dexamethasone implant disclosed did not show appreciable drug release until the beginning of the fourth week, unless a release enhancer, such as HPMC was added to the formulation.
• U.S. Pat. No. 5,824,072 discloses implants for introduction into a suprachoroidal space or an avascular region of the eye, and describes a methylcellulose (i.e. non-biodegradable) implant comprising dexamethasone. WO 9513765 discloses implants comprising active agents for introduction into a suprachoroidal or an avascular region of an eye for therapeutic purposes.
• U.S. Pat. 4,997,652 and 5,164,188 disclose biodegradable ocular implants comprising microencapsulated drugs, and describes implanting microcapsules comprising hydrocortisone succinate into the posterior segment of the eye.
• U.S. Pat. 5,164,188 discloses encapsulated agents for introduction into the suprachoroid of the eye, and describes placing microcapsules and plaques comprising hydrocortisone into the pars plana. U.S. Pat. Nos. 5,443,505 and 5,766,242 discloses implants comprising active agents for introduction into a suprachoroidal space or an avascular region of the eye, and describes placing microcapsules and plaques comprising hydrocortisone into the pars plana.
• Zhou et al. disclose a multiple-drug implant comprising 5-fluorouridine, triamcinolone, and human recombinant tissue plasminogen activator for intraocular management of proliferative vitreoretinopathy (PVR). Zhou, T, et al. (1998). Development of a multiple-drug delivery implant for intraocular management of proliferative vitreoretinopathy, Journal of Controlled Release 55: 281-295.
• U.S. Pat. 6,046,187 discusses methods and compositions for modulating local anesthetic by administering one or more glucocorticosteroid agents before, simultaneously with or after the administration of a local anesthetic at a site in a patient.
• U.S. Pat. 3,986,510 discusses ocular inserts having one or more inner reservoirs of a drug formulation confined within a bioerodible drug release rate controlling material of a shape adapted for insertion and retention in the “sac of the eye,” which is indicated as being bounded by the surfaces of the bulbar conjunctiva of the sclera of the eyeball and the palpebral conjunctiva of the eyelid, or for placement over the corneal section of the eye.
• U.S. Pat. 6,369,116 discusses an implant with a release modifier inserted in a scleral flap.
• EP 0 654256 discusses use of a scleral plug after surgery on a vitreous body, for plugging an incision.
• U.S. Pat. 4,863,457 discusses the use of a bioerodible implant to prevent failure of glaucoma filtration surgery by positioning the implant either in the subconjunctival region between the conjunctival membrane overlying it and the sclera beneath it or within the sclera itself within a partial thickness sclera flap.
• EP 488 401 discusses intraocular implants, made of certain polylactic acids, to be applied to the interior of the eye after a surgical operation for disorders of the retina/vitreous body or for glaucoma.
• EP 430539 discusses use of a bioerodible implant which is inserted in the suprachoroid.
• U.S. Pat. 6,726,918 discusses implants for treating inflammation mediated conditions of the eye.
• Significantly, it is known that PLGA co-polymer formulations of a bioerodible polymer comprising an active agent typically release the active agent with a characteristic sigmoidal release profile (as viewed as time vs percent of total active agent released), that is after a relatively long initial lag period (the first release phase) when little if any active agent is released, there is a high positive slope period when most of the active agent is released (the second release phase) followed by another near horizontal (third) release phase, when the drug release reaches a plateau.
• One of the alternatives to intravitreal injection to administer drugs is the placement of biodegradable implants under the sclera or into the subconjunctival or suprachoroidal space, as described in U.S. 4,863,457 to Lee; WO 95/13765 to Wong et al.; WO 00/37056 to Wong et al.; EP 430,539 to Wong; in Gould et al., Can. J. Ophthalmol. 29(4):168-171 (1994); and in Apel et al., Curr. Eye Res. 14:659-667 (1995).
• Furthermore, the controlled release of drugs from polylactide/polyglycolide (PLGA) copolymers into the vitreous has been disclosed, e.g., in U.S. 5,501,856 to Ohtori et al. and EP 654,256 to Ogura.
• Recent experimental work has demonstrated that uncapped PLGA degrades faster than capped (end-capped) PLGA (Park et al., J. Control. Rel. 55:181-191 (1998); Tracy et al., Biomaterials 20:1057-1062 (1999); and Jong et al., Polymer 42:2795-2802 (2001). Accordingly, implants containing mixtures of uncapped and capped PLGA have been formed to modulate drug release. For example, U.S. 6,217,911 to Vaughn et al. (‘911) and U.S. 6,309,669 to Setterstrom et al. (‘669) disclose the delivery of drugs from a blend of uncapped and capped PLGA copolymer to curtail initial burst release of the drugs. In the ‘911 patent, the composition delivers non-steroidal anti-inflammatory drugs from PLGA microspheres made by a solvent extraction process or PLGA microcapsules prepared by a solvent evaporation process over a duration of 24 hours to 2 months. In the ‘669 patent, the composition delivers various pharmaceuticals from PLGA microcapsules over a duration of 1-100 days. The PLGA microspheres or microcapsules are administered orally or as an aqueous injectable formulation. As mentioned above, there is poor partitioning of drug into the eye with oral administration. Furthermore, use of an aqueous injectable drug composition (for injecting into the eye) should be avoided since the eye is a closed space (limited volume) with intraocular pressure ranges that are strictly maintained. Administration of an injectable may increase intraocular volume to a point where intraocular pressures would then become pathologic.
• Potent corticosteroids such as dexamethasone suppress inflammation by inhibiting edema, fibrin deposition, capillary leakage and phagocytic migration, all key features of the inflammatory response. Corticosteroids prevent the release of prostaglandins, some of which have been identified as mediators of cystoid macular oedema (Leopold IH. Nonsteroidal and steroidal anti-inflammatory agents. In: Sears M, Tarkkanen A, eds. Surgical pharmacology of the eye. New York, NY: Raven Press; 1985:83-133; Tennant JL. Cystoid maculopathy: 125 prostaglandins in ophthalmology. In: Emery JM, ed. Current concepts in cataract surgery: selected proceedings of the fifth biennial cataract surgical congress, Section 3. St. Louis, MO: CV Mosby; 1978;360-362). Additionally, corticosteroids including dexamethasone have been shown to inhibit the expression of vascular endothelial growth factor (VEGF), a cytokine which is a potent promoter of vascular permeability (Nauck M, Karakiulakis G, Perruchoud AP, Papakonstantinou E, Roth M. Corticosteroids inhibit the expression of the vascular endothelial growth factor gene in human vascular smooth muscle cells. Eur J Pharmacol 1998;341:309-315).
• The use of dexamethasone to date, by conventional routes of administration, has yielded limited success in treating retinal disorders, including macular oedema, largely due to the inability to deliver and maintain adequate quantities of the drug to the posterior segment without resultant toxicity. After topical administration of dexamethasone, only about 1% reaches the anterior segment, and only a fraction of that amount moves into the posterior segment (Lee VHL, Pince KJ, Frambach DA, Martini B. Drug delivery to the posterior segment. In: Ogden TE, Schachat AP, eds. Retina. St. Louis, MO: CV Mosby, 1989, chap 25:483-498). Although intravitreal injections of dexamethasone have been used, the exposure to the drug is very brief as the half-life of the drug within the eye is approximately 3 hours (Peyman GA, Herbst R. Bacterial endophthalmitis. Arch Ophthalmol 1974;91:416-418). Periocular and posterior sub-Tenon’s injections of dexamethasone also have a short term treatment effect (Riordan-Eva P, Lightman S. Orbital floor steroid injections in the treatment of uveitis. Eye 1994;8 (Pt 1):66-69; Jennings T, Rusin M, Tessler H, Cunha-Vaz J. Posterior sub-Tenon’s injections of corticosteroids in uveitis patients with cystoid macular edema. Jpn J Ophthalmol 1988;32:385-391).
• Adverse reactions listed for conventional ophthalmic dexamethasone preparations include: ocular hypertension, glaucoma, posterior subcapsular cataract formation, and secondary ocular infection from pathogens including herpes simplex (Lee et al, 1989 supra; Skalka HW, Prchal JT. Effect of corticosteroids on cataract formation. Arch Ophthalmol 1980;98:1773-1777; Renfro L, Snow JS. Ocular effects of topical and systemic steroids. Dermatol Clin 1992;10(3):505-512; Physician’s Desk Reference, 2003). Systemic doses are associated with additional hazardous side-effects including hypertension, hyperglycemias, increased susceptibility to infection, and peptic ulcers (Physician’s Desk Reference, 2003).
• By delivering a drug directly into the vitreous cavity, blood eye barriers can be circumvented and intraocular therapeutic levels can be achieved with minimal risk of systemic toxicity (Lee et al, 1989 supra). This route of administration typically results in a short half-life unless the drug can be delivered using a formulation capable of providing sustained release.
• Consequently, a biodegradable implant for delivering a therapeutic agent to an ocular region may provide significant medical benefit for patients afflicted with a medical condition of the eye.

Claims (13)

We claim:

1. A method for treating uveitis or macular edema in the eye of a patient, the method comprising implanting into an ocular region of an eye of a patient in need thereof a bioerodible implant comprising particles of an active agent dispersed within a biodegradable polymer matrix, wherein

at least 75% of the particles of the active agent have a diameter of less than 20 µm,

the biodegradable polymer comprises poly(lactic-co-glycolic)acid (PLGA) copolymer,

the ratio of lactic to glycolic acid monomers in the PLGA copolymer is 50/50 weight percentage, and

the bioerodible implant is prepared by milling the biodegradable polymer and subjecting the active agent and the biodegradable polymer to a double extrusion process.

2. The method of claim 1, wherein at least 99% of the particles of the active agent have a diameter of less than 20 µm.

3. The method of claim 1, wherein the active agent is selected from the group consisting of ace-inhibitors, endogenous cytokines, agents that influence basement membrane, agents that influence the growth of endothelial cells, adrenergic agonists or blockers, cholinergic agonists or blockers, aldose reductase inhibitors, analgesics, anesthetics, antiallergics, anti-inflammatory agents, steroids, antihypertensives, pressors, antibacterials, antivirals, antifungals, antiprotozoals, anti-infective agents, antitumor agents, antimetabolites and antiangiogenic agents.

4. The method of claim 1, wherein the active agent comprises an anti-inflammatory agent or any derivative thereof.

5. The method of claim 4, wherein the anti-inflammatory agent comprises a steroidal anti-inflammatory agent.

6. The method of claim 5, wherein the steroidal anti-inflammatory agent is selected from the group consisting of cortisone, dexamethasone, fluocinolone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone and any derivative thereof.

7. The method of claim 6, wherein the steroidal anti-inflammatory agent comprises dexamethasone.

8. The method of claim 1, wherein the implant is sized for implantation in an ocular region.

9. The method of claim 8, wherein the ocular region is selected from the group consisting of the anterior chamber, the posterior chamber, the vitreous cavity, the choroid, the suprachoroidal space, the conjunctiva, the subconjunctival space, the episcleral space, the intracorneal space, the epicomeal space, the sclera, the pars plana, surgically-induced avascular regions, the macula and the retina.

10. The method of claim 9, wherein the ocular region is the vitreous cavity.

11. The method of claim 1, wherein the PLGA copolymer is 40% by weight of the bioerodible implant.

12. The method of claim 7, wherein the method is effective to treat uveitis.

13. The method of claim 7, wherein the method is effective to treat macular edema.

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