US20050048099A1 - Ocular implant made by a double extrusion process - Google Patents
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- US20050048099A1 US20050048099A1 US10/918,597 US91859704A US2005048099A1 US 20050048099 A1 US20050048099 A1 US 20050048099A1 US 91859704 A US91859704 A US 91859704A US 2005048099 A1 US2005048099 A1 US 2005048099A1
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- dexamethasone
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- JFLXXQZZJJSDRB-UHFFFAOYSA-N COC(C)C(=O)OCC(=O)O Chemical compound COC(C)C(=O)OCC(=O)O JFLXXQZZJJSDRB-UHFFFAOYSA-N 0.000 description 1
- RIBAVTIQBCCICW-UHFFFAOYSA-N COC(C)C(=O)OCC(C)=O Chemical compound COC(C)C(=O)OCC(C)=O RIBAVTIQBCCICW-UHFFFAOYSA-N 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N [H][C@@]12C[C@@]([H])(C)[C@](O)(C(=O)CO)[C@@]1(C)C[C@]([H])(O)[C@]1(F)[C@@]3(C)C=CC(=O)C=C3CC[C@@]21[H] Chemical compound [H][C@@]12C[C@@]([H])(C)[C@](O)(C(=O)CO)[C@@]1(C)C[C@]([H])(O)[C@]1(F)[C@@]3(C)C=CC(=O)C=C3CC[C@@]21[H] UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
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- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F9/00—Methods or devices for treatment of the eyes; Devices for putting-in contact lenses; Devices to correct squinting; Apparatus to guide the blind; Protective devices for the eyes, carried on the body or in the hand
- A61F9/0008—Introducing ophthalmic products into the ocular cavity or retaining products therein
- A61F9/0017—Introducing ophthalmic products into the ocular cavity or retaining products therein implantable in, or in contact with, the eye, e.g. ocular inserts
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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- A61K9/204—Polyesters, e.g. poly(lactide-co-glycolide)
Definitions
- This invention relates to implants and methods for treating an ocular condition.
- 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.
- 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.
- 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.
- 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 neuro
- 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.
- an ocular condition such as an anterior ocular condition or a posterior ocular condition
- 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.
- AMD age related macular degeneration
- 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.
- 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.
- 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.
- macular edema resolves spontaneously or with short-term treatment.
- Therapeutic choices for macular oedema depend on the cause and severity of the condition.
- 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 R S. The early treatment diabetic retinopathy study. In: Kertes P S, Conway M D, eds. Clinical trials in ophthalmology: a summary and practice guide. Baltimore, Md.: Lippincott Williams & Wilkins; 1998:15-35; Frank R N. Etiologic mechanisms in diabetic retinopathy.
- 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.
- an ocular condition such as a posterior ocular condition, which involves inflammation, such as an uveitis or macula edema.
- 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.
- Systemic glucocorticoid administration can be used alone or in addition to topical glucocorticoids for the treatment of uveitis.
- 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.
- intravitreal injection of a drug has 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.
- U.S. Pat. No. 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. No. 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. No. 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.
- PLGA polylactic acid polyglycolic acid
- the 100-120 ⁇ g 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. No. 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. No. 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).
- PVR proliferative vitreoretinopathy
- U.S. Pat. No. 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. No. 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 conjuctiva 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. No. 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. No. 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. No. 6,726,918 discusses implants for treating inflammation mediated conditions of the eye.
- 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. Pat. No. 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).
- 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.
- 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.
- an aqueous injectable drug composition for injecting into the eye
- 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 I H. Nonsteroidal and steroidal anti-inflammatory agents. In: Sears M, Tarkkanen A, eds. Surgical pharmacology of the eye. New York, N.Y.: Raven Press; 1985:83-133; Tennant J L. Cystoid maculopathy: 125 prostaglandins in ophthalmology.
- VEGF vascular endothelial growth factor
- cytokine which is a potent promoter of vascular permeability
- 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.
- topical administration of dexamethasone only about 1% reaches the anterior segment, and only a fraction of that amount moves into the posterior segment (Lee V H L, Pince K J, Frambach D A, Martini B. Drug delivery to the posterior segment. In: Ogden T E, Schachat A P, eds. Retina. St. Louis, Mo.: C V Mosby, 1989, chap 25:483-498).
- 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 H W, Prchal J T. Effect of corticosteroids on cataract formation. Arch Ophthalmol 1980;98:1773-1777; Renfro L, Snow J S. 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).
- 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.
- FIG. 1 shows the in vivo concentration of dexamethasone in the vitreous of rabbit eyes over a 42 day period after implantation of compressed and extruded biodegradable implants containing 350 ⁇ g dexamethasone into the posterior segment of rabbit eyes.
- FIG. 2 shows the in vivo cumulative percentage release of dexamethasone in the vitreous of rabbit eyes over a 42 day period after implantation of compressed and extruded biodegradable implants containing 350 ⁇ g dexamethasone and 700 ⁇ g dexamethasone into the posterior segment of rabbit eyes.
- FIG. 3 shows the in vivo concentration of dexamethasone in the aqueous humor of rabbit eyes over a 42 day period after implantation of compressed and extruded biodegradable implants containing 350 jig dexamethasone into the posterior segment of rabbit eyes.
- FIG. 4 shows the in vivo concentration of dexamethasone in the plasma (from a rabbit blood sample) over a 42 day period after implantation of compressed and extruded biodegradable implants containing 350 ⁇ g dexamethasone into the posterior segment of rabbit eyes.
- FIG. 5 shows the in vivo concentration of dexamethasone in the vitreous of rabbit eyes over a 42 day period after implantation of compressed and extruded biodegradable implants containing 700 ⁇ g dexamethasone into the posterior segment of rabbit eyes.
- FIG. 6 shows the in vivo concentration of dexamethasone in the aqueous humor of rabbit eyes over a 42 day period after implantation of compressed and extruded biodegradable implants containing 700 ⁇ g dexamethasone into the posterior segment of rabbit eyes.
- FIG. 7 shows the in vivo concentration of dexamethasone in the plasma (from a rabbit blood sample) over a 42 day period after implantation of compressed and extruded biodegradable implants containing 700 ⁇ g dexamethasone into the posterior segment of rabbit eyes.
- FIG. 8 shows the in vivo concentration of dexamethasone in the vitreous of rabbit eyes over a 42 day period after implantation of compressed and extruded biodegradable implants containing 350 ⁇ g dexamethasone and 700 ⁇ g dexamethasone into the posterior segment of rabbit eyes.
- FIG. 9 shows the in vitro total cumulative percentage release of dexamethasone into a saline solution at 37° C. from 60/40 w/w dexamethasone/PLGA implants having a weight ratio of 40:0 hydrophobic end to hydrophilic end PLGA (312-140-2), weight ratio of 30:10 hydrophobic end to hydrophilic end PLGA (312-140-4), weight ratio of 20:20 hydrophobic end to hydrophilic end PLGA (312-140-3), and weight ratio of 0:40 hydrophobic end to hydrophilic end PLGA (312-140-1).
- FIG. 10 compares the in vitro cumulative percentage release of dexamethasone into a saline solution at 37° C. for six lots of extruded implants having 60% by weight dexamethasone, 30% by weight hydrophilic end PLGA, and 10% by weight hydrophobic end PLGA.
- FIG. 11 is a flow chart illustrating manufacturing processes for tablet, single and double extrusion methods for making an ocular implant within the scope of the present invention.
- FIG. 12 is a graph which shows the cumulative amount of dexamethasone released in vitro over time for an ocular implant made by either tabletting or a single extrusion processes.
- FIG. 13 are scanning electromicrographs (SEM) pictures of DEX PS DDS implants made by a tabletting process and by a single extrusion process.
- FIG. 14 shows two graphs of batch to batch vs within batch variability of % LC (% of total dexamethasone) for implants made from either unmilled or milled PLGAs.
- FIG. 15 is a graph showing in vitro release of dexamethasone from DEX PS DDS implants made by either a single extrusion or by a double extrusion process.
- FIG. 16 is a flow chart illustrating a double extrusion manufacturing processes for making an ocular implant within the scope of the present invention.
- FIG. 17 provides a cut-away side view of an applicator to implant an ocular implant within the scope of the present invention.
- Active agent and “drug” are used interchangeably and refer to any substance used to treat an ocular condition.
- Bioerodible polymer means a polymer which degrades in vivo, and wherein erosion of the polymer over time is required to achieve the active agent release kinetics according to the present invention.
- hydrogels such as methylcellulose which act to release drug through polymer swelling are specifically excluded from the term “bioerodible (or biodegradable) polymer”.
- bioerodible and biodegradable are synonymous and are used interchangeably herein.
- “Concentration equivalent to dexamethasone”, or “dexamethasone equivalent” means a concentration of an active agent, such as a steroidal anti-inflammatory agent, necessary to have approximately the same efficacy in vivo as a particular dose of dexamethasone.
- an active agent such as a steroidal anti-inflammatory agent
- hydrocortisone is approximately twenty five fold less potent than dexamethasone, and thus a 25 mg dose of hydrocortisone would be equivalent to a 1 mg dose of dexamethasone.
- concentration equivalent to dexamethasone for a particular steroidal anti-inflammatory agent from one of several standard tests known in the art.
- “Cumulative release profile” means to the cumulative total percent of an active agent released from an implant into an ocular region or site in vivo over time or into a specific release medium in vitro over time.
- Glaucoma means primary, secondary and/or congenital glaucoma.
- Primary glaucoma can include open angle and closed angle glaucoma.
- Secondary glaucoma can occur as a complication of a variety of other conditions, such as injury, inflammation, vascular disease and diabetes.
- “Inflammation-mediated” in relation to an ocular condition means any condition of the eye which can benefit from treatment with an anti-inflammatory agent, and is meant to include, but is not limited to, uveitis, macular edema, acute macular degeneration, retinal detachment, ocular tumors, fungal or viral infections, multifocal choroiditis, diabetic uveitis, proliferative vitreoretinopathy (PVR), sympathetic opthalmia, Vogt Koyanagi-Harada (VKH) syndrome, histoplasmosis, and uveal diffusion.
- PVR proliferative vitreoretinopathy
- VKH Vogt Koyanagi-Harada
- “Injury” or “damage” are interchangeable and refer to the cellular and morphological manifestations and symptoms resulting from an inflammatory-mediated condition, such as, for example, inflammation.
- Measured under infinite sink conditions in vitro means assays to measure drug release in vitro, wherein the experiment is designed such that the drug concentration in the receptor medium never exceeds 5% of saturation. Examples of suitable assays may be found, for example, in USP 23; NF 18 (1995) pp. 1790-1798.
- “Ocular condition” means a disease, aliment or condition which affects or involves the eye or one or the parts or regions of the eye, such as a retinal disease.
- 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. :“Ocular condition” is synonymous with “medical condition of the eye”
- “Plurality” means two or more.
- Posterior ocular condition means a disease, ailment or condition which 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 nerve which vascularize or innervate a posterior ocular region or site.
- 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 nerve which vascularize or innervate a posterior ocular region or site.
- Stemoidal anti-inflammatory agent and “glucocorticoid” are used interchangeably herein, and are meant to include steroidal agents, compounds or drugs which reduce inflammation when administered at a therapeutically effective level.
- “Substantially” in relation to the release profile or the release characteristic of an active agent from a bioerodible implant as in the phrase “substantially continuous rate” of the active agent release rate from the implant means, that the rate of release (i.e. amount of active agent released/unit of time) does not vary by more than 100%, and preferably does not vary by more than 50%, over the period of time selected (i.e. a number of days). “Substantially” in relation to the blending, mixing or dispersing of an active agent in a polymer, as in the phrase “substantially homogenously dispersed” means that there are no or essentially no particles (i.e. aggregations) of active agent in such a homogenous dispersal.
- Suitable for insertion (or implantation) in (or into) an ocular region or site means an implant which has a size (dimensions) such that it can be inserted or implanted without causing excessive tissue damage and without unduly physically interfering with the existing vision of the patient into which the implant is implanted or inserted.
- “Therapeutic levels” or “therapeutic amount” means an amount or a concentration of an active agent that has been locally delivered to an ocular region that is appropriate to safely treat an ocular condition so as to reduce or prevent a symptom of an ocular condition.
- Our invention encompasses a bioerodible implant for treating a medical condition of the eye comprising an active agent dispersed within a biodegradable polymer matrix, wherein at least about 75% of the particles of the active agent have a diameter of less than about 10 ⁇ m. Preferably, at least about 99% of the particles have a diameter of s than about 20 ⁇ m.
- the active agent can be 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 (such as a steroidal anti-inflammatory agent), antihypertensives, pressors, antibacterials, antivirals, antifungals, antiprotozoals, anti-infective agents, antitumor agents, antimetabolites, and antiangiogenic agents.
- the active agent can be cortisone, dexamethasone, fluocinolone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, and any derivative thereof.
- the bioerodible implant is sized for implantation in an ocular region.
- Te ocular region can be any one or more 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 epicorneal space, the sclera, the pars plana, surgically-induced avascular regions, the macula, and the retina.
- An alternate embodiment of the bioerodible implant can comprise a steroid active agent dispersed within a biodegradable polymer matrix, wherein at least about 75% of the particles of the active agent have a diameter of less than about 20 ⁇ m.
- Our present invention also encompasses a method for making a bioerodible implant for treating a medical condition of the eye, the method comprising a plurality of extrusions of a biodegradable polymer.
- This method can also comprise the step of milling the biodegradable polymer prior to the extrusion.
- the biodegradable polymer can be a poly(lactic-co-glycolic)acid (PLGA) copolymer.
- the ratio of lactic to glycolic acid monomers in the polymer can be about 50/50 weight percentage.
- the PLGA copolymer can be about 20 to about 90 weight percent of the bioerodible implant. Alternately, the PLGA copolymer can be about 40 percent by weight of the bioerodible implant.
- a detailed method for making a bioerodible implant for treating a medical condition of the eye can have the steps of: (a) milling a biodegradable polymer; (b) blending the milled biodegradable polymer and particles of an active agent, to thereby obtain a blended mixture of the milled biodegradable polymer and the particles of the active agent, wherein at least about 75% of the particles of the active agent have a diameter of less than about 20 ⁇ m; (c) carrying out a first extrusion of the blended mixture, to thereby obtain a first extrusion product; (d) pelletizing the first extrusion product, and; (e) carrying out a second extrusion of the pelletized first extrusion product, thereby obtaining a bioerodible implant for treating a medical condition of the eye.
- Our invention also includes a bioerodible implant for treating a medical condition of the eye made by this detailed method.
- the present invention provides biodegradable ocular implants and methods for treating medical conditions of the eye.
- the implants are formed to be monolithic, i.e., the particles of active agent are distributed throughout the biodegradable polymer matrix.
- the implants are formed to release an active agent into an ocular region of the eye over various time periods.
- the active agent may be release over a time period including, but is not limited to, approximately six months, approximately three months, approximately one month, or less than one month.
- the implants of the invention include an active agent dispersed within a biodegradable polymer.
- the implant compositions typically vary according to the preferred drug release profile, the particular active agent used, the condition being treated, and the medical history of the patient.
- Active agents that may be used include, but are not limited to, 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, antihypertensives, pressors, antibacterials, antivirals, antifungals, antiprotozoals, anti-infectives, antitumor agents, antimetabolites, and antiangiogenic agents.
- the active agent is methotrexate. In another variation, the active agent is retinoic acid.
- the anti-inflammatory agent is a nonsteroidal anti-inflammatory agent.
- Nonsteroidal anti-inflammatory agents that may be used include, but are not limited to, aspirin, diclofenac, flurbiprofen, ibuprofen, ketorolac, naproxen, and suprofen. In a more preferred variation, the anti-inflammatory agent is a steroidal anti-inflammatory agent.
- the steroidal anti-inflammatory agents that may be used in the ocular implants include, but are not limited to, 21-acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clobetasone, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difluprednate, enoxolone, fluazacort, flucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluperolone acetate, flupredniden
- cortisone, dexamethasone, fluocinolone, hydrocortisone, methylprednisolone, prednisolone, prednisone, and triamcinolone, and their derivatives are preferred steroidal anti-inflammatory agents.
- the steroidal anti-inflammatory agent is dexamethasone.
- the biodegradable implant includes a combination of two or more steroidal anti-inflammatory agents.
- the steroidal anti-inflammatory agent may constitute from about 10% to about 90% by weight of the implant. In one variation, the agent is from about 40% to about 80% by weight of the implant. In a preferred variation, the agent comprises about 60% by weight of the implant.
- the active agent may be homogeneously dispersed in the biodegradable polymer matrix of the implants.
- the selection of the biodegradable polymer matrix to be employed will vary with the desired release kinetics, patient tolerance, the nature of the disease to be treated, and the like. Polymer characteristics that are considered include, but are not limited to, the biocompatibility and biodegradability at the site of implantation, compatibility with the active agent of interest, and processing temperatures.
- the biodegradable polymer matrix usually comprises at least about 10, at least about 20, at least about 30, at least about 40, at least about 50, at least about 60, at least about 70, at least about 80, or at least about 90 weight percent of the implant. In one variation, the biodegradable polymer matrix comprises about 40% by weight of the implant.
- Biodegradable polymer matrices which may be employed include, but are not limited to, polymers made of monomers such as organic esters or ethers, which when degraded result in physiologically acceptable degradation products. Anhydrides, amides, orthoesters, or the like, by themselves or in combination with other monomers, may also be used.
- the polymers are generally condensation polymers.
- the polymers may be crosslinked or non-crosslinked. If crosslinked, they are usually not more than lightly crosslinked, and are less than 5% crosslinked, usually less than 1% crosslinked.
- the polymers will include oxygen and nitrogen, particularly oxygen.
- the oxygen may be present as oxy, e.g., hydroxy or ether, carbonyl, e.g., non-oxo-carbonyl, such as carboxylic acid ester, and the like.
- the nitrogen may be present as amide, cyano, and amino.
- polymers of hydroxyaliphatic carboxylic acids include polymers of hydroxyaliphatic carboxylic acids, either homo- or copolymers, and polysaccharides. Included among the polyesters of interest are homo- or copolymers of D-lactic acid, L-lactic acid, racemic lactic acid, glycolic acid, caprolactone, and combinations thereof. Copolymers of glycolic and lactic acid are of particular interest, where the rate of biodegradation is controlled by the ratio of glycolic to lactic acid.
- the percent of each monomer in poly(lactic-co-glycolic)acid (PLGA) copolymer may be 0-100%, about 15-85%, about 25-75%, or about 35-65%. In a preferred variation, a 50/50 PLGA copolymer is used. More preferably, a random copolymer of 50/50 PLGA is used.
- Biodegradable polymer matrices that include mixtures of hydrophilic and hydrophobic ended PLGA may also be employed, and are useful in modulating polymer matrix degradation rates.
- Hydrophobic ended (also referred to as capped or end-capped) PLGA has an ester linkage hydrophobic in nature at the polymer terminus. Typical hydrophobic end groups include, but are not limited to alkyl esters and aromatic esters.
- Hydrophilic ended (also referred to as uncapped) PLGA has an end group hydrophilic in nature at the polymer terminus.
- PLGA with a hydrophilic end groups at the polymer terminus degrades faster than hydrophobic ended PLGA because it takes up water and undergoes hydrolysis at a faster rate (Tracy et al., Biomaterials 20:1057-1062 (1999)).
- suitable hydrophilic end groups that may be incorporated to enhance hydrolysis include, but are not limited to, carboxyl, hydroxyl, and polyethylene glycol.
- the specific end group will typically result from the initiator employed in the polymerization process. For example, if the initiator is water or carboxylic acid, the resulting end groups will be carboxyl and hydroxyl. Similarly, if the initiator is a monofunctional alcohol, the resulting end groups will be ester or hydroxyl.
- the implants may be formed from all hydrophilic end PLGA or all hydrophobic end PLGA.
- the ratio of hydrophilic end to hydrophobic end PLGA in the biodegradable polymer matrices of this invention range from about 10:1 to about 1:10 by weight.
- the ratio may be 3:1, 2:1, or 1:1 by weight.
- an implant with a ratio of hydrophilic end to hydrophobic end PLGA of 3:1 w/w is used.
- buffering agents and preservatives may be employed.
- Preservatives which may be used include, but are not limited to, sodium bisulfite, sodium bisulfate, sodium thiosulfate, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, phenylmercuric nitrate, methylparaben, polyvinyl alcohol and phenylethyl alcohol.
- buffering agents that may be employed include, but are not limited to, sodium carbonate, sodium borate, sodium phosphate, sodium acetate, sodium bicarbonate, and the like, as approved by the FDA for the desired route of administration.
- Electrolytes such as sodium chloride and potassium chloride may also be included in the formulation.
- the biodegradable ocular implants may also include additional hydrophilic or hydrophobic compounds that accelerate or retard release of the active agent. Furthermore, the inventors believe that because hydrophilic end PLGA has a higher degradation rate than hydrophobic end PLGA due to its ability to take up water more readily, increasing the amount of hydrophilic end PLGA in the implant polymer matrix will result in faster dissolution rates.
- FIG. 9 shows that the time from implantation to significant release of active agent (lag time) increases with decreasing amounts of hydrophilic end PLGA in the ocular implant.
- the lag time for implants having 0% hydrophilic end PLGA (40% w/w hydrophobic end) was shown to be about 21 days. In comparison, a significant reduction in lag time was seen with implants having 10% w/w and 20% w/w hydrophilic end PLGA.
- the implants of the invention are formulated with particles of an active agent dispersed within a biodegradable polymer matrix. Without being bound by theory, the inventors believe that release of the active agent is achieved by erosion of the biodegradable polymer matrix and by diffusion of the particulate agent into an ocular fluid, e.g., the vitreous, with subsequent dissolution of the polymer matrix and release of the active agent.
- the factors that influence the release kinetics include such characteristics as the size of the active agent particles, the solubility of the active agent, the ratio of active agent to polymer(s), the method of manufacture, the surface area exposed, and the erosion rate of the polymer(s).
- the release kinetics achieved by this form of active agent release are different than that achieved through formulations which release active agents through polymer swelling, such as with crosslinked hydrogels. In that case, the active agent is not released through polymer erosion, but through polymer swelling, which releases agent as liquid diffuses through the pathways exposed.
- the release rate of the active agent depends at least in part on the rate of degradation of the polymer backbone component or components making up the biodegradable polymer matrix.
- condensation polymers may be degraded by hydrolysis (among other mechanisms) and therefore any change in the composition of the implant that enhances water uptake by the implant will likely increase the rate of hydrolysis, thereby increasing the rate of polymer degradation and erosion, and thus increasing the rate of active agent release.
- the release kinetics of the implants of the invention are dependent in part on the surface area of the implants.
- a larger surface area exposes more polymer and active agent to ocular fluid, causing faster erosion of the polymer matrix and dissolution of the active agent particles in the fluid.
- the size and shape of the implant may also be used to control the rate of release, period of treatment, and active agent concentration at the site of implantation. At equal active agent loads, larger implants will deliver a proportionately larger dose, but depending on the surface to mass ratio, may possess a slower release rate.
- the total weight of the implant preferably ranges, e.g., from about 100-5000 ⁇ g, usually from about 500-1500 ⁇ g. In one variation, the total weight of the implant is about 600 ⁇ g. In another variation, the total weight of the implant is about 1200 ⁇ g.
- the bioerodible implants are typically solid, and may be formed as particles, sheets, patches, plaques, films, discs, fibers, rods, and the like, or may be of any size or shape compatible with the selected site of implantation, as long as the implants have the desired release kinetics and deliver an amount of active agent that is therapeutic for the intended medical condition of the eye.
- the upper limit for the implant size will be determined by factors such as the desired release kinetics, toleration for the implant at the site of implantation, size limitations on insertion, and ease of handling.
- the vitreous chamber is able to accommodate relatively large rod-shaped implants, generally having diameters of about 0.05 mm to 3 mm and a length of about 0.5 to about 10 mm.
- the rods have diameters of about 0.1 mm to about 1 mm. In another variation, the rods have diameters of about 0.3 mm to about 0.75 mm. In yet a further variation, other implants having variable geometries but approximately similar volumes may also be used.
- the release of an active agent from a biodegradable polymer matrix may also be modulated by varying the ratio of hydrophilic end PLGA to hydrophobic end PLGA in the matrix. Release rates may be further manipulated by the method used to manufacture the implant. For instance, as illustrated in Examples 4-7, extruded 60/40 w/w dexamethasone/PLGA implants having a ratio of hydrophilic end and hydrophobic end PLGA of 3:1, compared to compressed tablet implants, demonstrate a different drug release profile and concentration of agent in the vitreous over about a one month period. Overall, a lower burst of agent release and a more consistent level of agent in the vitreous is demonstrated with the extruded implants.
- a higher initial burst of active agent release occurs on day one after implantation with the 350 ⁇ g dexamethasone compressed tablet implant (350T) in comparison to the 350 ⁇ g dexamethasone extruded implant (350E).
- a higher initial burst of active agent release also occurs with the 700 ⁇ g dexamethasone compressed implant (700T) in comparison to the 700 fig dexamethasone extruded implant (700E) on day 1, as shown in FIG. 2 and Examples 6 and 7.
- the proportions of active agent, biodegradable polymer matrix, and any other additives may be empirically determined by formulating several implants with varying proportions and determining the release profile in vitro or in vivo.
- a USP approved method for dissolution or release test can be used to measure the rate of release in vitro (USP 24; NF 19 (2000) pp. 1941-1951). For example, a weighed sample of the implant is added to a measured volume of a solution containing 0.9% NaCl in water, where the solution volume will be such that the active agent concentration after release is less than 20% of saturation. The mixture is maintained at 37° C. and stirred or shaken slowly to maintain the implants in suspension.
- the release of the dissolved active agent as a function of time may then be followed by various methods known in the art, such as spectrophotometrically, HPLC, mass spectroscopy, and the like, until the solution concentration becomes constant or until greater than 90% of the active agent has been released.
- the extruded implants described herewith may have in vivo cumulative percentage release profiles with the following described characteristics, as shown in FIG. 2 , where the release profiles are for release of the active agent in vivo after implantation of the implants into the vitreous of rabbit eyes.
- the volume of rabbit eyes is approximately 60-70% of human eyes.
- the percentage in vivo cumulative release may be between about 0% and about 15%, and more usually between about 0% and about 10%. At day one after implantation, the percentage in vivo cumulative release may be less than about 15%, and more usually less than about 10%.
- the percentage in vivo cumulative release may be between about 0% and about 20%, and more usually between about 5% and about 15%. At day three after implantation, the percentage in vivo cumulative release may be less than about 20%, and more usually less than about 15%.
- the percentage in vivo cumulative release may be between about 0% and about 35%, more usually between about 5% and about 30%, and more usually still between about 10% and about 25%.
- the percentage in vivo cumulative release may be greater than about 2%, more usually greater than about 5%, and more usually still greater than about 10%.
- the percentage in vivo cumulative release may be between about 20% and about 60%, more usually between about 25% and about 55%, and more usually still between about 30% and about 50%. At day fourteen after implantation, the percentage in vivo cumulative release may be greater than about 20%, more usually greater than about 25%, and more usually still greater than about 30%.
- the percentage in vivo cumulative release may be between about 55% and about 95%, more usually between about 60% and about 90%, and more usually still between about 65% and about 85%. At day twenty-one after implantation, the percentage in vivo cumulative release may be greater than about 55%, more usually greater than about 60%, and more usually still greater than about 65%.
- the percentage in vivo cumulative release may be between about 80% and about 100%, more usually between about 85% and about 100%, and more usually still between about 90% and about 100%. At day twenty-eight after implantation, the percentage in vivo cumulative release may be greater than about 80%, more usually greater than about 85%, and more usually still greater than about 90%.
- the percentage in vivo cumulative release may be between about 95% and about 100%, and more usually between about 97% and about 100%. At day thirty-five after implantation, the percentage in vivo cumulative release may be greater than about 95%, and more usually greater than about 97%.
- the percentage in vivo cumulative release has the following characteristics: one day after implantation it is less than about 15%; three days after implantation it is less than about 20%; seven days after implantation it is greater than about 5%; fourteen days after implantation it is greater than about 25%; twenty-one days after implantation it is greater than about 60%; and twenty-eight days after implantation it is greater than about 80%.
- the percentage in vivo cumulative release has the following characteristics: one day after implantation it is less than about 10%; three days after implantation it is less than about 15%; seven days after implantation it is greater than about 10%; fourteen days after implantation it is greater than about 30%; twenty-one days after implantation it is greater than about 65%; twenty-eight days after implantation it is greater than about 85%.
- the extruded implants described in this patent may have in vitro cumulative percentage release profiles in saline solution at 37° C. with the following characteristics, as further described below, and as shown in FIG. 10 .
- the percentage in vitro cumulative release at day one may be between about 0% and about 5%, and more usually between about 0% and about 3%.
- the percentage in vitro cumulative release at day one may be less than about 5%, and more usually less than about 3%.
- the percentage in vitro cumulative release at day four may be between about 0% and about 7%, and more usually between about 0% and about 5%.
- the percentage in vitro cumulative release at day four may be less than about 7%, and more usually less than about 5%.
- the percentage in vitro cumulative release at day seven may be between about 1% and about 10%, and more usually between about 2% and about 8%.
- the percentage in vitro cumulative release at day seven may be greater than about 1%, and more usually greater than about 2%.
- the percentage in vitro cumulative release at day 14 may be between about 25% and about 65%, more usually between about 30% and about 60%, and more usually still between about 35% and about 55%.
- the percentage in vitro cumulative release at day 14 may be greater than about 25%, more usually greater than about 30%, and more usually still greater than about 35%.
- the percentage in vitro cumulative release at day 21 may be between about 60% and about 100%, more usually between about 65% and about 95%, and more usually still between about 70% and about 90%.
- the percentage in vitro cumulative release at day 21 may be greater than about 60%, more usually greater than about 65%, and more usually still greater than about 70%.
- the percentage in vitro cumulative release at day 28 may be between about 75% and about 100%, more usually between about 80% and about 100%, and more usually still between about 85% and about 95%.
- the percentage in vitro cumulative release at day 28 may be greater than about 75%, more usually greater than about 80%, and more usually still greater than about 85%.
- the percentage in vitro cumulative release at day 35 may be between about 85% and about 100%, more usually between about 90% and about 100%, and more usually still between about 95% and about 100%.
- the percentage in vitro cumulative release at day 35 may be greater than about 85%, more usually greater than about 90%, and more usually still greater than about 95%.
- the percentage in vitro cumulative release has the following characteristics: after one day it is less than about 1%; after four days it is less than about 7%; after seven days it is greater than about 2%; after 14 days it is greater than about 30%; after 21 days it is greater than about 65%; after 28 days it is greater than about 80%; and after 35 days it is greater than about 90%.
- the percentage in vitro cumulative release has the following characteristics: after one day it is less than about 3%; after four days it is less than about 5%; after seven days it is greater than about 2%; after 14 days it is greater than about 35%; after 21 days it is greater than about 70%; after 28 days it is greater than about 85%; and after 35 days it is greater than about 90%.
- FIGS. 2 and 10 show that after 28 days in vivo in rabbit eyes, or in vitro in a saline solution at 37° C., respectively, almost all of the active agent has been released from the implants. Furthermore, FIGS. 2 and 10 show that the active agent release profiles for the extruded implants in vivo (from the time of implantation) and in vitro (from the time of placement into a saline solution at 37° C.) are substantially similar and follow approximately a sigmoidal curve, releasing substantially all of the active agent over 28 days.
- the curves show approximately an upward curvature (i.e., the derivative of the curve increases as time increases), and from approximately day 17 onwards the curves show approximately a downward curvature (i.e., the derivative of the curve decreases as time increases).
- the plots shown in FIG. 2 for the 350 ⁇ g and 700 ⁇ g dexamethasone compressed tablet implants exhibit a higher initial burst of agent release generally followed by a gradual increase in release.
- implantation of a compressed implant results in different concentrations of active agent in the vitreous at various time points from implants that have been extruded. For example, as shown in FIGS. 1 and 5 , with extruded implants there is a gradual increase, plateau, and gradual decrease in intravitreal agent concentrations.
- intravitreal concentration curve for extruded implants results in more sustained levels of active agent in the ocular region.
- implants may also be formulated to release a therapeutic agent for any desirable duration of time, for example, for about one week, for about two weeks, for about three weeks, for about four weeks, for about five weeks, for about six weeks, for about seven weeks, for about eight weeks, for about nine weeks, for about ten weeks, for about eleven weeks, for about twelve weeks, or for more than 12 weeks.
- extruded implants Another important feature of the extruded implants is that different concentration levels of active agent may be established in the vitreous using different doses of the active agent. As illustrated in FIG. 8 , the concentration of agent in the vitreous is significantly larger with the 700 ⁇ g dexamethasone extruded implant than with the 350 ⁇ g dexamethasone extruded implant. Different active agent concentrations are not demonstrated with the compressed tablet implant. Thus, by using an extruded implant, it is possible to more easily control the concentration of active agent in the vitreous. In particular, specific dose-response relationships may be established since the implants can be sized to deliver a predetermined amount of active agent.
- Examples of medical conditions of the eye which may be treated by the implants and methods of the invention include, but are not limited to, uveitis, macular edema, macular degeneration, retinal detachment, ocular tumors, fungal or viral infections, multifocal choroiditis, diabetic retinopathy, proliferative vitreoretinopathy (PVR), sympathetic opthalmia, Vogt Koyanagi-Harada (VKH) syndrome, histoplasmosis, uveal diffusion, and vascular occlusion.
- the implants are particularly useful in treating such medical conditions as uveitis, macular edema, vascular occlusive conditions, proliferative vitreoretinopathy (PVR), and various other retinopathies.
- the biodegradable implants may be inserted into the eye by a variety of methods, including placement by forceps, by trocar, or by other types of applicators, after making an incision in the sclera. In some instances, a trocar or applicator may be used without creating an incision. In a preferred variation, a hand held applicator is used to insert one or more biodegradable implants into the eye.
- the hand held applicator typically comprises an 18-30 GA stainless steel needle, a lever, an actuator, and a plunger.
- the method of implantation generally first involves accessing the target area within the ocular region with the needle. Once within the target area, e.g., the vitreous cavity, the lever on the hand held device is depressed to cause the actuator to drive the plunger forward. As the plunger moves forward, it pushes the implant into the target area.
- the target area e.g., the vitreous cavity
- extrusion methods allows for large-scale manufacture of implants and results in implants with a homogeneous dispersion of the drug within the polymer matrix.
- the polymers and active agents that are chosen are stable at temperatures required for manufacturing, usually at least about 50° C.
- Extrusion methods use temperatures of about 25° C. to about 150° C., more preferably about 60° C. to about 130° C.
- Different extrusion methods may yield implants with different characteristics, including but not limited to the homogeneity of the dispersion of the active agent within the polymer matrix.
- a piston extruder a single screw extruder, and a twin screw extruder will generally produce implants with progressively more homogeneous dispersion of the active.
- extrusion parameters such as temperature, extrusion speed, die geometry, and die surface finish will have an effect on the release profile of the implants produced.
- the drug and polymer are first mixed at room temperature and then heated to a temperature range of about 60° C. to about 150° C., more usually to about 130° C. for a time period of about 0 to about 1 hour, more usually from about 0 to about 30 minutes, more usually still from about 5 minutes to about 15 minutes, and most usually for about 10 minutes.
- the implants are then extruded at a temperature of between about 60° C. to about 130° C., preferably at a temperature of between about 75° C. and 110° C., and more preferably at a temperature of about 90° C.
- the powder blend of active agent and PLGA is added to a single or twin screw extruder preset at a temperature of about 80° C. to about 130° C., and directly extruded as a filament or rod with minimal residence time in the extruder.
- the extruded filament or rod is then cut into small implants having the loading dose of active agent appropriate to treat the medical condition of its intended use.
- the present invention is based upon the discovery of an intraocular drug delivery system which can address many of the problems associated with conventional therapies for the treatment of ocular conditions, such as posterior segment inflammation, including fluctuating drug levels, short intraocular half-life, and prolonged systemic exposure to high levels of corticosteroids.
- the intraocular drug delivery system of the present invention encompasses use of dexamethasone as the active pharmaceutical agent, in which case the intraocular drug delivery system of the present invention can be referred to as a Dexamethasone Posterior Segment Drug Delivery System (DEX PS DDS).
- the DEX PS DDS is intended for placement into the posterior segment by a pars plana injection, a familiar method of administration for ophthalmologists.
- the DEX PS DDS can be comprised of a biodegradable copolymer, poly(lactic glycolic) acid (PLGA), containing micronised dexamethasone.
- the DEX PS DDS an release dexamethasone, providing a total dose of approximately 350 or 700 ⁇ g over approximately 35 days.
- other routes of administration topical, periocular, systemic and standard intravitreal injections
- Topical administration of 2 drops of dexamethasone ophthalmic suspension 0.1% four times daily to both eyes is equivalent to almost 500 ⁇ g per day.
- Systemic doses may be as high as 1,000 ⁇ g/kg/day (Pinar V. Intermediate uveitis. Massachusetts Eye & Ear Infirmary Immunology Service. http://www.immunology.meei.harvard.edu/imed.htm. 1998; Weisbecker C A, Fraunfelder F T, Naidoff M, Tippermann R, eds. 1999 Physicians' Desk Reference for Ophthalmology, 27th ed. Montvale, N.J.: Medical Economics Company, 1998; 7-8, 278-279).
- substantially lower daily doses of dexamethasone can be administered directly to the posterior segment compared to the doses needed with conventional topical, systemic, or intravitreal therapies, thereby minimizing potential side effects. While releasing dexamethasone, the polymer can gradually degrades completely over time so there is no need to remove the DEX PS DDS after it's placement into the posterior segment of a patient eye.
- an applicator has been designed to deliver the DEX PS DDS directly into the vitreous.
- the DDS Applicator allows placement of the DEX PS DDS into the posterior segment through a small hollow gauge needle, thereby decreasing the morbidity associated with surgery and pars plana injection at vitrectomy.
- the extruded DEX PS DDS is placed in the Applicator during the manufacturing of the sterile finished drug product.
- the DEX PS DDS Applicator System can be a single-use only device.
- Dexamethasone Posterior Segment Drug Delivery System can be used in the treatment of, for example, patients with macular oedema following central retinal vein occlusion or branch retinal vein occlusion.
- Dexamethasone can be obtained from Aventis Pharma, Montvale, N.J., U.S.A.
- the chemical name of dexamethasone is pregna-1,4-diene-3,20-dione-9-fluoro-11,17,21-trihydroxy-16-methyl-, (11 ⁇ , 16 ⁇ ), and it's chemical structure can be represented diagrammatically as follows:
- dexamethasone has 8 chiral centres and is optically active Description: White or almost white, crystalline powder pH and pKa: Dexamethasone has no ionisable groups Melting Point: 253° C. to 255° C. Solubility: Water: practically insoluble Ethanol: Sparingly soluble Methylene chloride: slightly soluble
- DEX PS DDS is an implant (a drug delivery system or DDS) for intravitreal (i.e. posterior segment, or PS) use, comprised of dexamethasone (i.e. DEX) (drug substance) and a polymer matrix of 50:50 poly (D,L-lactide-co-glycolide) PLGA, constituted of two grades of PLGA (50:50 PLGA ester and 50:50 PLGA acid). See Table 1 for details.
- This biodegradable drug delivery system is designed to release the drug substance into the posterior segment of the eye over a 35-day period.
- DEX PS DDS can be implanted into the vitreous humour of the eye using an applicator system.
- the drug substance used in the DEX PS DDS is dexamethasone micronised.
- DEX PS DDS can contain two excipients (i.e. non-active ingredients) which can be present as two different grades of the same biodegradable polymer 50:50 Poly (D,L lactide-co-glycolide) (PLGA), which can be supplied by Boehringer Ingelheim: 50:50 PLGA ester and 50:50 PLGA acid.
- excipients i.e. non-active ingredients
- PLGA D,L lactide-co-glycolide
- Poly D,L lactide-co-glycolide has been used for more than 15 years in parenteral products and is a main component of absorbable sutures.
- a list of some of the medical products commercially available is supplied in Table 3. TABLE 3 List of commercial medical products containing PLGA Manu- Drug Mode of Name facturer Substance
- Dosage form administration Vicryl ® Ethicon Suture used in ocular surgery Enantone ® Tadeka Leuprorelin Microsphere Injection suspension (SC or IM) Prostap ® Wyeth Leuprorelin Microsphere Injection acetate suspension (SC or IM) Bigonist ® Aventis Buserelin Implant Injection (SC) Somatuline ® Beaufour Lanreotide Micro- Injection (IM) Ipsen acetate particle Pharma suspension Sandostatin ® Novartis Octreotide Microsphere Injection (IM) acetate suspension Zoladex ® Astra Goserilin Implant Injection (SC) Zeneca acetate Risperd
- PLGA exists in different grades depending on the ratio of lactide to glycolide and polymer chain ending. All PLGAs degrade via backbone hydrolysis (bulk erosion), and the degradation products, lactic acid and glycolic acid, are ultimately metabolised by the body into CO 2 and H 2 O.
- the two PLGAs combination as presented in Table 2 was chosen in order to obtain a drug substance release over a 35-day period. General properties of the chosen PLGAs are presented in Table 4.
- DEX PS DDS was designed to release dexamethasone in the posterior segment of the eye over an extended period of 35 days. This extended release is achieved by including dexamethasone in a biodegradable polymer matrix.
- the polymer chosen is 50:50 PLGA.
- the rate of release is mainly linked to the rate of degradation of the PLGA, depending on several factors such as molecular weight and weight distribution, lactide to glycolide ratio, polymeric chain endings, etc.
- the mechanism for the degradation of PLGA is a hydrolysis triggered by the presence of body fluids i.e. vitreous humour in the case of DEX PS DDS.
- Micronized dexamethasone (Pharmacia, Peapack, N.J.) and micronized hydrophobic end 50/50 PLGA (Birmingham Polymers, Inc., Birmingham, Ala.) were accurately weighed and placed in a stainless steel mixing vessel. The vessel was sealed, placed on a Turbula mixer and mixed at a prescribed intensity, e.g., 96 rpm, and time, e.g., 15 minutes. The resulting powder blend was loaded one unit dose at a time into a single-cavity tablet press.
- a prescribed intensity e.g., 96 rpm
- time e.g. 15 minutes
- the press was activated at a pre-set pressure, e.g., 25 psi, and duration, e.g., 6 seconds, and the tablet was formed and ejected from the press at room temperature.
- the ratio of dexamethasone to PLGA was 70/30 w/w for all compressed tablet implants.
- Micronized dexamethasone (Pharmacia, Peapack, N.J.) and unmicronized PLGA were accurately weighed and placed in a stainless steel mixing vessel. The vessel was sealed, placed on a Turbula mixer and mixed at a prescribed intensity, e.g., 96 rpm, and time, e.g., 10-15 minutes.
- the unmicronized PLGA composition comprised a 30/10 w/w mixture of hydrophilic end PLGA (Boehringer Ingelheim, Wallingford, Conn.) and hydrophobic end PLGA (Boehringer Ingelheim, Wallingford, Conn.).
- the resulting powder blend was fed into a DACA Microcompounder-Extruder (DACA, Goleta, Calif.) and subjected to a pre-set temperature, e.g., 115° C., and screw speed, e.g., 12 rpm.
- the filament was extruded into a guide mechanism and cut into exact lengths that corresponded to the designated implant weight.
- the ratio of dexamethasone to total PLGA (hydrophilic and hydrophobic end) was 60/40 w/w for all extruded implants.
- Implants were placed into the posterior segment of the right eye of New Zealand White Rabbits by incising the conjunctiva and sclera between the 10 and 12 o'clock positions with a 20-gauge microvitreoretinal (MVR) blade. Fifty to 100 ⁇ L of vitreous humor was removed with a 1-cc syringe fitted with a 27-gauge needle. A sterile trocar, preloaded with the appropriate implant (drug delivery system, DDS), was inserted 5 mm through the sclerotomy, and then retracted with the push wire in place, leaving the implant in the posterior segment. Sclerae and conjunctivae were than closed using a 7-0 Vicryl suture.
- DDS drug delivery system
- Example 4 demonstrates the high initial release but generally lower intravitreal concentration of dexamethasone from compressed tablet implants as compared to extruded implants.
- the 350 ⁇ g compressed tablet implant (350T) was placed in the right eye of New Zealand White Rabbits as described in Example 3.
- Vitreous samples were taken periodically and assayed by LC/MS/MS to determine in vivo dexamethasone delivery performance.
- dexamethasone reached detectable mean intravitreal concentrations from day 1 (142.20 ng/ml) through day 35 (2.72 ng/ml), and the intravitreal concentration of dexamethasone gradually decreased over time.
- aqueous humor and plasma samples were also taken.
- the 350T showed a gradual decrease in aqueous humor dexamethasone concentrations over time, exhibiting a detectable mean dexamethasone aqueous humor concentration at day 1 (14.88 ng/ml) through day 21 (3.07 ng/ml), as demonstrated in FIG. 3 .
- the levels of dexamethasone in the aqueous humor strongly correlated with the levels of dexamethasone in the vitreous humor, but at a much lower level (approximately 10-fold lower).
- FIG. 4 shows that only trace amounts of dexamethasone was found in the plasma.
- Example 5 demonstrates the lower initial release and generally more sustained intravitreal concentration of dexamethasone from extruded implants.
- the 350 ⁇ g extruded implant (350E) was placed in the right eye of New Zealand White Rabbits as described in Example 3. Vitreous samples were taken periodically and assayed by LC/MS/MS to determine in vivo dexamethasone delivery performance. Referring to FIG. 1 , 350E showed detectable mean vitreous humor concentrations on day 1 (10.66 ng/ml) through day 28 (6.99 ng/ml).
- aqueous humor and plasma samples were also taken.
- the 350E showed detectable mean dexamethasone aqueous humor concentrations at day 1 (6.67 ng/ml) through day 42 (2.58 ng/ml) with the exception of day 35 in which the values were below the quantification limit.
- the levels of dexamethasone in the aqueous strongly correlated with the levels of dexamethasone in the vitreous humor, but at a much lower level (approximately 10-fold lower).
- FIG. 4 demonstrates that only a trace amount of dexamethasone was found in the plasma.
- Example 6 also shows the high initial release and generally lower intravitreal concentration of dexamethasone from compressed tablet implants.
- the 700 ⁇ g compressed tablet dosage form (700T) was placed in the right eye of New Zealand White Rabbits as described in Example 3. Vitreous samples were taken periodically and assayed by LC/MS/MS to determine in vivo dexamethasone delivery performance. As seen in FIG. 5 , the 700T reached detectable mean dexamethasone vitreous humor concentrations at day 1 (198.56 ng/ml) through day 42 (2.89 ng/ml), and a gradual decrease in the intravitreal dexamethasone concentration over time.
- aqueous humor and plasma samples were also obtained.
- the 700T exhibited a gradual decrease in aqueous humor dexamethasone concentrations over time, and reached detectable mean dexamethasone aqueous humor concentrations at day 1 (25.90 ng/ml) through day 42 (2.64 ng/ml) with the exception of day 35 in which the values were below the quantification limit.
- the levels of dexamethasone in the aqueous humor strongly correlated with the levels of dexamethasone in the vitreous humor, but at a much lower level (approximately 10-fold lower).
- FIG. 7 demonstrates that only a trace amount of dexamethasone was found in the plasma.
- Example 7 also illustrates the lower initial release and generally higher intravitreal concentration of dexamethasone from extruded implants.
- the 700 ⁇ g extruded implant (700E) was placed in the right eye of New Zealand White Rabbits as described in Example 3. Vitreous samples were taken periodically and assayed by LC/MS/MS to determine in vivo dexamethasone delivery performance. As seen in FIG. 5 , the 700E had a mean detectable vitreous humor concentration of dexamethasone from day 1 (52.63 ng/ml) through day 28 (119.70 ng/ml).
- aqueous humor and plasma samples were also taken. As seen in FIG. 6 , the 700E reached a detectable mean aqueous humor concentration on day 1 (5.04 ng/ml) through day 28 (5.93 ng/ml). The levels of dexamethasone in the aqueous strongly correlated with the levels of dexamethasone in the vitreous humor, but at a much lower level (approximately 10-fold lower). FIG. 7 demonstrates that only a trace amount of dexamethasone was found in the plasma.
- DEX PS DDS implants were made by a tabletting process, by a single extrusion process and by a double extrusion process.
- excipients (polymers) used for the DEX PS DDS implant made were two grades of 50:50 Poly (D,L lactide co glycolide) ester end and acid end. Both excipients were a pharmaceutical grade of non-compendial material.
- Polymer composition It was determined that the ratio of lactide to glycolide is essential for the kinetic of degradation of the polymer and hence the dexamethasone release profile of the implant. It was controlled in a 48% to 52% (wt %) range to ensure consistency of active agent release.
- Inherent viscosity the inherent viscosity is essential for the kinetics of degradation of the polymer and hence the dexamethasone release profile of the implant. It is a measure of the size of the polymer backbone and the size distribution (i.e. molecular weight and weight distribution). It was controlled in a 0.16 to 0.24 dl/g range to ensure consistency of release.
- the moisture content of the polymer influences its stability during the shelf life and is a facilitating factor for the biodegradation of the polymer matrix. It was controlled below 0.5% to ensure stability of the excipients as well as the drug substance (dexamethasone) and to ensure consistency of the (dexamethasone) release profile.
- Residual monomers residual monomers indicate the completion of the synthesis of the polymer and was controlled below 0.5 wt. %.
- Acid number the acid number measures the number of chain ends in the PLGA acid polymer. The number of acid polymer endings facilitates the ingress of moisture upon injection of the implant and influences the release profile of the implant. It was controlled to be higher than 6.5 mg KOH /g to ensure consistency of release profile.
- the particle size and particle size distribution of the dexamethasone is regarded as a critical parameter for the homogeneity of the DEX PS DDS.
- a preferred dexamethasone particle size distribution has at least 75% of the particles of dexamethasone smaller than (i.e. diameter less than) 10 ⁇ m.
- a more preferred dexamethasone particle size distribution has at least 99% of the particles of dexamethasone smaller than (i.e. diameter less than) 20 ⁇ m.
- dexamethasone a particle size and particle size distribution is an important factor because homogeneity of the dexamethasone affects release characteristics.
- the dexamethasone used in the present invention comprise ⁇ [1% of total impurities, including ⁇ 0.50% of dexamethasone acetate, ⁇ 0.25% of bethamethasone, ⁇ 0.25% of 3 keto delta 4 derivative and ⁇ 0.10% of any other impurity.
- a representative formula for a typical 80 g manufacturing batch (used to make an implant manufactured by the tabletting, single extrusion or double extrusion process) is provided in Table 2.
- Table 2 A representative formula for a typical 80 g manufacturing batch (used to make an implant manufactured by the tabletting, single extrusion or double extrusion process) is provided in Table 2.
- the bulk manufacturing and terminal sterilisation processes are identical.
- FIG. 11 A flow diagram of the three different manufacturing processes is shown by FIG. 11 .
- a single extrusion process was used to made an implant.
- the micronised dexamethasone and un-micronised polymer was blended, before being loaded into a twin-screw compound extruder, and then subjected to a set temperature and screw speed.
- the filament was extruded into a guide mechanism and cut into exact lengths that correspond to the correct DEX PS DDS weight.
- This continuous extrusion process was more controllable and more predictable than the tabletting process. This is illustrated in the in vitro release profiles of the DEX PS DDS as show in FIG. 12 .
- FIG. 13 shows that the single extruded DEX PS DDS is more uniform than was the tabletted implant. It was found that not only is this gives a more consistent in vitro release profile from the single extruded implant, but also with its increased resistance to crushing. Using a texture analyser it was shown that a 3-fold increase in force (1200 g compared to 400 g) was required to crush a single extruded implant compared to a tabletted one. This demonstrates that the extruded product is more able to withstand handling.
- DEX PS DDS made by single extrusion and by double extrusion processes is stable during a minimum of 12 months (and for as long as 18-24 months) when stored at 25° C./60% RH and a minimum of 6 months at 40° C./75% RH. Stability was determined based upon dexamethasone potency, dexamethasone impurities (acid, ketone, aldehyde and total impurities), moisture content, applicator actuation force, implant fracture force/fracture energy and in vitro dissolution dexamethasone release profile and sterility.
- the inventors improved the single extrusion process by (1) micronising the polymers prior to blending and (2) adding a second extrusion after pelletisation of the first extruded filament.
- an acceptable DEX PS DDS homogeneity was obtained. Homogeneity promotes a more even and regular dissolution of the polymer and release of the dexamethazone active agent.
- the PLGAs were milled using an air jet process.
- FIG. 14 presents batch-to-batch versus in-batch variability from batches made of milled (i.e. micronised) and un-milled (i.e. unmicronized) PLGAs.
- LC means label claim (a regulatory term), that is the amount of dexamethasone present in the implant (350 ⁇ g or 700 ⁇ g), as measured by various in vitro assays, such as by HPLC.
- Double extrusion processes were compared. As shown by FIG. 15 implants made by a double extrusion process had released about 60% of the dexamethasone by day 14, while the single extrusion implants had released about 40% of its dexamethasone load by day 14, although total dexamethasone released was comparable by day 21. Therefore, where more release of dexamethasone is desired sooner, the double extrusion process is a preferred process for making the DEX PS DDS. A double extrusion process also provides for a higher yield of the desired filament implant, i.e. with a uniform distribution of dexamethasone throughout the implant polymer.
- FIG. 16 A detailed manufacturing schematic flow diagram for the double extrusion implant is provided by FIG. 16 .
- the major equipment used in the manufacture of DEX PS DDS is listed in Table C. TABLE C Major Equipment Used in the Manufacture of DEX PS DDS Step Purpose Equipment Description 1 Milling both PLGAs Jet Mill 2 Powder blending Shaker 3 First extrusion Extruder and Force Feeder, Puller Assembly and Filament Cutter 4 Pelletising Stainless steel ball and bottle Shaker 5 Second extrusion Extruder and Force Feeder, Puller Assembly and Filament Cutter 6 Automated DDS cutting and Guillotine Cutter and inspection procedure Vision Inspection System 7-8 Applicator Assembly Applicator loading fixture and Heat sealer
- RG502 (50:50 PLGA ester) were milled using the Jet-Mill (a vibratory feeder) at milling pressures of 60 psi, 80 psi and 80 psi for the pusher nozzle, grinding nozzle, and grinding nozzle, respectively.
- 60 grams of RG502H were milled using the Jet-Mill at milling pressure of 20 psi, 40 psi and 40 psi for the pusher nozzle, grinding nozzle, and grinding nozzle, respectively.
- the mean particle size of both RG502 and RG502H was measured using a TSI 3225 Aerosizer DSP Particle Size Analyzer.
- both milled polymers must have a mean particle size of no greater than 20 um.
- the filaments from step 3 above were pelletized using the Turbula Shaker and one 19 mm stainless steel ball set at 96 RPM for 5 minutes.
- DEX PS DDS was be prepared as 350 ⁇ g or 700 ⁇ g dosage forms by cutting the filaments to the appropriate length.
- the DEX PS DDS was inserted into the Applicator System during the applicator assembly process. All operations took place in a Class 10 000 clean room.
- the assembled DEX PS DDS Applicator System was placed into a foil pouch containing a small bag of desiccant and heat-sealed. Samples for pre-sterilisation bioburden testing were taken prior to step 9.
- the sealed foil pouches containing the finished DEX PS DDS Applicator System and a small desiccant bag were placed into a cardboard box and the box sealed. Terminal sterilisation of these product containing boxes was accomplished by exposure to a dose within the range of 25-40 kGy of gamma-radiation. Samples from each batch were tested for sterility according to Ph. Eur. and USP requirement.
- Table F sets forth further preferred specifications for both the DEX PS DDS implant and the applicator. TABLE F Preferred specifications Attribute Specifications Implant appearance White to off-white, rod shaped Drug Delivery System (DDS), essentially free of foreign matter. Fracture Force Minimum 2.0 g Energy Minimum 0.85 ⁇ joule Moisture content No more than 1% Foreign particulates No visible foreign material Insoluble matter Record particle count for information only (diameter ⁇ 10 ⁇ m and ⁇ 25 ⁇ m) Dexamethasone identity Positive for dexamethasone Dexamethasone potency 90.0 to 110.0% LC Impurities Dexamethasone acid not greater than 0.5% HPLC area Dexamethasone ketone not greater than 1.0% HPLC area Dexamethasone aldehyde not greater than 1.0% HPLC area Total degradation not greater than 2% HPLC area Weight Range 700 ⁇ g dose: 1.050 mg to 1.284 mg (1.167 mg +/ ⁇ 10%) 350 ⁇ g dose: 0.525 mg to 0.6
- Implants and Applicators made as set forth above were found to be within the parameters of the preferred specifications.
- a preferred applicator to use to implant the DEX PS DDS is shown in international patent publication WO 2004/026106, published Apr. 1, 2004.
- the applicator was designed to facilitate the insertion of the implant in the posterior segment of the eye.
- the implant is housed in the needle of the applicator.
- the applicator is designed to fit comfortably into the hand of the physician, and to allow for single-handed operation. It is similar in size to retinal forceps, measuring 165 mm in length by 13 mm in width.
- FIG. 17 provides a cut-away side view of the applicator illustrating the typical functions and positions of all the elements.
- the lever As the lever is depressed, it applies a force on the linkage, which collapses and moves the plunger forward into the needle, pushing the DEX PS DDS into the posterior chamber of the eye. Once the DEX PS DDS is delivered, the lever then latches within the Applicator housing to signal use and prevent any reuse.
- the needle used is a 22-gauge thin-wall hypodermic needle. A silicone o-ring, is placed into a slot in the needle to retain the DEX PS DDS within the needle and remains outside the eye, in contact with the conjunctiva. To ensure that air is not introduced into the eye, the applicator has been designed to vent.
- a small gap between the DEX PS DDS and inner needle wall allows air to move back through and out of the needle as the DEX PS DDS is being delivered.
- the small size of this gap prevents fluid from flowing out of the eye through the needle.
- the components of the Applicator that may contact the patient during use are the plunger, needle and o-ring.
- the plunger and needle are manufactured from materials of known biocompatibility, and with a history of human use. Biocompatibility of the o-ring was evaluated through cytotoxicity testing.
- the applicator is packed with desiccant in a pouch designed to protect the implant from humidity.
- the packaged implant in the applicator is then sterilised by gamma irradiation.
- the pouch also ensures that the product remains sterile during the shelf life.
- the DEX PS DDS is terminally sterilised by gamma irradiation, in its applicator as presented packed in the foil pouch, using a 25 to 40 kGy dose.
- Terminal sterilisation process steam sterilisation (autoclaving) is not used because the polymers used for the controlled release are extremely sensitive to moisture and heat and degrade even with non-compendial low temperature sterilisation cycles.
- the DEX PS DDS Applicator System is a sterile, single use applicator intended to deliver one DEX PS DDS.
- the DEX PS DDS is loaded into the needle of the Applicator during the assembly process. It is then packaged in a foil pouch with desiccant and terminally sterilised by gamma irradiation.
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Priority Applications (47)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/918,597 US20050048099A1 (en) | 2003-01-09 | 2004-08-13 | Ocular implant made by a double extrusion process |
BRPI0513849A BRPI0513849B8 (pt) | 2004-08-13 | 2005-07-25 | implante ocular fabricado por um processo de extrusão dupla |
NZ552679A NZ552679A (en) | 2004-08-13 | 2005-07-25 | Ocular implant made by a double extrusion process |
CN201110225755.8A CN102319432B (zh) | 2004-08-13 | 2005-07-25 | 由双挤压法制备的眼植入物 |
EP05814028A EP1776091B1 (en) | 2004-08-13 | 2005-07-25 | Ocular implant made by a double extrusion process |
PL382452A PL382452A1 (pl) | 2004-08-13 | 2005-07-25 | Implant do oka wytwarzany w procesie podwójnego wytłaczania |
RU2007103318/15A RU2389479C2 (ru) | 2004-08-13 | 2005-07-25 | Глазной имплантат, изготавливаемый способом двойной экструзии |
CN200910224822.7A CN101721354B (zh) | 2004-08-13 | 2005-07-25 | 由双挤压法制备的眼植入物 |
KR1020077003441A KR101365772B1 (ko) | 2004-08-13 | 2005-07-25 | 이중 압출 공정으로 제조된 안과용 임플란트 |
AT05814028T ATE381319T1 (de) | 2004-08-13 | 2005-07-25 | Mit doppelextrusionsverfahren hergestelltes augenimplantat |
JP2007525641A JP4949245B2 (ja) | 2004-08-13 | 2005-07-25 | 二段押出法によって製造される眼インプラント |
ES07017089T ES2412881T3 (es) | 2004-08-13 | 2005-07-25 | Implante ocular fabricado por un proceso de extrusión doble |
KR1020137025447A KR101451060B1 (ko) | 2004-08-13 | 2005-07-25 | 이중 압출 공정으로 제조된 안과용 임플란트 |
AU2005290240A AU2005290240B2 (en) | 2004-08-13 | 2005-07-25 | Ocular implant made by a double extrusion process |
DE602005003957T DE602005003957T2 (de) | 2004-08-13 | 2005-07-25 | Mit doppelextrusionsverfahren hergestelltes augenimplantat |
MX2007001538A MX2007001538A (es) | 2004-08-13 | 2005-07-25 | Implante ocular elaborado mediante un proceso de doble extrusion. |
ES05814028T ES2297766T3 (es) | 2004-08-13 | 2005-07-25 | Implante ocular realizado mediante un proceso de extrusion doble. |
CA2576392A CA2576392C (en) | 2004-08-13 | 2005-07-25 | Ocular implant made by a double extrusion process |
CN2005800273099A CN101083976B (zh) | 2004-08-13 | 2005-07-25 | 由双挤压法制备的眼植入物 |
ES10185774T ES2414231T3 (es) | 2004-08-13 | 2005-07-25 | Implante ocular fabricado por un proceso de extrusión doble |
PT05814028T PT1776091E (pt) | 2004-08-13 | 2005-07-25 | ''implante ocular produzido por um processo de depla extrusão'' |
PL05814028T PL1776091T3 (pl) | 2004-08-13 | 2005-07-25 | Wszczep oczny wytworzony w procesie podwójnego wyciskania |
DK05814028T DK1776091T3 (da) | 2004-08-13 | 2005-07-25 | Okulært implantat fremstillet ved en dobbelt ekstrusionsproces |
PCT/US2005/026500 WO2006036280A1 (en) | 2004-08-13 | 2005-07-25 | Ocular implant made by a double extrusion process |
SI200530161T SI1776091T1 (sl) | 2004-08-13 | 2005-07-25 | Ocesni implantat, pripravljen z dvojnim ekstruzijskim postopkom |
EP10185774A EP2329811B1 (en) | 2004-08-13 | 2005-07-25 | Ocular implant obtained by double extrusion process |
EP07017089A EP1870092B1 (en) | 2004-08-13 | 2005-07-25 | Ocular implant made by a double extrusion process |
TW094127159A TWI332846B (en) | 2004-08-13 | 2005-08-10 | Ocular implant made by a double extrusion process |
ARP050103402A AR051278A1 (es) | 2004-08-13 | 2005-08-12 | Implante bioerosionable para tratar una afeccion ocular y metodo para prepararlo |
IL180865A IL180865A (he) | 2004-08-13 | 2007-01-22 | שיטה לייצור שתל מתכלה ביולוגית לטיפול במחלת עיניים |
NO20070992A NO342740B1 (no) | 2004-08-13 | 2007-02-21 | Fremgangsmåte for fremstilling av et bioeroderbart implantat, og bioeroderbart implantat fremstilt derved |
US11/931,954 US8034370B2 (en) | 2003-01-09 | 2007-10-31 | Ocular implant made by a double extrusion process |
US11/932,101 US8034366B2 (en) | 2003-01-09 | 2007-10-31 | Ocular implant made by a double extrusion process |
CY20081100251T CY1107823T1 (el) | 2004-08-13 | 2008-03-04 | Οφθαλμικο εμφυτευμα με μια διαδικασια διπλης διελασης |
HK08106971.2A HK1111912A1 (en) | 2004-08-13 | 2008-06-23 | Ocular implant made by a double extrusion process |
US12/173,746 US8048445B2 (en) | 2003-01-09 | 2008-07-15 | Ocular implant made by a double extrusion process |
AU2010235967A AU2010235967C1 (en) | 2004-08-13 | 2010-10-22 | Ocular implant made by a double extrusion process |
IL209771A IL209771A (he) | 2004-08-13 | 2010-12-05 | שתל עיני המתכלה בתהליך ביולוגי המיוצר בתהליך שיחול כפול |
US13/213,473 US8506987B2 (en) | 2003-01-09 | 2011-08-19 | Ocular implant made by a double extrusion process |
US13/224,041 US8318070B2 (en) | 2003-01-09 | 2011-09-01 | Ocular implant made by a double extrusion process |
HK11111214.4A HK1156856A1 (en) | 2004-08-13 | 2011-10-19 | Ocular implant obtained by double extrusion process |
US13/797,230 US8778381B2 (en) | 2003-01-09 | 2013-03-12 | Ocular implant made by a double extrusion process |
US13/922,482 US9192511B2 (en) | 2003-01-09 | 2013-06-20 | Ocular implant made by a double extrusion process |
US14/949,454 US10076526B2 (en) | 2003-01-09 | 2015-11-23 | Ocular implant made by a double extrusion process |
US16/132,857 US10702539B2 (en) | 2003-01-09 | 2018-09-17 | Ocular implant made by a double extrusion process |
US16/915,017 US20210113592A1 (en) | 2003-01-09 | 2020-06-29 | Ocular implant made by a double extrusion proces |
US17/812,133 US20230172948A1 (en) | 2004-08-13 | 2022-07-12 | Ocular implant made by a double extrusion proces |
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US10/340,237 US20040137059A1 (en) | 2003-01-09 | 2003-01-09 | Biodegradable ocular implant |
US10/918,597 US20050048099A1 (en) | 2003-01-09 | 2004-08-13 | Ocular implant made by a double extrusion process |
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US10/340,237 Continuation-In-Part US20040137059A1 (en) | 2003-01-09 | 2003-01-09 | Biodegradable ocular implant |
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US11/932,101 Continuation US8034366B2 (en) | 2003-01-09 | 2007-10-31 | Ocular implant made by a double extrusion process |
US11/931,954 Continuation US8034370B2 (en) | 2003-01-09 | 2007-10-31 | Ocular implant made by a double extrusion process |
US12/173,746 Division US8048445B2 (en) | 2003-01-09 | 2008-07-15 | Ocular implant made by a double extrusion process |
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US10/918,597 Abandoned US20050048099A1 (en) | 2003-01-09 | 2004-08-13 | Ocular implant made by a double extrusion process |
US11/932,101 Expired - Fee Related US8034366B2 (en) | 2003-01-09 | 2007-10-31 | Ocular implant made by a double extrusion process |
US11/931,954 Expired - Fee Related US8034370B2 (en) | 2003-01-09 | 2007-10-31 | Ocular implant made by a double extrusion process |
US12/173,746 Expired - Fee Related US8048445B2 (en) | 2003-01-09 | 2008-07-15 | Ocular implant made by a double extrusion process |
US13/213,473 Expired - Lifetime US8506987B2 (en) | 2003-01-09 | 2011-08-19 | Ocular implant made by a double extrusion process |
US13/224,041 Expired - Lifetime US8318070B2 (en) | 2003-01-09 | 2011-09-01 | Ocular implant made by a double extrusion process |
US13/797,230 Expired - Lifetime US8778381B2 (en) | 2003-01-09 | 2013-03-12 | Ocular implant made by a double extrusion process |
US13/922,482 Expired - Fee Related US9192511B2 (en) | 2003-01-09 | 2013-06-20 | Ocular implant made by a double extrusion process |
US14/949,454 Expired - Lifetime US10076526B2 (en) | 2003-01-09 | 2015-11-23 | Ocular implant made by a double extrusion process |
US16/132,857 Expired - Lifetime US10702539B2 (en) | 2003-01-09 | 2018-09-17 | Ocular implant made by a double extrusion process |
US16/915,017 Abandoned US20210113592A1 (en) | 2003-01-09 | 2020-06-29 | Ocular implant made by a double extrusion proces |
US17/812,133 Pending US20230172948A1 (en) | 2004-08-13 | 2022-07-12 | Ocular implant made by a double extrusion proces |
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US11/932,101 Expired - Fee Related US8034366B2 (en) | 2003-01-09 | 2007-10-31 | Ocular implant made by a double extrusion process |
US11/931,954 Expired - Fee Related US8034370B2 (en) | 2003-01-09 | 2007-10-31 | Ocular implant made by a double extrusion process |
US12/173,746 Expired - Fee Related US8048445B2 (en) | 2003-01-09 | 2008-07-15 | Ocular implant made by a double extrusion process |
US13/213,473 Expired - Lifetime US8506987B2 (en) | 2003-01-09 | 2011-08-19 | Ocular implant made by a double extrusion process |
US13/224,041 Expired - Lifetime US8318070B2 (en) | 2003-01-09 | 2011-09-01 | Ocular implant made by a double extrusion process |
US13/797,230 Expired - Lifetime US8778381B2 (en) | 2003-01-09 | 2013-03-12 | Ocular implant made by a double extrusion process |
US13/922,482 Expired - Fee Related US9192511B2 (en) | 2003-01-09 | 2013-06-20 | Ocular implant made by a double extrusion process |
US14/949,454 Expired - Lifetime US10076526B2 (en) | 2003-01-09 | 2015-11-23 | Ocular implant made by a double extrusion process |
US16/132,857 Expired - Lifetime US10702539B2 (en) | 2003-01-09 | 2018-09-17 | Ocular implant made by a double extrusion process |
US16/915,017 Abandoned US20210113592A1 (en) | 2003-01-09 | 2020-06-29 | Ocular implant made by a double extrusion proces |
US17/812,133 Pending US20230172948A1 (en) | 2004-08-13 | 2022-07-12 | Ocular implant made by a double extrusion proces |
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EP (3) | EP1870092B1 (he) |
JP (1) | JP4949245B2 (he) |
KR (2) | KR101451060B1 (he) |
CN (3) | CN102319432B (he) |
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NZ (1) | NZ552679A (he) |
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PT (1) | PT1776091E (he) |
RU (1) | RU2389479C2 (he) |
SI (1) | SI1776091T1 (he) |
TW (1) | TWI332846B (he) |
WO (1) | WO2006036280A1 (he) |
Cited By (53)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050191334A1 (en) * | 1995-06-02 | 2005-09-01 | Allergan, Inc. | Formulation for controlled release of drugs by combining hydrophilic and hydrophobic agents |
US20050244461A1 (en) * | 2004-04-30 | 2005-11-03 | Allergan, Inc. | Controlled release drug delivery systems and methods for treatment of an eye |
US20050244469A1 (en) * | 2004-04-30 | 2005-11-03 | Allergan, Inc. | Extended therapeutic effect ocular implant treatments |
US20060204548A1 (en) * | 2005-03-01 | 2006-09-14 | Allergan, Inc. | Microimplants for ocular administration |
US20060280774A1 (en) * | 1995-06-02 | 2006-12-14 | Allergan, Inc. | Compositions and methods for treating glaucoma |
US20070178138A1 (en) * | 2006-02-01 | 2007-08-02 | Allergan, Inc. | Biodegradable non-opthalmic implants and related methods |
US20070190112A1 (en) * | 2000-11-29 | 2007-08-16 | Allergan, Inc. | Methods for reducing or preventing transplant rejection in the eye and intraocular implants for use therefor |
US20070212395A1 (en) * | 2006-03-08 | 2007-09-13 | Allergan, Inc. | Ocular therapy using sirtuin-activating agents |
US20070260203A1 (en) * | 2006-05-04 | 2007-11-08 | Allergan, Inc. | Vasoactive agent intraocular implant |
US20080107712A1 (en) * | 2003-01-09 | 2008-05-08 | Allergan, Inc. | Ocular implant made by a double extrusion process |
US20080145403A1 (en) * | 2006-12-19 | 2008-06-19 | Allergan, Inc. | Low temperature processes for making cyclic lipid implants for intraocular use |
EP1937210A2 (en) * | 2005-10-18 | 2008-07-02 | Allergan, Inc. | Ocular therapy using glucocorticoid derivatives selectively penetrating posterior segment tissues |
US20080292679A1 (en) * | 2007-05-24 | 2008-11-27 | Allergan, Inc. | Biodegradable drug delivery system |
US20090123518A1 (en) * | 2007-10-18 | 2009-05-14 | Su Il Yum | Biodegradable implants with controlled bulk density |
WO2009063222A2 (en) * | 2007-11-15 | 2009-05-22 | Ucl Business Plc | Solid compositions |
US20090281520A1 (en) * | 2007-11-08 | 2009-11-12 | Brian Highley | Ocular Implantation Device |
US20100098772A1 (en) * | 2008-10-21 | 2010-04-22 | Allergan, Inc. | Drug delivery systems and methods for treating neovascularization |
US7756524B1 (en) | 2006-01-31 | 2010-07-13 | Nextel Communications Inc. | System and method for partially count-based allocation of vocoder resources |
US20100204325A1 (en) * | 2009-02-11 | 2010-08-12 | Allergan, Inc. | Valproic acid drug delivery systems and intraocular therapeutic uses thereof |
US20110190250A1 (en) * | 2009-07-14 | 2011-08-04 | Yamagata University | Eye drop with difluprednate for macular edema treatment |
EP2374451A2 (en) | 2005-07-27 | 2011-10-12 | University of Florida Research Foundation, Inc. | Histone deacetylase inhibitors (HDAC) that correct protein misfolding and uses thereof |
WO2011124359A1 (de) * | 2010-04-07 | 2011-10-13 | Acino Ag | Freisetzungsverfahren für implantate |
EP2482818A1 (en) * | 2009-09-29 | 2012-08-08 | Eyegate Pharmaceuticals, Inc. | Positively-charged poly (d,l-lactide-co-glycolide) nanoparticles and fabrication methods of the same |
US8242099B2 (en) | 2000-07-05 | 2012-08-14 | Allergan, Inc. | Implants and methods for treating inflammation-mediated conditions of the eye |
WO2012174064A1 (en) | 2011-06-14 | 2012-12-20 | Bikam Pharmaceuticals, Inc. | Opsin-binding ligands, compositions and methods of use |
WO2013081642A1 (en) | 2011-12-01 | 2013-06-06 | Bikam Pharmaceuticals, Inc. | Opsin-binding ligands, compositions and methods of use |
US20130210310A1 (en) * | 2005-12-28 | 2013-08-15 | Ethicon, Inc. | Bioabsorbable polymer compositions exhibiting enhanced crystallization and hydrolysis rates |
US20130315963A1 (en) * | 2012-05-24 | 2013-11-28 | Ethicon, Inc. | Mechanically Strong Absorbable Polymeric Blend Compositions of Precisely Controllable Absorption Rates, Processing Methods, And Products Therefrom |
US8663194B2 (en) | 2008-05-12 | 2014-03-04 | University Of Utah Research Foundation | Intraocular drug delivery device and associated methods |
US8715712B2 (en) | 2011-09-14 | 2014-05-06 | Forsight Vision5, Inc. | Ocular insert apparatus and methods |
US8802128B2 (en) | 2006-06-23 | 2014-08-12 | Allergan, Inc. | Steroid-containing sustained release intraocular implants and related methods |
US8915877B2 (en) | 2010-10-12 | 2014-12-23 | Emmett T. Cunningham, JR. | Glaucoma drainage device and uses thereof |
US20150140062A1 (en) * | 2013-11-15 | 2015-05-21 | Allergan, Inc. | Methods of treatment of ocular conditions with a sustained drug delivery implant |
US20150148496A1 (en) * | 2013-11-27 | 2015-05-28 | Ethicon, Inc. | Absorbable Polymeric Blend Compositions with Precisely Controllable Absorption Rates, Processing Methods, and Dimensionally Stable Medical Devices Therefrom |
US9056076B2 (en) | 2005-10-08 | 2015-06-16 | Potentia Pharmaceuticals, Inc. | Method of treating age-related macular degeneration comprising administering a compstatin analog |
US9095404B2 (en) | 2008-05-12 | 2015-08-04 | University Of Utah Research Foundation | Intraocular drug delivery device and associated methods |
EP2944628A1 (en) | 2011-11-30 | 2015-11-18 | Bikam Pharmaceuticals, Inc. | Opsin-binding ligands, compositions and methods of use |
WO2016042163A3 (en) * | 2014-09-19 | 2016-05-12 | Precision Ocular Limited | Ophthalmic drug compositions |
US9370444B2 (en) | 2010-10-12 | 2016-06-21 | Emmett T. Cunningham, JR. | Subconjunctival conformer device and uses thereof |
US9421126B2 (en) | 2009-06-03 | 2016-08-23 | Forsight Vision5, Inc. | Anterior segment drug delivery |
US20160278915A1 (en) * | 2013-10-24 | 2016-09-29 | Aaren Scientific Inc. | Hydrophilic iol packaging system |
EP3100723A1 (en) | 2009-06-16 | 2016-12-07 | Bikam Pharmaceuticals, Inc. | Opsin-binding ligands, compositions and methods of use |
US9750636B2 (en) | 2012-10-26 | 2017-09-05 | Forsight Vision5, Inc. | Ophthalmic system for sustained release of drug to eye |
US9877973B2 (en) | 2008-05-12 | 2018-01-30 | University Of Utah Research Foundation | Intraocular drug delivery device and associated methods |
US10064819B2 (en) | 2008-05-12 | 2018-09-04 | University Of Utah Research Foundation | Intraocular drug delivery device and associated methods |
RU2676102C2 (ru) * | 2012-09-27 | 2018-12-26 | Аллерган, Инк. | Биодеградируемые системы доставки лекарственных средств для долговременного высвобождения белков |
US10308687B2 (en) | 2013-03-15 | 2019-06-04 | Apellis Pharmaceuticals, Inc. | Cell-penetrating compstatin analogs and uses thereof |
US10875893B2 (en) | 2012-11-15 | 2020-12-29 | Apellis Pharmaceuticals, Inc. | Cell-reactive, long-acting, or targeted compstatin analogs and related compositions and methods |
US11040107B2 (en) | 2017-04-07 | 2021-06-22 | Apellis Pharmaceuticals, Inc. | Dosing regimens and related compositions and methods |
US11224602B2 (en) | 2015-04-13 | 2022-01-18 | Forsight Vision5, Inc. | Ocular insert composition of a semi-crystalline or crystalline pharmaceutically active agent |
US20220233564A1 (en) * | 2021-01-25 | 2022-07-28 | University Of South Florida | Ophthalmological formulations for the prevention of a coronavirus infection |
US11564834B2 (en) | 2017-09-15 | 2023-01-31 | Oxular Limited | Sterile lyophilized drug compositions and methods for treating ocular diseases or conditions |
US11903994B2 (en) | 2015-10-07 | 2024-02-20 | Apellis Pharmaceuticals, Inc. | Dosing regimens |
Families Citing this family (54)
Publication number | Priority date | Publication date | Assignee | Title |
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US8911496B2 (en) | 2006-07-11 | 2014-12-16 | Refocus Group, Inc. | Scleral prosthesis for treating presbyopia and other eye disorders and related devices and methods |
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US20090196905A1 (en) * | 2008-02-06 | 2009-08-06 | Spada Lon T | Stabilization of mitochondrial membranes in ocular diseases and conditions |
US8557273B2 (en) * | 2008-04-18 | 2013-10-15 | Medtronic, Inc. | Medical devices and methods including polymers having biologically active agents therein |
USRE48948E1 (en) | 2008-04-18 | 2022-03-01 | Warsaw Orthopedic, Inc. | Clonidine compounds in a biodegradable polymer |
BRPI0905078A2 (pt) * | 2008-04-18 | 2015-06-30 | Medtronic Inc | Métodos para tratar hérnia de disco intervertebral e para reduzir o tamanho de uma hérnia de disco intervertebral, e, depósito implantável de drogas |
MX2011005311A (es) * | 2008-11-19 | 2011-07-29 | Refocus Group Inc | Lente intraocular artificial, lente cristalino natural alterado, o capsula de lente cristalino natural relleno con una o mas protesis esclerales para funcionamiento mejorado. |
US20100239632A1 (en) | 2009-03-23 | 2010-09-23 | Warsaw Orthopedic, Inc. | Drug depots for treatment of pain and inflammation in sinus and nasal cavities or cardiac tissue |
US10206813B2 (en) | 2009-05-18 | 2019-02-19 | Dose Medical Corporation | Implants with controlled drug delivery features and methods of using same |
MY160217A (en) | 2009-11-09 | 2017-02-28 | Allergan Inc | Compositions and methods for stimulating hair growth |
WO2011133370A1 (en) * | 2010-04-23 | 2011-10-27 | Medtronic, Inc. | Shelf stable pharmaceutical depot |
US9821159B2 (en) | 2010-11-16 | 2017-11-21 | The Board Of Trustees Of The Leland Stanford Junior University | Stimulation devices and methods |
WO2012068247A1 (en) | 2010-11-16 | 2012-05-24 | The Board Of Trustees Of The Leland Stanford Junior University | Systems and methods for treatment of dry eye |
US9005634B2 (en) | 2011-04-13 | 2015-04-14 | Medtronic, Inc. | Shelf stable pharmaceutical depot |
US10245178B1 (en) | 2011-06-07 | 2019-04-02 | Glaukos Corporation | Anterior chamber drug-eluting ocular implant |
GB201120771D0 (en) * | 2011-12-02 | 2012-01-11 | Ljt Projects Ltd | tear duct resistance measuring system |
US8945214B2 (en) | 2011-12-19 | 2015-02-03 | Allergan, Inc. | Intravitreal applicator |
EP2945686A4 (en) * | 2013-01-15 | 2016-08-31 | Univ Colorado Regents | APPARATUS FOR DRUG DELIVERY IN THE TISSUE SYSTEM |
JP6511401B2 (ja) | 2013-02-15 | 2019-05-15 | アラーガン、インコーポレイテッドAllergan,Incorporated | 持続型薬物送達インプラント |
RU2699007C2 (ru) | 2013-02-18 | 2019-09-02 | Ведженикс Пти Лимитед | Молекулы, связывающие лиганды, и их применение |
EP2967817B1 (en) * | 2013-03-12 | 2021-03-10 | Oculeve, Inc. | Implant delivery devices and systems |
EP2981248B1 (en) * | 2013-04-01 | 2020-09-02 | Allergan, Inc. | Microsphere drug delivery system for sustained intraocular release |
US10155108B2 (en) | 2013-04-19 | 2018-12-18 | Oculeve, Inc. | Nasal stimulation devices and methods |
CA2915255A1 (en) | 2013-07-12 | 2015-01-15 | Ophthotech Corporation | Methods for treating or preventing ophthalmological conditions |
EP3110405B1 (en) | 2014-02-25 | 2020-05-06 | Oculeve, Inc. | Polymer formulations for nasolacrimal stimulation |
RU2557925C1 (ru) * | 2014-03-17 | 2015-07-27 | Новиков Сергей Викторович | Биодеградируемый многослойный имплант для введения лекарственных веществ в витреальную полость глаза |
US20150342875A1 (en) | 2014-05-29 | 2015-12-03 | Dose Medical Corporation | Implants with controlled drug delivery features and methods of using same |
ES2792856T3 (es) | 2014-07-25 | 2020-11-12 | Oculeve Inc | Patrones de estimulación para tratar la sequedad ocular |
CN104164505B (zh) * | 2014-08-08 | 2016-01-13 | 重庆医科大学附属第一医院 | 一种用于检测vkh综合征的试剂盒 |
EP3209371A4 (en) | 2014-10-22 | 2018-10-24 | Oculeve, Inc. | Implantable nasal stimulator systems and methods |
BR112017008267A2 (pt) | 2014-10-22 | 2017-12-19 | Oculeve Inc | dispositivos e métodos para tratar olho seco |
AU2015335772B2 (en) | 2014-10-22 | 2020-07-09 | Oculeve, Inc. | Contact lens for increasing tear production |
US11925578B2 (en) | 2015-09-02 | 2024-03-12 | Glaukos Corporation | Drug delivery implants with bi-directional delivery capacity |
US11564833B2 (en) | 2015-09-25 | 2023-01-31 | Glaukos Corporation | Punctal implants with controlled drug delivery features and methods of using same |
JP6885609B2 (ja) | 2015-11-23 | 2021-06-16 | ザ リージェンツ オブ ザ ユニバーシティ オブ コロラド,ア ボディー コーポレイトTHE REGENTS OF THE UNIVERSITY OF COLORADO,a body corporate | 薬物送達のための涙器システム |
US10426958B2 (en) | 2015-12-04 | 2019-10-01 | Oculeve, Inc. | Intranasal stimulation for enhanced release of ocular mucins and other tear proteins |
US10252048B2 (en) | 2016-02-19 | 2019-04-09 | Oculeve, Inc. | Nasal stimulation for rhinitis, nasal congestion, and ocular allergies |
CN109937025B (zh) | 2016-04-20 | 2022-07-29 | 多斯医学公司 | 生物可吸收眼部药物的递送装置 |
CA3022683A1 (en) | 2016-05-02 | 2017-11-09 | Oculeve, Inc. | Intranasal stimulation for treatment of meibomian gland disease and blepharitis |
CA3024912A1 (en) | 2016-05-20 | 2017-11-23 | The Regents Of The University Of Colorado, A Body Corporate | Lacrimal drug delivery device |
AU2017368154A1 (en) | 2016-12-02 | 2019-06-13 | Oculeve, Inc. | Apparatus and method for dry eye forecast and treatment recommendation |
US11273072B2 (en) | 2017-01-13 | 2022-03-15 | Gyroscope Therapeutics Limited | Suprachoroidal injection device |
CN109265458B (zh) * | 2018-11-12 | 2020-09-15 | 中国医学科学院药用植物研究所 | 一种基于苦参碱的抗肿瘤药物化合物 |
CN109464705B (zh) * | 2018-11-19 | 2021-08-17 | 爱尔眼科医院集团股份有限公司 | 一种rpe细胞片及其应用和制备方法 |
US11039954B2 (en) | 2019-03-21 | 2021-06-22 | Microoptx Inc. | Implantable ocular drug delivery devices and methods |
WO2020227407A1 (en) * | 2019-05-07 | 2020-11-12 | Cornell University | Temporary synthetic carrier for corneal tissue insertion and tissue delivery |
CA3144406A1 (en) | 2019-06-27 | 2020-12-30 | Layerbio, Inc. | Ocular device delivery methods and systems |
US20230086256A1 (en) * | 2020-01-28 | 2023-03-23 | Merck Sharp & Dohme Llc | Drug delivery system for the delivery of steroid to vitreous chamber of the eye |
WO2022111379A1 (zh) * | 2020-11-26 | 2022-06-02 | 成都康弘药业集团股份有限公司 | 一种阿西替尼眼内植入剂 |
CA3238759A1 (en) * | 2021-12-06 | 2023-06-15 | Ocular Therapeutix, Inc. | Extruded ocular inserts or implants and methods thereof |
Citations (94)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3432592A (en) * | 1962-08-31 | 1969-03-11 | Ciba Geigy Corp | Injection-moulded oral medicament in solid form |
US3914402A (en) * | 1973-06-14 | 1975-10-21 | Alza Corp | Ophthalmic dosage form, for releasing medication over time |
US3961628A (en) * | 1974-04-10 | 1976-06-08 | Alza Corporation | Ocular drug dispensing system |
US3986510A (en) * | 1971-09-09 | 1976-10-19 | Alza Corporation | Bioerodible ocular device |
US4008864A (en) * | 1974-02-18 | 1977-02-22 | Nils Gustav Yngve Torphammar | Locking mechanism for a safety belt |
US4014334A (en) * | 1976-02-02 | 1977-03-29 | Alza Corporation | Laminated osmotic system for dispensing beneficial agent |
US4088864A (en) * | 1974-11-18 | 1978-05-09 | Alza Corporation | Process for forming outlet passageways in pills using a laser |
US4144317A (en) * | 1975-05-30 | 1979-03-13 | Alza Corporation | Device consisting of copolymer having acetoxy groups for delivering drugs |
US4186184A (en) * | 1977-12-27 | 1980-01-29 | Alza Corporation | Selective administration of drug with ocular therapeutic system |
US4200098A (en) * | 1978-10-23 | 1980-04-29 | Alza Corporation | Osmotic system with distribution zone for dispensing beneficial agent |
US4201210A (en) * | 1976-06-22 | 1980-05-06 | The United States Of America As Represented By The Secretary Of Agriculture | Veterinary ocular ring device for sustained drug release |
US4285987A (en) * | 1978-10-23 | 1981-08-25 | Alza Corporation | Process for manufacturing device with dispersion zone |
US4327725A (en) * | 1980-11-25 | 1982-05-04 | Alza Corporation | Osmotic device with hydrogel driving member |
US4402979A (en) * | 1980-03-21 | 1983-09-06 | Merck & Co., Inc. & Laboratories | Ophthalmic formulations of 5-fluoro-2-methyl-1-(p-methylthiobenzylidene)-3-indenylacetic acid |
US4451254A (en) * | 1982-03-15 | 1984-05-29 | Eli Lilly And Company | Implant system |
US4474451A (en) * | 1982-02-19 | 1984-10-02 | Olympus Optical Co., Ltd. | Diaphragm control circuit for TTL automatic electronic flash |
US4478818A (en) * | 1982-12-27 | 1984-10-23 | Alza Corporation | Ocular preparation housing steroid in two different therapeutic forms |
US4494274A (en) * | 1982-05-28 | 1985-01-22 | Thurlow Heida L | Cookware with covers having metal handles |
US4521210A (en) * | 1982-12-27 | 1985-06-04 | Wong Vernon G | Eye implant for relieving glaucoma, and device and method for use therewith |
US4599353A (en) * | 1982-05-03 | 1986-07-08 | The Trustees Of Columbia University In The City Of New York | Use of eicosanoids and their derivatives for treatment of ocular hypertension and glaucoma |
US4668506A (en) * | 1985-08-16 | 1987-05-26 | Bausch & Lomb Incorporated | Sustained-release formulation containing and amino acid polymer |
US4756911A (en) * | 1986-04-16 | 1988-07-12 | E. R. Squibb & Sons, Inc. | Controlled release formulation |
US4801460A (en) * | 1986-04-11 | 1989-01-31 | Basf Aktiengesellschaft | Preparation of solid pharmaceutical forms |
US4806337A (en) * | 1984-07-23 | 1989-02-21 | Zetachron, Inc. | Erodible matrix for sustained release bioactive composition |
US4853224A (en) * | 1987-12-22 | 1989-08-01 | Visionex | Biodegradable ocular implants |
US4863457A (en) * | 1986-11-24 | 1989-09-05 | Lee David A | Drug delivery device |
US4865846A (en) * | 1988-06-03 | 1989-09-12 | Kaufman Herbert E | Drug delivery system |
US4945089A (en) * | 1987-12-29 | 1990-07-31 | Alcon Laboratories, Inc. | Use of tetrahydrocortexolone to prevent elevations in intraocular pressure caused by corticosteroids |
US4959217A (en) * | 1986-05-22 | 1990-09-25 | Syntex (U.S.A.) Inc. | Delayed/sustained release of macromolecules |
US4966849A (en) * | 1985-09-20 | 1990-10-30 | President And Fellows Of Harvard College | CDNA and genes for human angiogenin (angiogenesis factor) and methods of expression |
US4997652A (en) * | 1987-12-22 | 1991-03-05 | Visionex | Biodegradable ocular implants |
US5004614A (en) * | 1988-08-26 | 1991-04-02 | Forum Chemicals Ltd. | Controlled release device with an impermeable coating having an orifice for release of drug |
US5004601A (en) * | 1988-10-14 | 1991-04-02 | Zetachron, Inc. | Low-melting moldable pharmaceutical excipient and dosage forms prepared therewith |
US5006342A (en) * | 1986-12-22 | 1991-04-09 | Cygnus Corporation | Resilient transdermal drug delivery device |
US5019400A (en) * | 1989-05-01 | 1991-05-28 | Enzytech, Inc. | Very low temperature casting of controlled release microspheres |
US5028624A (en) * | 1989-07-27 | 1991-07-02 | Allergan, Inc. | Intraocular pressure reducing 9,15-diacyl prostaglandins |
US5034413A (en) * | 1989-07-27 | 1991-07-23 | Allergan, Inc. | Intraocular pressure reducing 9,11-diacyl prostaglandins |
US5082655A (en) * | 1984-07-23 | 1992-01-21 | Zetachron, Inc. | Pharmaceutical composition for drugs subject to supercooling |
US5314419A (en) * | 1992-10-30 | 1994-05-24 | Pelling George E | Method for dispensing ophthalmic drugs to the eye |
US5322691A (en) * | 1986-10-02 | 1994-06-21 | Sohrab Darougar | Ocular insert with anchoring protrusions |
US5330992A (en) * | 1992-10-23 | 1994-07-19 | Sterling Winthrop Inc. | 1-cyclopropyl-4-pyridyl-quinolinones |
US5356629A (en) * | 1991-07-12 | 1994-10-18 | United States Surgical Corporation | Composition for effecting bone repair |
US5378475A (en) * | 1991-02-21 | 1995-01-03 | University Of Kentucky Research Foundation | Sustained release drug delivery devices |
US5384333A (en) * | 1992-03-17 | 1995-01-24 | University Of Miami | Biodegradable injectable drug delivery polymer |
US5385887A (en) * | 1993-09-10 | 1995-01-31 | Genetics Institute, Inc. | Formulations for delivery of osteogenic proteins |
US5443505A (en) * | 1993-11-15 | 1995-08-22 | Oculex Pharmaceuticals, Inc. | Biocompatible ocular implants |
US5501856A (en) * | 1990-11-30 | 1996-03-26 | Senju Pharmaceutical Co., Ltd. | Controlled-release pharmaceutical preparation for intra-ocular implant |
US5597897A (en) * | 1991-06-21 | 1997-01-28 | Genetics Institute, Inc. | Pharmaceutical formulations of osteogenic proteins |
US5601844A (en) * | 1992-11-18 | 1997-02-11 | Fujisawa Pharmaceutical Co., Ltd. | Sustained release medicinal preparation |
US5656297A (en) * | 1992-03-12 | 1997-08-12 | Alkermes Controlled Therapeutics, Incorporated | Modulated release from biocompatible polymers |
US5660847A (en) * | 1989-09-14 | 1997-08-26 | Alza Corporation | Implantable delivery dispenser comprising exit port |
US5660851A (en) * | 1989-12-26 | 1997-08-26 | Yissum Research Development Company Of The Hebrew Univ. Of Jerusalem | Ocular inserts |
US5707643A (en) * | 1993-02-26 | 1998-01-13 | Santen Pharmaceutical Co., Ltd. | Biodegradable scleral plug |
US5755785A (en) * | 1994-08-12 | 1998-05-26 | The University Of South Florida | Sutureless corneal transplantation method |
US5773019A (en) * | 1995-09-27 | 1998-06-30 | The University Of Kentucky Research Foundation | Implantable controlled release device to deliver drugs directly to an internal portion of the body |
US5824074A (en) * | 1994-02-03 | 1998-10-20 | Koch; Hans-Reinhard | Intraoccular lens arrangement and method for correcting astigmatism |
US5869079A (en) * | 1995-06-02 | 1999-02-09 | Oculex Pharmaceuticals, Inc. | Formulation for controlled release of drugs by combining hydrophilic and hydrophobic agents |
US5882682A (en) * | 1991-12-27 | 1999-03-16 | Merck & Co., Inc. | Controlled release simvastatin delivery device |
US5902598A (en) * | 1997-08-28 | 1999-05-11 | Control Delivery Systems, Inc. | Sustained release drug delivery devices |
US5941250A (en) * | 1996-11-21 | 1999-08-24 | University Of Louisville Research Foundation Inc. | Retinal tissue implantation method |
US5962027A (en) * | 1989-08-14 | 1999-10-05 | Photogenesis, Inc. | Retinal cell transplant |
US5972369A (en) * | 1997-03-31 | 1999-10-26 | Alza Corporation | Diffusional implantable delivery system |
US6045791A (en) * | 1992-03-06 | 2000-04-04 | Photogenesis, Inc. | Retinal pigment epithelium transplantation |
US6046187A (en) * | 1996-09-16 | 2000-04-04 | Children's Medical Center Corporation | Formulations and methods for providing prolonged local anesthesia |
US6051576A (en) * | 1994-01-28 | 2000-04-18 | University Of Kentucky Research Foundation | Means to achieve sustained release of synergistic drugs by conjugation |
US6063116A (en) * | 1994-10-26 | 2000-05-16 | Medarex, Inc. | Modulation of cell proliferation and wound healing |
US6074661A (en) * | 1997-08-11 | 2000-06-13 | Allergan Sales, Inc. | Sterile bioerodible occular implant device with a retinoid for improved biocompatability |
US6217911B1 (en) * | 1995-05-22 | 2001-04-17 | The United States Of America As Represented By The Secretary Of The Army | sustained release non-steroidal, anti-inflammatory and lidocaine PLGA microspheres |
US6217895B1 (en) * | 1999-03-22 | 2001-04-17 | Control Delivery Systems | Method for treating and/or preventing retinal diseases with sustained release corticosteroids |
US6309669B1 (en) * | 1984-03-16 | 2001-10-30 | The United States Of America As Represented By The Secretary Of The Army | Therapeutic treatment and prevention of infections with a bioactive materials encapsulated within a biodegradable-biocompatible polymeric matrix |
US6369116B1 (en) * | 1995-06-02 | 2002-04-09 | Oculex Pharmaceuticals, Inc. | Composition and method for treating glaucoma |
US6403649B1 (en) * | 1992-09-21 | 2002-06-11 | Allergan Sales, Inc. | Non-acidic cyclopentane heptanoic acid,2-cycloalkyl or arylalkyl derivatives as therapeutic agents |
US6534542B2 (en) * | 2001-02-27 | 2003-03-18 | Allergen Sales, Inc. | (2-hydroxy)ethyl-thioureas useful as modulators of α2B adrenergic receptors |
US6537568B2 (en) * | 1997-08-11 | 2003-03-25 | Allergan, Inc. | Implant device with a retinoid for improved biocompatibility |
US6545182B2 (en) * | 2000-04-13 | 2003-04-08 | Allergan Sales, Inc. | Methods and compositions for modulating alpha adrenergic receptor activity |
US20040019098A1 (en) * | 2002-04-03 | 2004-01-29 | Allergan, Inc. | (3Z)-3-(2,3-dihydro-1H-inden-1-ylidene)-1,3-dihydro-2H-indol-2-ones as kinase inhibitors |
US6699493B2 (en) * | 2000-11-29 | 2004-03-02 | Oculex Pharmaceuticals, Inc. | Method for reducing or preventing transplant rejection in the eye and intraocular implants for use therefor |
US6713081B2 (en) * | 2001-03-15 | 2004-03-30 | The United States Of America As Represented By The Department Of Health And Human Services | Ocular therapeutic agent delivery devices and methods for making and using such devices |
US6726918B1 (en) * | 2000-07-05 | 2004-04-27 | Oculex Pharmaceuticals, Inc. | Methods for treating inflammation-mediated conditions of the eye |
US20040132824A1 (en) * | 2002-05-21 | 2004-07-08 | Allergan, Inc. | Novel methods and compositions for alleviating pain |
US20040137059A1 (en) * | 2003-01-09 | 2004-07-15 | Thierry Nivaggioli | Biodegradable ocular implant |
US20040151753A1 (en) * | 2002-11-06 | 2004-08-05 | Guohua Chen | Controlled release depot formulations |
US20040170665A1 (en) * | 2000-06-02 | 2004-09-02 | Allergan, Inc. | Intravitreal botulinum toxin implant |
US6841684B2 (en) * | 1997-12-04 | 2005-01-11 | Allergan, Inc. | Imidiazoles having reduced side effects |
US20050059744A1 (en) * | 2003-09-12 | 2005-03-17 | Allergan, Inc. | Methods and compositions for the treatment of pain and other alpha 2 adrenergic-mediated conditions |
US20050059664A1 (en) * | 2003-09-12 | 2005-03-17 | Allergan, Inc. | Novel methods for identifying improved, non-sedating alpha-2 agonists |
US20050058696A1 (en) * | 2003-09-12 | 2005-03-17 | Allergan, Inc. | Methods and compositions for the treatment of pain and other alpha 2 adrenergic-mediated conditions |
US20050101582A1 (en) * | 2003-11-12 | 2005-05-12 | Allergan, Inc. | Compositions and methods for treating a posterior segment of an eye |
US20050181017A1 (en) * | 2004-01-20 | 2005-08-18 | Allergan, Inc. | Compositions and methods for localized therapy of the eye |
US20060009498A1 (en) * | 2004-07-12 | 2006-01-12 | Allergan, Inc. | Ophthalmic compositions and methods for treating ophthalmic conditions |
US7056339B2 (en) * | 2001-04-20 | 2006-06-06 | The Board Of Trustees Of The Leland Stanford Junior University | Drug delivery platform |
US7091232B2 (en) * | 2002-05-21 | 2006-08-15 | Allergan, Inc. | 4-(substituted cycloalkylmethyl) imidazole-2-thiones, 4-(substituted cycloalkenylmethyl) imidazole-2-thiones, 4-(substituted cycloalkylmethyl) imidazol-2-ones and 4-(substituted cycloalkenylmethyl) imidazol-2-ones and related compounds |
US20070224246A1 (en) * | 2004-04-30 | 2007-09-27 | Hughes Patrick M | Oil-in-oil emulsified polymeric implants containing a hypotensive lipid and related methods |
US7335803B2 (en) * | 2001-10-19 | 2008-02-26 | Allergan, Inc. | Methods and compositions for modulating alpha adrenergic receptor activity |
Family Cites Families (76)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3416530A (en) | 1966-03-02 | 1968-12-17 | Richard A. Ness | Eyeball medication dispensing tablet |
US3845770A (en) | 1972-06-05 | 1974-11-05 | Alza Corp | Osmatic dispensing device for releasing beneficial agent |
US3916899A (en) | 1973-04-25 | 1975-11-04 | Alza Corp | Osmotic dispensing device with maximum and minimum sizes for the passageway |
US3921632A (en) | 1974-08-16 | 1975-11-25 | Frank M Bardani | Implant device |
US4180646A (en) | 1975-01-28 | 1979-12-25 | Alza Corporation | Novel orthoester polymers and orthocarbonate polymers |
US4063064A (en) | 1976-02-23 | 1977-12-13 | Coherent Radiation | Apparatus for tracking moving workpiece by a laser beam |
US4300557A (en) | 1980-01-07 | 1981-11-17 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Method for treating intraocular malignancies |
US4304765A (en) | 1980-10-14 | 1981-12-08 | Alza Corporation | Ocular insert housing steroid in two different therapeutic forms |
DE3168032D1 (en) | 1980-11-10 | 1985-02-14 | Alza Corp | Erodible polymer containing erosion rate modifier |
US4530840A (en) | 1982-07-29 | 1985-07-23 | The Stolle Research And Development Corporation | Injectable, long-acting microparticle formulation for the delivery of anti-inflammatory agents |
IT1229075B (it) | 1985-04-05 | 1991-07-17 | Fidia Farmaceutici | Medicamenti per uso topico, ottenuti tramite l'impiego dell'acido ialuronico |
DE3734223A1 (de) | 1987-10-09 | 1989-04-20 | Boehringer Ingelheim Kg | Implantierbares, biologisch abbaubares wirkstofffreigabesystem |
ATE227576T1 (de) | 1988-09-06 | 2002-11-15 | Pharmacia Ab | Prostaglandinderivate zur behandlung des grünen stars oder einer okularen hypertension |
US5268178A (en) | 1989-09-25 | 1993-12-07 | The Board Of Regents, The University Of Texas System | Biodegradable antibiotic implants and methods of their use in treating and preventing infections |
US5164188A (en) | 1989-11-22 | 1992-11-17 | Visionex, Inc. | Biodegradable ocular implants |
US5175235A (en) | 1990-06-04 | 1992-12-29 | Nova Pharmaceutical Corporation | Branched polyanhydrides |
US5075115A (en) | 1990-04-02 | 1991-12-24 | Fmc Corporation | Process for polymerizing poly(lactic acid) |
EP0526488B1 (en) | 1990-04-02 | 1994-11-30 | Pfizer Inc. | Benzylphosphonic acid tyrosine kinase inhibitors |
DE69101291T2 (de) | 1990-08-30 | 1994-07-07 | Senju Pharma Co | Zusammensetzung zur kontrollierten Abgabe von Medikamenten. |
JPH06503095A (ja) | 1991-05-29 | 1994-04-07 | ファイザー・インコーポレーテッド | 三環式ポリヒドロキシ系のチロシンキナーゼ阻害薬 |
US5169638A (en) | 1991-10-23 | 1992-12-08 | E. R. Squibb & Sons, Inc. | Buoyant controlled release powder formulation |
CA2123405C (en) | 1991-11-22 | 2008-01-15 | Abbot F. Clark | Angiostatic steroids |
US5178635A (en) | 1992-05-04 | 1993-01-12 | Allergan, Inc. | Method for determining amount of medication in an implantable device |
AU672224B2 (en) | 1992-08-06 | 1996-09-26 | Warner-Lambert Company | 2-thioindoles (selenoindoles) and related disulfides (selenides) which inhibit protein tyrosine kinases and whichhave antitumor properties |
US5922340A (en) * | 1992-09-10 | 1999-07-13 | Children's Medical Center Corporation | High load formulations and methods for providing prolonged local anesthesia |
US5688819A (en) | 1992-09-21 | 1997-11-18 | Allergan | Cyclopentane heptanoic acid, 2-cycloalkyl or arylalkyl derivatives as therapeutic agents |
DK0666868T4 (da) | 1992-10-28 | 2006-09-18 | Genentech Inc | Anvendelse af anti-VEGF-antistoffer til behandling af cancer |
GB9226855D0 (en) | 1992-12-23 | 1993-02-17 | Erba Carlo Spa | Vinylene-azaindole derivatives and process for their preparation |
US5538735A (en) | 1993-02-19 | 1996-07-23 | Ahn; Sam S. | Method of making a drug delivery system using hollow fibers |
CA2118515A1 (en) | 1993-02-26 | 1994-02-23 | Yuichiro Ogura | Biodegradable scleral plug |
JP3000187B2 (ja) * | 1993-02-26 | 2000-01-17 | 参天製薬株式会社 | 生体分解性強膜プラグ |
US5773021A (en) * | 1994-03-14 | 1998-06-30 | Vetoquinol S.A. | Bioadhesive ophthalmic insert |
US6586006B2 (en) * | 1994-08-04 | 2003-07-01 | Elan Drug Delivery Limited | Solid delivery systems for controlled release of molecules incorporated therein and methods of making same |
US5693335A (en) | 1995-06-07 | 1997-12-02 | Cygnus, Inc. | Skin permeation enhancer composition for use with sex steroids |
WO1997026869A1 (en) | 1996-01-24 | 1997-07-31 | United States Government Represented By The Secretary Of The Army | Novel 'burst-free' sustained release poly-(lactide/glycolide) microspheres |
WO1998007435A1 (en) * | 1996-08-20 | 1998-02-26 | The Regents Of The University Of California | Eye treatments using synthetic thyroid hormone compositions |
WO1998022130A1 (en) | 1996-11-19 | 1998-05-28 | The Schepens Eye Research Institute, Inc. | Local use of il-1ra in corneal transplant rejection or disorders of the eye |
US20020111603A1 (en) | 1996-12-02 | 2002-08-15 | Societe De Conseils De Recherches Et D'application | Device for local administration of solid or semi-solid formulations and delayed-release formulations for proposal parental administration and preparation process |
WO1999001156A1 (fr) | 1997-07-02 | 1999-01-14 | Santen Pharmaceutical Co., Ltd. | Bouchons scleraux d'acide polylactique |
JPH1170138A (ja) * | 1997-07-02 | 1999-03-16 | Santen Pharmaceut Co Ltd | ポリ乳酸強膜プラグ |
US6329369B1 (en) | 1997-12-04 | 2001-12-11 | Allergan Sales, Inc. | Methods of treating pain and other conditions |
US6196993B1 (en) | 1998-04-20 | 2001-03-06 | Eyelab Group, Llc | Ophthalmic insert and method for sustained release of medication to the eye |
CN1311684A (zh) | 1998-07-10 | 2001-09-05 | 悉尼大学 | 黄斑变性中新生血管形成的预防治疗 |
US6406498B1 (en) * | 1998-09-04 | 2002-06-18 | Bionx Implants Oy | Bioactive, bioabsorbable surgical composite material |
WO2000030532A1 (en) | 1998-11-20 | 2000-06-02 | University Of Connecticut | Generic integrated implantable potentiostat telemetry unit for electrochemical sensors |
AU7711800A (en) | 1999-09-23 | 2001-04-24 | Sloan-Kettering Institute For Cancer Research | Novel uses of 2-bromopalmitate |
US6331313B1 (en) | 1999-10-22 | 2001-12-18 | Oculex Pharmaceticals, Inc. | Controlled-release biocompatible ocular drug delivery implant devices and methods |
US6579533B1 (en) * | 1999-11-30 | 2003-06-17 | Bioasborbable Concepts, Ltd. | Bioabsorbable drug delivery system for local treatment and prevention of infections |
US7708711B2 (en) | 2000-04-14 | 2010-05-04 | Glaukos Corporation | Ocular implant with therapeutic agents and methods thereof |
US20040208910A1 (en) | 2000-04-26 | 2004-10-21 | Control Delivery Systems, Inc. | Sustained release device and method for ocular delivery of adrenergic agents |
EP1550471A1 (en) | 2000-11-29 | 2005-07-06 | Allergan Inc. | Intraocular implants for preventing transplant rejection in the eye |
EP1387671A1 (en) | 2001-05-03 | 2004-02-11 | MASSACHUSETTS EYE & EAR INFIRMARY | Implantable drug delivery device and use thereof |
CA2451187C (en) * | 2001-06-22 | 2012-08-14 | Southern Biosystems, Inc. | Zero-order prolonged release coaxial implants |
AU2002343681B2 (en) * | 2001-11-12 | 2006-07-06 | Alkermes Controlled Therapeutics, Inc. | Biocompatible polymer blends and uses thereof |
WO2003094888A1 (en) | 2002-05-07 | 2003-11-20 | Control Delivery Systems, Inc. | Processes for forming a drug delivery device |
US20040266776A1 (en) | 2003-06-25 | 2004-12-30 | Gil Daniel W. | Methods of preventing and reducing the severity of stress-associated conditions |
US7276522B2 (en) | 2002-05-21 | 2007-10-02 | Allergan, Inc. | 4-(substituted cycloalkylmethyl) imidazole-2-thiones, 4-(substituted cycloalkenylmethyl) imidazole-2-thiones, 4-(substituted cycloalkylmethyl) imidazol-2-ones, 4-(substituted cycloalkenylmethyl) imidazol-2-ones and related compounds |
US6899717B2 (en) | 2002-09-18 | 2005-05-31 | Allergan, Inc. | Methods and apparatus for delivery of ocular implants |
MXPA05002841A (es) | 2002-09-18 | 2005-05-27 | Oculex Pharm Inc | Metodo y aparato de administracion de implantes oculares. |
US7468065B2 (en) | 2002-09-18 | 2008-12-23 | Allergan, Inc. | Apparatus for delivery of ocular implants |
US20050048099A1 (en) | 2003-01-09 | 2005-03-03 | Allergan, Inc. | Ocular implant made by a double extrusion process |
AU2004207507B2 (en) * | 2003-01-24 | 2009-11-19 | Eyepoint Pharmaceuticals Us, Inc. | Sustained release device and method for ocular delivery of carbonic anhydrase inhibitors |
US7141597B2 (en) | 2003-09-12 | 2006-11-28 | Allergan, Inc. | Nonsedating α-2 agonists |
US7691381B2 (en) | 2004-04-15 | 2010-04-06 | Allergan, Inc. | Stabilized biodegradable neurotoxin implants |
US20050244469A1 (en) | 2004-04-30 | 2005-11-03 | Allergan, Inc. | Extended therapeutic effect ocular implant treatments |
US8685435B2 (en) | 2004-04-30 | 2014-04-01 | Allergan, Inc. | Extended release biodegradable ocular implants |
US20050244458A1 (en) | 2004-04-30 | 2005-11-03 | Allergan, Inc. | Sustained release intraocular implants and methods for treating ocular neuropathies |
US20050244471A1 (en) | 2004-04-30 | 2005-11-03 | Allergan, Inc. | Estradiol derivative and estratopone containing sustained release intraocular implants and related methods |
US7799336B2 (en) | 2004-04-30 | 2010-09-21 | Allergan, Inc. | Hypotensive lipid-containing biodegradable intraocular implants and related methods |
US8119154B2 (en) | 2004-04-30 | 2012-02-21 | Allergan, Inc. | Sustained release intraocular implants and related methods |
US20060204548A1 (en) | 2005-03-01 | 2006-09-14 | Allergan, Inc. | Microimplants for ocular administration |
US20060233857A1 (en) | 2005-04-14 | 2006-10-19 | Amsden Brian G | Degradable elastomeric network |
US20070260203A1 (en) | 2006-05-04 | 2007-11-08 | Allergan, Inc. | Vasoactive agent intraocular implant |
US20070298073A1 (en) | 2006-06-23 | 2007-12-27 | Allergan, Inc. | Steroid-containing sustained release intraocular implants and related methods |
ES2558544T3 (es) | 2007-03-16 | 2016-02-05 | The Regents Of The University Of California | Implantes médicos revestidos en la superficie de nanoestructura y métodos de empleo de los mismos |
US7740604B2 (en) | 2007-09-24 | 2010-06-22 | Ivantis, Inc. | Ocular implants for placement in schlemm's canal |
-
2004
- 2004-08-13 US US10/918,597 patent/US20050048099A1/en not_active Abandoned
-
2005
- 2005-07-25 JP JP2007525641A patent/JP4949245B2/ja active Active
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- 2005-07-25 PL PL05814028T patent/PL1776091T3/pl unknown
- 2005-07-25 SI SI200530161T patent/SI1776091T1/sl unknown
- 2005-07-25 CN CN200910224822.7A patent/CN101721354B/zh active Active
- 2005-07-25 MX MX2007001538A patent/MX2007001538A/es active IP Right Grant
- 2005-07-25 KR KR1020077003441A patent/KR101365772B1/ko active IP Right Grant
- 2005-07-25 ES ES07017089T patent/ES2412881T3/es active Active
- 2005-07-25 EP EP10185774A patent/EP2329811B1/en not_active Revoked
- 2005-07-25 ES ES05814028T patent/ES2297766T3/es active Active
- 2005-07-25 RU RU2007103318/15A patent/RU2389479C2/ru active
- 2005-07-25 NZ NZ552679A patent/NZ552679A/en unknown
- 2005-07-25 CN CN2005800273099A patent/CN101083976B/zh active Active
- 2005-08-10 TW TW094127159A patent/TWI332846B/zh active
- 2005-08-12 AR ARP050103402A patent/AR051278A1/es not_active Application Discontinuation
-
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- 2007-01-22 IL IL180865A patent/IL180865A/he active IP Right Grant
- 2007-02-21 NO NO20070992A patent/NO342740B1/no unknown
- 2007-10-31 US US11/932,101 patent/US8034366B2/en not_active Expired - Fee Related
- 2007-10-31 US US11/931,954 patent/US8034370B2/en not_active Expired - Fee Related
-
2008
- 2008-03-04 CY CY20081100251T patent/CY1107823T1/el unknown
- 2008-06-23 HK HK08106971.2A patent/HK1111912A1/xx not_active IP Right Cessation
- 2008-07-15 US US12/173,746 patent/US8048445B2/en not_active Expired - Fee Related
-
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- 2010-10-22 AU AU2010235967A patent/AU2010235967C1/en active Active
- 2010-12-05 IL IL209771A patent/IL209771A/he active IP Right Grant
-
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- 2011-08-19 US US13/213,473 patent/US8506987B2/en not_active Expired - Lifetime
- 2011-09-01 US US13/224,041 patent/US8318070B2/en not_active Expired - Lifetime
- 2011-10-19 HK HK11111214.4A patent/HK1156856A1/xx not_active IP Right Cessation
-
2013
- 2013-03-12 US US13/797,230 patent/US8778381B2/en not_active Expired - Lifetime
- 2013-06-20 US US13/922,482 patent/US9192511B2/en not_active Expired - Fee Related
-
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- 2015-11-23 US US14/949,454 patent/US10076526B2/en not_active Expired - Lifetime
-
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- 2018-09-17 US US16/132,857 patent/US10702539B2/en not_active Expired - Lifetime
-
2020
- 2020-06-29 US US16/915,017 patent/US20210113592A1/en not_active Abandoned
-
2022
- 2022-07-12 US US17/812,133 patent/US20230172948A1/en active Pending
Patent Citations (98)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3432592A (en) * | 1962-08-31 | 1969-03-11 | Ciba Geigy Corp | Injection-moulded oral medicament in solid form |
US3986510A (en) * | 1971-09-09 | 1976-10-19 | Alza Corporation | Bioerodible ocular device |
US3914402A (en) * | 1973-06-14 | 1975-10-21 | Alza Corp | Ophthalmic dosage form, for releasing medication over time |
US4008864A (en) * | 1974-02-18 | 1977-02-22 | Nils Gustav Yngve Torphammar | Locking mechanism for a safety belt |
US3961628A (en) * | 1974-04-10 | 1976-06-08 | Alza Corporation | Ocular drug dispensing system |
US4088864A (en) * | 1974-11-18 | 1978-05-09 | Alza Corporation | Process for forming outlet passageways in pills using a laser |
US4144317A (en) * | 1975-05-30 | 1979-03-13 | Alza Corporation | Device consisting of copolymer having acetoxy groups for delivering drugs |
US4014334A (en) * | 1976-02-02 | 1977-03-29 | Alza Corporation | Laminated osmotic system for dispensing beneficial agent |
US4201210A (en) * | 1976-06-22 | 1980-05-06 | The United States Of America As Represented By The Secretary Of Agriculture | Veterinary ocular ring device for sustained drug release |
US4186184A (en) * | 1977-12-27 | 1980-01-29 | Alza Corporation | Selective administration of drug with ocular therapeutic system |
US4200098A (en) * | 1978-10-23 | 1980-04-29 | Alza Corporation | Osmotic system with distribution zone for dispensing beneficial agent |
US4285987A (en) * | 1978-10-23 | 1981-08-25 | Alza Corporation | Process for manufacturing device with dispersion zone |
US4402979A (en) * | 1980-03-21 | 1983-09-06 | Merck & Co., Inc. & Laboratories | Ophthalmic formulations of 5-fluoro-2-methyl-1-(p-methylthiobenzylidene)-3-indenylacetic acid |
US4327725A (en) * | 1980-11-25 | 1982-05-04 | Alza Corporation | Osmotic device with hydrogel driving member |
US4474451A (en) * | 1982-02-19 | 1984-10-02 | Olympus Optical Co., Ltd. | Diaphragm control circuit for TTL automatic electronic flash |
US4451254A (en) * | 1982-03-15 | 1984-05-29 | Eli Lilly And Company | Implant system |
US4599353A (en) * | 1982-05-03 | 1986-07-08 | The Trustees Of Columbia University In The City Of New York | Use of eicosanoids and their derivatives for treatment of ocular hypertension and glaucoma |
US4494274A (en) * | 1982-05-28 | 1985-01-22 | Thurlow Heida L | Cookware with covers having metal handles |
US4521210A (en) * | 1982-12-27 | 1985-06-04 | Wong Vernon G | Eye implant for relieving glaucoma, and device and method for use therewith |
US4478818A (en) * | 1982-12-27 | 1984-10-23 | Alza Corporation | Ocular preparation housing steroid in two different therapeutic forms |
US6309669B1 (en) * | 1984-03-16 | 2001-10-30 | The United States Of America As Represented By The Secretary Of The Army | Therapeutic treatment and prevention of infections with a bioactive materials encapsulated within a biodegradable-biocompatible polymeric matrix |
US5082655A (en) * | 1984-07-23 | 1992-01-21 | Zetachron, Inc. | Pharmaceutical composition for drugs subject to supercooling |
US4806337A (en) * | 1984-07-23 | 1989-02-21 | Zetachron, Inc. | Erodible matrix for sustained release bioactive composition |
US4668506A (en) * | 1985-08-16 | 1987-05-26 | Bausch & Lomb Incorporated | Sustained-release formulation containing and amino acid polymer |
US4966849A (en) * | 1985-09-20 | 1990-10-30 | President And Fellows Of Harvard College | CDNA and genes for human angiogenin (angiogenesis factor) and methods of expression |
US4801460A (en) * | 1986-04-11 | 1989-01-31 | Basf Aktiengesellschaft | Preparation of solid pharmaceutical forms |
US4756911A (en) * | 1986-04-16 | 1988-07-12 | E. R. Squibb & Sons, Inc. | Controlled release formulation |
US4959217A (en) * | 1986-05-22 | 1990-09-25 | Syntex (U.S.A.) Inc. | Delayed/sustained release of macromolecules |
US5322691A (en) * | 1986-10-02 | 1994-06-21 | Sohrab Darougar | Ocular insert with anchoring protrusions |
US4863457A (en) * | 1986-11-24 | 1989-09-05 | Lee David A | Drug delivery device |
US5006342A (en) * | 1986-12-22 | 1991-04-09 | Cygnus Corporation | Resilient transdermal drug delivery device |
US4853224A (en) * | 1987-12-22 | 1989-08-01 | Visionex | Biodegradable ocular implants |
US4997652A (en) * | 1987-12-22 | 1991-03-05 | Visionex | Biodegradable ocular implants |
US4945089A (en) * | 1987-12-29 | 1990-07-31 | Alcon Laboratories, Inc. | Use of tetrahydrocortexolone to prevent elevations in intraocular pressure caused by corticosteroids |
US4865846A (en) * | 1988-06-03 | 1989-09-12 | Kaufman Herbert E | Drug delivery system |
US5004614A (en) * | 1988-08-26 | 1991-04-02 | Forum Chemicals Ltd. | Controlled release device with an impermeable coating having an orifice for release of drug |
US5004601A (en) * | 1988-10-14 | 1991-04-02 | Zetachron, Inc. | Low-melting moldable pharmaceutical excipient and dosage forms prepared therewith |
US5019400A (en) * | 1989-05-01 | 1991-05-28 | Enzytech, Inc. | Very low temperature casting of controlled release microspheres |
US5028624A (en) * | 1989-07-27 | 1991-07-02 | Allergan, Inc. | Intraocular pressure reducing 9,15-diacyl prostaglandins |
US5034413A (en) * | 1989-07-27 | 1991-07-23 | Allergan, Inc. | Intraocular pressure reducing 9,11-diacyl prostaglandins |
US5962027A (en) * | 1989-08-14 | 1999-10-05 | Photogenesis, Inc. | Retinal cell transplant |
US5660847A (en) * | 1989-09-14 | 1997-08-26 | Alza Corporation | Implantable delivery dispenser comprising exit port |
US5660851A (en) * | 1989-12-26 | 1997-08-26 | Yissum Research Development Company Of The Hebrew Univ. Of Jerusalem | Ocular inserts |
US5501856A (en) * | 1990-11-30 | 1996-03-26 | Senju Pharmaceutical Co., Ltd. | Controlled-release pharmaceutical preparation for intra-ocular implant |
US5378475A (en) * | 1991-02-21 | 1995-01-03 | University Of Kentucky Research Foundation | Sustained release drug delivery devices |
US5597897A (en) * | 1991-06-21 | 1997-01-28 | Genetics Institute, Inc. | Pharmaceutical formulations of osteogenic proteins |
US5356629A (en) * | 1991-07-12 | 1994-10-18 | United States Surgical Corporation | Composition for effecting bone repair |
US5882682A (en) * | 1991-12-27 | 1999-03-16 | Merck & Co., Inc. | Controlled release simvastatin delivery device |
US6045791A (en) * | 1992-03-06 | 2000-04-04 | Photogenesis, Inc. | Retinal pigment epithelium transplantation |
US5656297A (en) * | 1992-03-12 | 1997-08-12 | Alkermes Controlled Therapeutics, Incorporated | Modulated release from biocompatible polymers |
US5384333A (en) * | 1992-03-17 | 1995-01-24 | University Of Miami | Biodegradable injectable drug delivery polymer |
US6403649B1 (en) * | 1992-09-21 | 2002-06-11 | Allergan Sales, Inc. | Non-acidic cyclopentane heptanoic acid,2-cycloalkyl or arylalkyl derivatives as therapeutic agents |
US5330992A (en) * | 1992-10-23 | 1994-07-19 | Sterling Winthrop Inc. | 1-cyclopropyl-4-pyridyl-quinolinones |
US5314419A (en) * | 1992-10-30 | 1994-05-24 | Pelling George E | Method for dispensing ophthalmic drugs to the eye |
US5601844A (en) * | 1992-11-18 | 1997-02-11 | Fujisawa Pharmaceutical Co., Ltd. | Sustained release medicinal preparation |
US5707643A (en) * | 1993-02-26 | 1998-01-13 | Santen Pharmaceutical Co., Ltd. | Biodegradable scleral plug |
US5385887A (en) * | 1993-09-10 | 1995-01-31 | Genetics Institute, Inc. | Formulations for delivery of osteogenic proteins |
US5824072A (en) * | 1993-11-15 | 1998-10-20 | Oculex Pharmaceuticals, Inc. | Biocompatible ocular implants |
US5443505A (en) * | 1993-11-15 | 1995-08-22 | Oculex Pharmaceuticals, Inc. | Biocompatible ocular implants |
US5766242A (en) * | 1993-11-15 | 1998-06-16 | Oculex Pharmaceuticals, Inc. | Biocompatible ocular implants |
US6051576A (en) * | 1994-01-28 | 2000-04-18 | University Of Kentucky Research Foundation | Means to achieve sustained release of synergistic drugs by conjugation |
US5824074A (en) * | 1994-02-03 | 1998-10-20 | Koch; Hans-Reinhard | Intraoccular lens arrangement and method for correcting astigmatism |
US5755785A (en) * | 1994-08-12 | 1998-05-26 | The University Of South Florida | Sutureless corneal transplantation method |
US6063116A (en) * | 1994-10-26 | 2000-05-16 | Medarex, Inc. | Modulation of cell proliferation and wound healing |
US6217911B1 (en) * | 1995-05-22 | 2001-04-17 | The United States Of America As Represented By The Secretary Of The Army | sustained release non-steroidal, anti-inflammatory and lidocaine PLGA microspheres |
US7048946B1 (en) * | 1995-06-02 | 2006-05-23 | Allergan, Inc. | Formulation for controlled release of drugs by combining hyrophilic and hydrophobic agents |
US5869079A (en) * | 1995-06-02 | 1999-02-09 | Oculex Pharmaceuticals, Inc. | Formulation for controlled release of drugs by combining hydrophilic and hydrophobic agents |
US6369116B1 (en) * | 1995-06-02 | 2002-04-09 | Oculex Pharmaceuticals, Inc. | Composition and method for treating glaucoma |
US5773019A (en) * | 1995-09-27 | 1998-06-30 | The University Of Kentucky Research Foundation | Implantable controlled release device to deliver drugs directly to an internal portion of the body |
US6046187A (en) * | 1996-09-16 | 2000-04-04 | Children's Medical Center Corporation | Formulations and methods for providing prolonged local anesthesia |
US5941250A (en) * | 1996-11-21 | 1999-08-24 | University Of Louisville Research Foundation Inc. | Retinal tissue implantation method |
US5972369A (en) * | 1997-03-31 | 1999-10-26 | Alza Corporation | Diffusional implantable delivery system |
US6074661A (en) * | 1997-08-11 | 2000-06-13 | Allergan Sales, Inc. | Sterile bioerodible occular implant device with a retinoid for improved biocompatability |
US6537568B2 (en) * | 1997-08-11 | 2003-03-25 | Allergan, Inc. | Implant device with a retinoid for improved biocompatibility |
US5902598A (en) * | 1997-08-28 | 1999-05-11 | Control Delivery Systems, Inc. | Sustained release drug delivery devices |
US6841684B2 (en) * | 1997-12-04 | 2005-01-11 | Allergan, Inc. | Imidiazoles having reduced side effects |
US6548078B2 (en) * | 1999-03-22 | 2003-04-15 | Control Delivery Systems | Method for treating and/or preventing retinal diseases with sustained release corticosteroids |
US6217895B1 (en) * | 1999-03-22 | 2001-04-17 | Control Delivery Systems | Method for treating and/or preventing retinal diseases with sustained release corticosteroids |
US6545182B2 (en) * | 2000-04-13 | 2003-04-08 | Allergan Sales, Inc. | Methods and compositions for modulating alpha adrenergic receptor activity |
US20040170665A1 (en) * | 2000-06-02 | 2004-09-02 | Allergan, Inc. | Intravitreal botulinum toxin implant |
US6726918B1 (en) * | 2000-07-05 | 2004-04-27 | Oculex Pharmaceuticals, Inc. | Methods for treating inflammation-mediated conditions of the eye |
US6699493B2 (en) * | 2000-11-29 | 2004-03-02 | Oculex Pharmaceuticals, Inc. | Method for reducing or preventing transplant rejection in the eye and intraocular implants for use therefor |
US6534542B2 (en) * | 2001-02-27 | 2003-03-18 | Allergen Sales, Inc. | (2-hydroxy)ethyl-thioureas useful as modulators of α2B adrenergic receptors |
US6713081B2 (en) * | 2001-03-15 | 2004-03-30 | The United States Of America As Represented By The Department Of Health And Human Services | Ocular therapeutic agent delivery devices and methods for making and using such devices |
US7056339B2 (en) * | 2001-04-20 | 2006-06-06 | The Board Of Trustees Of The Leland Stanford Junior University | Drug delivery platform |
US7335803B2 (en) * | 2001-10-19 | 2008-02-26 | Allergan, Inc. | Methods and compositions for modulating alpha adrenergic receptor activity |
US20040019098A1 (en) * | 2002-04-03 | 2004-01-29 | Allergan, Inc. | (3Z)-3-(2,3-dihydro-1H-inden-1-ylidene)-1,3-dihydro-2H-indol-2-ones as kinase inhibitors |
US20040132824A1 (en) * | 2002-05-21 | 2004-07-08 | Allergan, Inc. | Novel methods and compositions for alleviating pain |
US7091232B2 (en) * | 2002-05-21 | 2006-08-15 | Allergan, Inc. | 4-(substituted cycloalkylmethyl) imidazole-2-thiones, 4-(substituted cycloalkenylmethyl) imidazole-2-thiones, 4-(substituted cycloalkylmethyl) imidazol-2-ones and 4-(substituted cycloalkenylmethyl) imidazol-2-ones and related compounds |
US20040151753A1 (en) * | 2002-11-06 | 2004-08-05 | Guohua Chen | Controlled release depot formulations |
US20040137059A1 (en) * | 2003-01-09 | 2004-07-15 | Thierry Nivaggioli | Biodegradable ocular implant |
US20050058696A1 (en) * | 2003-09-12 | 2005-03-17 | Allergan, Inc. | Methods and compositions for the treatment of pain and other alpha 2 adrenergic-mediated conditions |
US20050059664A1 (en) * | 2003-09-12 | 2005-03-17 | Allergan, Inc. | Novel methods for identifying improved, non-sedating alpha-2 agonists |
US20050059744A1 (en) * | 2003-09-12 | 2005-03-17 | Allergan, Inc. | Methods and compositions for the treatment of pain and other alpha 2 adrenergic-mediated conditions |
US20050101582A1 (en) * | 2003-11-12 | 2005-05-12 | Allergan, Inc. | Compositions and methods for treating a posterior segment of an eye |
US20050181017A1 (en) * | 2004-01-20 | 2005-08-18 | Allergan, Inc. | Compositions and methods for localized therapy of the eye |
US20070224246A1 (en) * | 2004-04-30 | 2007-09-27 | Hughes Patrick M | Oil-in-oil emulsified polymeric implants containing a hypotensive lipid and related methods |
US20060009498A1 (en) * | 2004-07-12 | 2006-01-12 | Allergan, Inc. | Ophthalmic compositions and methods for treating ophthalmic conditions |
Cited By (128)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050191334A1 (en) * | 1995-06-02 | 2005-09-01 | Allergan, Inc. | Formulation for controlled release of drugs by combining hydrophilic and hydrophobic agents |
US20060204543A1 (en) * | 1995-06-02 | 2006-09-14 | Allergan, Inc. | Formulation for controlled release of drugs by combining hydrophilic and hydrophobic agents |
US20060280774A1 (en) * | 1995-06-02 | 2006-12-14 | Allergan, Inc. | Compositions and methods for treating glaucoma |
US9775849B2 (en) | 2000-07-05 | 2017-10-03 | Allergan, Inc. | Implants and methods for treating inflammation-mediated conditions of the eye |
US10206934B2 (en) | 2000-07-05 | 2019-02-19 | Allergan, Inc. | Implants and methods for treating inflammation-mediated conditions of the eye |
US9012437B2 (en) | 2000-07-05 | 2015-04-21 | Allergan, Inc. | Implants and methods for treating inflammation-mediated conditions of the eye |
US8242099B2 (en) | 2000-07-05 | 2012-08-14 | Allergan, Inc. | Implants and methods for treating inflammation-mediated conditions of the eye |
US8071120B2 (en) | 2000-11-29 | 2011-12-06 | Allergan, Inc. | Methods for treating neovascularization and intravitreal implants |
US20090062249A1 (en) * | 2000-11-29 | 2009-03-05 | Allergan, Inc. | Methods for reducing or preventing transplant rejection in the eye and intraocular implants for use therefor |
US20070190112A1 (en) * | 2000-11-29 | 2007-08-16 | Allergan, Inc. | Methods for reducing or preventing transplant rejection in the eye and intraocular implants for use therefor |
US8043628B2 (en) | 2000-11-29 | 2011-10-25 | Allergan, Inc. | Methods for reducing edema |
US9283178B2 (en) | 2000-11-29 | 2016-03-15 | Allergan, Inc. | Methods for treating edema in the eye and intraocular implants for use therefor |
US20070298076A1 (en) * | 2000-11-29 | 2007-12-27 | Allergan, Inc. | Method for reducing or preventing transplant rejection in the eye and intraocular implants for use therefor |
US9592242B2 (en) | 2000-11-29 | 2017-03-14 | Allergan, Inc. | Methods for treating edema in the eye and intraocular implants for use therefor |
US20080069859A1 (en) * | 2000-11-29 | 2008-03-20 | Allergan, Inc. | Method for treating neovascularization and intravitreal implants |
US7846468B2 (en) | 2000-11-29 | 2010-12-07 | Allergan, Inc. | Methods for reducing or preventing transplant rejection in the eye and intraocular implants for use therefor |
US8088407B2 (en) | 2000-11-29 | 2012-01-03 | Allergan, Inc. | Method for reducing or preventing transplant rejection in the eye and intraocular implants for use therefor |
US7767223B2 (en) | 2000-11-29 | 2010-08-03 | Allergan, Inc. | Methods for reducing or preventing transplant rejection in the eye and intraocular implants for use |
US8828446B2 (en) | 2000-11-29 | 2014-09-09 | Allergan, Inc. | Method for reducing transplant rejection in the eye and intraocular implants for use therefor |
US8506987B2 (en) | 2003-01-09 | 2013-08-13 | Allergan, Inc. | Ocular implant made by a double extrusion process |
US20080107712A1 (en) * | 2003-01-09 | 2008-05-08 | Allergan, Inc. | Ocular implant made by a double extrusion process |
US10702539B2 (en) | 2003-01-09 | 2020-07-07 | Allergan, Inc. | Ocular implant made by a double extrusion process |
US8318070B2 (en) | 2003-01-09 | 2012-11-27 | Allergan, Inc. | Ocular implant made by a double extrusion process |
US10076526B2 (en) | 2003-01-09 | 2018-09-18 | Allergan, Inc. | Ocular implant made by a double extrusion process |
US8034370B2 (en) | 2003-01-09 | 2011-10-11 | Allergan, Inc. | Ocular implant made by a double extrusion process |
US8778381B2 (en) | 2003-01-09 | 2014-07-15 | Allergan, Inc. | Ocular implant made by a double extrusion process |
US8034366B2 (en) | 2003-01-09 | 2011-10-11 | Allergan, Inc. | Ocular implant made by a double extrusion process |
US9192511B2 (en) | 2003-01-09 | 2015-11-24 | Allergan, Inc. | Ocular implant made by a double extrusion process |
US8802129B2 (en) | 2004-04-30 | 2014-08-12 | Allergan, Inc. | Methods for treating retinopathy with extended therapeutic effect |
US8911768B2 (en) | 2004-04-30 | 2014-12-16 | Allergan, Inc. | Methods for treating retinopathy with extended therapeutic effect |
US20050244469A1 (en) * | 2004-04-30 | 2005-11-03 | Allergan, Inc. | Extended therapeutic effect ocular implant treatments |
US9233071B2 (en) | 2004-04-30 | 2016-01-12 | Allergan, Inc. | Methods for treating retinopathy with extended therapeutic effect |
US20050244461A1 (en) * | 2004-04-30 | 2005-11-03 | Allergan, Inc. | Controlled release drug delivery systems and methods for treatment of an eye |
US20060233859A1 (en) * | 2004-04-30 | 2006-10-19 | Allergan, Inc. | Methods for treating retinopathy with extended therapeutic effect |
US20060204548A1 (en) * | 2005-03-01 | 2006-09-14 | Allergan, Inc. | Microimplants for ocular administration |
EP2374451A2 (en) | 2005-07-27 | 2011-10-12 | University of Florida Research Foundation, Inc. | Histone deacetylase inhibitors (HDAC) that correct protein misfolding and uses thereof |
US9056076B2 (en) | 2005-10-08 | 2015-06-16 | Potentia Pharmaceuticals, Inc. | Method of treating age-related macular degeneration comprising administering a compstatin analog |
US10407466B2 (en) | 2005-10-08 | 2019-09-10 | Apellis Pharmaceuticals, Inc. | Methods of selecting compstatin mimetics |
EP1937210B1 (en) * | 2005-10-18 | 2017-05-31 | Allergan, Inc. | Ocular therapy using glucocorticoid derivatives selectively penetrating posterior segment tissues |
US9820995B2 (en) | 2005-10-18 | 2017-11-21 | Allergan, Inc. | Ocular therapy using glucocorticoid derivatives selectively penetrating posterior segment tissues |
US8840872B2 (en) | 2005-10-18 | 2014-09-23 | Allergan, Inc. | Ocular therapy using glucocorticoid derivatives selectively penetrating posterior segment tissues |
US10188665B2 (en) | 2005-10-18 | 2019-01-29 | Allergan, Inc. | Ocular therapy using glucocorticoid derivatives selectively penetrating posterior segment tissues |
KR101430760B1 (ko) * | 2005-10-18 | 2014-08-19 | 알러간, 인코포레이티드 | 후안부 조직으로 선택적으로 침투하는 글루코코르티코이드유도체를 사용한 안과 요법 |
EP1937210A2 (en) * | 2005-10-18 | 2008-07-02 | Allergan, Inc. | Ocular therapy using glucocorticoid derivatives selectively penetrating posterior segment tissues |
US9238094B2 (en) * | 2005-12-28 | 2016-01-19 | Ethicon, Inc. | Bioabsorbable polymer compositions exhibiting enhanced crystallization and hydrolysis rates |
US9173980B2 (en) * | 2005-12-28 | 2015-11-03 | Ethicon, Inc. | Bioabsorbable polymer compositions exhibiting enhanced crystallization and hydrolysis rates |
US20130210310A1 (en) * | 2005-12-28 | 2013-08-15 | Ethicon, Inc. | Bioabsorbable polymer compositions exhibiting enhanced crystallization and hydrolysis rates |
US20130225538A1 (en) * | 2005-12-28 | 2013-08-29 | Ethicon, Inc. | Bioabsorbable polymer compositions exhibiting enhanced crystallization and hydrolysis rates |
US7756524B1 (en) | 2006-01-31 | 2010-07-13 | Nextel Communications Inc. | System and method for partially count-based allocation of vocoder resources |
WO2007089544A3 (en) * | 2006-02-01 | 2008-03-13 | Allergan Inc | Biodegradable non-ophthalmic implants and related methods |
AU2007210155B2 (en) * | 2006-02-01 | 2011-06-23 | Allergan, Inc. | Biodegradable non-ophthalmic implants and related methods |
US20070178138A1 (en) * | 2006-02-01 | 2007-08-02 | Allergan, Inc. | Biodegradable non-opthalmic implants and related methods |
WO2007089544A2 (en) * | 2006-02-01 | 2007-08-09 | Allergan, Inc. | Biodegradable non-ophthalmic implants and related methods |
US20070212395A1 (en) * | 2006-03-08 | 2007-09-13 | Allergan, Inc. | Ocular therapy using sirtuin-activating agents |
US20070260203A1 (en) * | 2006-05-04 | 2007-11-08 | Allergan, Inc. | Vasoactive agent intraocular implant |
US8802128B2 (en) | 2006-06-23 | 2014-08-12 | Allergan, Inc. | Steroid-containing sustained release intraocular implants and related methods |
US20080145403A1 (en) * | 2006-12-19 | 2008-06-19 | Allergan, Inc. | Low temperature processes for making cyclic lipid implants for intraocular use |
EP2712610A1 (en) | 2006-12-19 | 2014-04-02 | Allergan, Inc. | Processes for making cyclic lipid implants for intraocular use |
US9149428B2 (en) | 2006-12-19 | 2015-10-06 | Allergan, Inc. | Processes for making cyclic lipid implants for intraocular use |
EP3308769A1 (en) | 2006-12-19 | 2018-04-18 | Allergan, Inc. | Processes for making cyclic lipid implants for intraocular use |
US8846073B2 (en) | 2006-12-19 | 2014-09-30 | Allergan, Inc. | Low temperature processes for making cyclic lipid implants for intraocular use |
US8956655B2 (en) | 2007-05-24 | 2015-02-17 | Allergan, Inc. | Biodegradable drug delivery system |
US20080292679A1 (en) * | 2007-05-24 | 2008-11-27 | Allergan, Inc. | Biodegradable drug delivery system |
US8231892B2 (en) * | 2007-05-24 | 2012-07-31 | Allergan, Inc. | Biodegradable drug delivery system |
US20090123518A1 (en) * | 2007-10-18 | 2009-05-14 | Su Il Yum | Biodegradable implants with controlled bulk density |
US20090281520A1 (en) * | 2007-11-08 | 2009-11-12 | Brian Highley | Ocular Implantation Device |
US9849027B2 (en) * | 2007-11-08 | 2017-12-26 | Alimera Sciences, Inc. | Ocular implantation device |
JP2011503162A (ja) * | 2007-11-15 | 2011-01-27 | ユーシーエル ビジネス パブリック リミティド カンパニー | 固体組成物 |
US20100278896A1 (en) * | 2007-11-15 | 2010-11-04 | Ucl Business Plc | Solid compositions |
WO2009063222A2 (en) * | 2007-11-15 | 2009-05-22 | Ucl Business Plc | Solid compositions |
WO2009063222A3 (en) * | 2007-11-15 | 2009-07-30 | Ucl Business Plc | Solid compositions |
US8663194B2 (en) | 2008-05-12 | 2014-03-04 | University Of Utah Research Foundation | Intraocular drug delivery device and associated methods |
US10064819B2 (en) | 2008-05-12 | 2018-09-04 | University Of Utah Research Foundation | Intraocular drug delivery device and associated methods |
US9095404B2 (en) | 2008-05-12 | 2015-08-04 | University Of Utah Research Foundation | Intraocular drug delivery device and associated methods |
US9877973B2 (en) | 2008-05-12 | 2018-01-30 | University Of Utah Research Foundation | Intraocular drug delivery device and associated methods |
US20100098772A1 (en) * | 2008-10-21 | 2010-04-22 | Allergan, Inc. | Drug delivery systems and methods for treating neovascularization |
US20100204325A1 (en) * | 2009-02-11 | 2010-08-12 | Allergan, Inc. | Valproic acid drug delivery systems and intraocular therapeutic uses thereof |
US10004636B2 (en) | 2009-06-03 | 2018-06-26 | Forsight Vision5, Inc. | Anterior segment drug delivery |
US9421126B2 (en) | 2009-06-03 | 2016-08-23 | Forsight Vision5, Inc. | Anterior segment drug delivery |
US10736774B2 (en) | 2009-06-03 | 2020-08-11 | Forsight Vision5, Inc. | Anterior segment drug delivery |
EP3100723A1 (en) | 2009-06-16 | 2016-12-07 | Bikam Pharmaceuticals, Inc. | Opsin-binding ligands, compositions and methods of use |
US10092514B2 (en) | 2009-07-14 | 2018-10-09 | Yamagata University | Eye drop with difluprednate for macular edema treatment |
US9949926B2 (en) | 2009-07-14 | 2018-04-24 | Yamagata University | Eye drop with difluprednate for macular edema treatment |
US20110190250A1 (en) * | 2009-07-14 | 2011-08-04 | Yamagata University | Eye drop with difluprednate for macular edema treatment |
EP2482818A1 (en) * | 2009-09-29 | 2012-08-08 | Eyegate Pharmaceuticals, Inc. | Positively-charged poly (d,l-lactide-co-glycolide) nanoparticles and fabrication methods of the same |
EP2482818A4 (en) * | 2009-09-29 | 2014-04-09 | Eyegate Pharmaceuticals Inc | POSITIVELY CHARGED POLY (D, L-LACTIDE-CO-GLYCOLIDE) NANOPARTICLES AND METHODS OF MAKING SAME |
WO2011124359A1 (de) * | 2010-04-07 | 2011-10-13 | Acino Ag | Freisetzungsverfahren für implantate |
US9937073B2 (en) | 2010-06-01 | 2018-04-10 | Forsight Vision5, Inc. | Ocular insert apparatus and methods |
US8939948B2 (en) | 2010-06-01 | 2015-01-27 | Forsight Vision5, Inc. | Ocular insert apparatus and methods |
US9370444B2 (en) | 2010-10-12 | 2016-06-21 | Emmett T. Cunningham, JR. | Subconjunctival conformer device and uses thereof |
US8915877B2 (en) | 2010-10-12 | 2014-12-23 | Emmett T. Cunningham, JR. | Glaucoma drainage device and uses thereof |
WO2012174064A1 (en) | 2011-06-14 | 2012-12-20 | Bikam Pharmaceuticals, Inc. | Opsin-binding ligands, compositions and methods of use |
US10835416B2 (en) | 2011-09-14 | 2020-11-17 | Forsight Vision5, Inc. | Ocular insert apparatus and methods |
US8715712B2 (en) | 2011-09-14 | 2014-05-06 | Forsight Vision5, Inc. | Ocular insert apparatus and methods |
EP2944628A1 (en) | 2011-11-30 | 2015-11-18 | Bikam Pharmaceuticals, Inc. | Opsin-binding ligands, compositions and methods of use |
WO2013081642A1 (en) | 2011-12-01 | 2013-06-06 | Bikam Pharmaceuticals, Inc. | Opsin-binding ligands, compositions and methods of use |
AU2013266410B2 (en) * | 2012-05-24 | 2016-04-21 | Ethicon, Llc | Mechanically strong bioabsorbable telechelic polymeric compositions of precisely controllable absorption rates, processing methods, and products therefrom |
US9737629B2 (en) * | 2012-05-24 | 2017-08-22 | Ethicon, Llc | Mechanically strong absorbable polymeric blend compositions of precisely controllable absorption rates, processing methods, and products therefrom |
US10675376B2 (en) * | 2012-05-24 | 2020-06-09 | Ethicon Llc | Mechanically strong absorbable polymeric blend compositions of precisely controllable absorption rates, processing methods, and products therefrom |
US9737630B2 (en) * | 2012-05-24 | 2017-08-22 | Ethicon, Llc | Mechanically strong absorbable polymeric blend compositions of precisely controllable absorption rates, processing methods, and products therefrom |
US20130315963A1 (en) * | 2012-05-24 | 2013-11-28 | Ethicon, Inc. | Mechanically Strong Absorbable Polymeric Blend Compositions of Precisely Controllable Absorption Rates, Processing Methods, And Products Therefrom |
US20150174287A1 (en) * | 2012-05-24 | 2015-06-25 | Ethicon, Inc. | Mechanically Strong Absorbable Polymeric Blend Compositions of Precisely Controllable Absorption Rates, Processing Methods, and Products Therefrom |
US20150174288A1 (en) * | 2012-05-24 | 2015-06-25 | Ethicon, Inc. | Mechanically Strong absorbable Polymeric Blend Compositions of Precisely Controllable Absorption Rates, Processing Methods, and Products Therefrom |
RU2676102C2 (ru) * | 2012-09-27 | 2018-12-26 | Аллерган, Инк. | Биодеградируемые системы доставки лекарственных средств для долговременного высвобождения белков |
US10456293B2 (en) | 2012-10-26 | 2019-10-29 | Forsight Vision5, Inc. | Ophthalmic system for sustained release of drug to eye |
US9750636B2 (en) | 2012-10-26 | 2017-09-05 | Forsight Vision5, Inc. | Ophthalmic system for sustained release of drug to eye |
US10875893B2 (en) | 2012-11-15 | 2020-12-29 | Apellis Pharmaceuticals, Inc. | Cell-reactive, long-acting, or targeted compstatin analogs and related compositions and methods |
US11292815B2 (en) | 2012-11-15 | 2022-04-05 | Apellis Pharmaceuticals, Inc. | Cell-reactive, long-acting, or targeted compstatin analogs and related compositions and methods |
US11407789B2 (en) | 2013-03-15 | 2022-08-09 | Apellis Pharmaceuticals, Inc. | Cell-penetrating compstatin analogs and uses thereof |
US10308687B2 (en) | 2013-03-15 | 2019-06-04 | Apellis Pharmaceuticals, Inc. | Cell-penetrating compstatin analogs and uses thereof |
US10941184B2 (en) | 2013-03-15 | 2021-03-09 | Apellis Pharmaceuticals, Inc. | Cell-penetrating compstatin analogs and uses thereof |
US20160278915A1 (en) * | 2013-10-24 | 2016-09-29 | Aaren Scientific Inc. | Hydrophilic iol packaging system |
US10299914B2 (en) * | 2013-10-24 | 2019-05-28 | Carl Zeiss Meditec Production, LLC | Hydrophilic IOL packaging system |
US20150140062A1 (en) * | 2013-11-15 | 2015-05-21 | Allergan, Inc. | Methods of treatment of ocular conditions with a sustained drug delivery implant |
JP2017504675A (ja) * | 2013-11-27 | 2017-02-09 | エシコン・エルエルシーEthicon, LLC | 高精度で制御可能な吸収速度を有する吸収性ポリマーブレンド組成物、加工方法、及び該組成物により提供される寸法的に安定な医療装置 |
US20150148496A1 (en) * | 2013-11-27 | 2015-05-28 | Ethicon, Inc. | Absorbable Polymeric Blend Compositions with Precisely Controllable Absorption Rates, Processing Methods, and Dimensionally Stable Medical Devices Therefrom |
US10058637B2 (en) * | 2013-11-27 | 2018-08-28 | Ethicon, Llc | Absorbable polymeric blend compositions with precisely controllable absorption rates, processing methods, and dimensionally stable medical devices therefrom |
WO2016042163A3 (en) * | 2014-09-19 | 2016-05-12 | Precision Ocular Limited | Ophthalmic drug compositions |
AU2015316710B2 (en) * | 2014-09-19 | 2020-07-23 | Oxular Limited | Ophthalmic drug compositions |
GB2536517A (en) * | 2014-09-19 | 2016-09-21 | Prec Ocular Ltd | Opthalmic drug compositions |
GB2536517B (en) * | 2014-09-19 | 2019-05-29 | Oxular Ltd | Opthalmic drug compositions |
US11224602B2 (en) | 2015-04-13 | 2022-01-18 | Forsight Vision5, Inc. | Ocular insert composition of a semi-crystalline or crystalline pharmaceutically active agent |
US11903994B2 (en) | 2015-10-07 | 2024-02-20 | Apellis Pharmaceuticals, Inc. | Dosing regimens |
US11040107B2 (en) | 2017-04-07 | 2021-06-22 | Apellis Pharmaceuticals, Inc. | Dosing regimens and related compositions and methods |
US11844841B2 (en) | 2017-04-07 | 2023-12-19 | Apellis Pharmaceuticals, Inc. | Dosing regimens and related compositions and methods |
US11564834B2 (en) | 2017-09-15 | 2023-01-31 | Oxular Limited | Sterile lyophilized drug compositions and methods for treating ocular diseases or conditions |
US20220233564A1 (en) * | 2021-01-25 | 2022-07-28 | University Of South Florida | Ophthalmological formulations for the prevention of a coronavirus infection |
US11998562B2 (en) * | 2021-01-25 | 2024-06-04 | University Of South Florida | Ophthalmological formulations for the prevention of a coronavirus infection |
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