US20070224278A1 - Low immunogenicity corticosteroid compositions - Google Patents

Low immunogenicity corticosteroid compositions Download PDF

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US20070224278A1
US20070224278A1 US11741366 US74136607A US2007224278A1 US 20070224278 A1 US20070224278 A1 US 20070224278A1 US 11741366 US11741366 US 11741366 US 74136607 A US74136607 A US 74136607A US 2007224278 A1 US2007224278 A1 US 2007224278A1
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triamcinolone
composition
example
injection
intravitreal
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Robert Lyons
Michael Robinson
James Chang
Sam Lam
John Trogden
Scott Whitcup
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Allergan Inc
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Allergan Inc
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0019Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/56Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives, e.g. steroids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/56Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives, e.g. steroids
    • A61K31/57Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane, progesterone
    • A61K31/573Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane, progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/56Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives, e.g. steroids
    • A61K31/58Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/70Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02Inorganic compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40Cyclodextrins; Derivatives thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0048Eye, e.g. artificial tears

Abstract

Triamcinolone compositions, and methods of using such compositions, useful for injection into the vitreous of human eyes or into a joint are provided. Such compositions can include triamcinolone particles present in a therapeutically effective amount, a viscosity inducing component, and an aqueous carrier component. The compositions have viscosities of at least about 10 cps or about 100 cps at a shear rate of 0.1/second. In a preferred embodiment, the viscosity is in the range of from about 80,000 cps to about 300,000 cps. In a most preferred embodiment, the viscosity is in the range of from about 140,000 cps to about 280,000 cps t a shear rate of 0.1/second at 25° C. The compositions advantageously suspend the triamcinolone particles for prolonged periods of time.

Description

    CROSS REFERENCE
  • [0001]
    This application is a continuation in part of application Ser. No. 11/354,415, filed Feb. 14, 2006, which is a continuation in part of application Ser. No. 10/966,764, filed Oct. 14, 2004, which application claims the benefit of provisional patent application Ser. No. 60/519,237, filed Nov. 12, 2003 and provisional is patent application Ser. No. 60/530,062, filed Dec. 16, 2003, all of which applications are hereby incorporated herein by reference in their entireties.
  • BACKGROUND
  • [0002]
    The present invention relates to corticosteroid compositions and methods for treating and/or preventing ocular conditions, such as anterior ocular conditions and posterior ocular conditions, as well as for treating various articular pathologies. In particular the present invention relates to extended release and sustained release triamcinolone compositions, including injectable implants, for treating posterior ocular conditions, as well as for treating joint inflammation and/or joint pain.
  • [0003]
    A pharmaceutical composition (synonymously a composition) is a formulation which contains at least one active ingredient (for example a corticosteroid such as a triamcinolone) as well as, for example, one or more excipients, buffers, carriers, stabilizers, preservatives and/or bulking agents, and is suitable for administration to a patient to achieve a desired effect or result. The pharmaceutical compositions disclosed herein can have diagnostic, therapeutic, cosmetic and/or research utility in various species, such as for example in human patients or subjects.
  • [0004]
    An ocular condition can include a disease, aliment or condition which affects or involves the eye or one of the parts or regions of the eye. Broadly speaking the eye includes the eyeball and the tissues and fluids which constitute the eyeball, the periocular muscles (such as the oblique and rectus muscles) and the portion of the optic nerve which is within or adjacent to the eyeball. An anterior ocular condition is a disease, ailment or condition which affects or which involves an anterior (i.e. front of the eye) ocular region or site, such as a periocular muscle, an eye lid or an eye ball tissue or fluid which is located anterior to the posterior wall of the lens capsule or ciliary muscles. Thus, an anterior ocular condition primarily affects or involves, the conjunctiva, the cornea, the conjunctiva, the anterior chamber, the iris, the posterior chamber (behind the retina but in front of the posterior wall of the lens capsule), the lens or the lens capsule and blood vessels and nerve which vascularize or innervate an anterior ocular region or site. A posterior ocular (also referred to herein synonymously as a “posterior segment”) 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 (or posterior segment) region or site.
  • [0005]
    Thus, a posterior ocular condition can include a disease, ailment or condition, such as for example, macular degeneration (such as non-exudative age related macular degeneration and exudative age related macular degeneration); choroidal neovascularization; acute macular neuroretinopathy; macular edema (such as cystoid macular edema and diabetic macular edema); Behcet's disease, retinal disorders, diabetic retinopathy (including proliferative diabetic retinopathy); retinal arterial occlusive disease; central retinal vein occlusion; uveitis (including intermediate and anterior uveitis); retinal detachment; ocular trauma which affects a posterior ocular site or location; a posterior ocular condition caused by or influenced by an ocular laser treatment; posterior ocular conditions caused by or influenced by a photodynamic therapy; photocoagulation; radiation retinopathy; epiretinal membrane disorders; branch retinal vein occlusion; anterior ischemic optic neuropathy; non-retinopathy diabetic retinal dysfunction, retinitis pigmentosa and glaucoma. Glaucoma can be considered a posterior ocular condition because a therapeutic goal can be to prevent the loss of or reduce the occurrence of loss of vision due to damage to or loss of retinal cells or optic nerve cells (i.e. neuroprotection).
  • [0006]
    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).
  • [0007]
    Macular edema is a major cause of visual loss in patients with diabetes, central retinal vein occlusion (CRVO) and branch retinal vein occlusion (BRVO). Although laser photocoagulation can reduce further vision loss in patients with diabetic macular edema (DME), vision that has already been decreased by macular edema usually does not improve by use of laser photocoagulation. Currently, there is no FDA (U.S. Food and Drug Administration) approved treatment for macular edema associated with CRVO. For macular edema associated with BRVO, grid laser photocoagulation may be an effective treatment for some patients.
  • [0008]
    Diabetic macular edema results from abnormal leakage of macromolecules, such as lipoproteins, from retinal capillaries into the extravascular space followed by an oncotic influx of water into the extravascular space. Abnormalities in the retinal pigment epithelium may also cause or contribute to diabetic macular edema. These abnormalities can allow increased fluid from the choriocapillaries to enter the retina or they may decrease the normal efflux of fluid from the retina to the choriocapillaries. The mechanism of breakdown of the blood-retina barrier at the level of the retinal capillaries and the retinal pigment epithelium may be due to changes to tight junction proteins such as occludin. Antcliff R., et al Marshall J., The pathogenesis of edema in diabetic maculopathy, Semin Opthalmol 1999; 14:223-232.
  • [0009]
    Macular edema from venous occlusive disease can result from thrombus formation at the lamina cribrosa or at an arteriovenous crossing. These changes can result in an increase in retinal capillary permeability and accompanying retinal edema. The increase in retinal capillary permeability and subsequent retinal edema can ensue from of a breakdown of the blood retina barrier mediated in part by vascular endothelial growth factor (VEGF), a 45 kD glycoprotein, as it is known that VEGF can increase vascular permeability. VEGF may regulate vessel permeability by increasing phosphorylation of tight junction proteins such as occludin and zonula occluden. Similarly, in human non-ocular disease states such as ascites, VEGF has been characterized as a potent vascular permeability factor (VPF).
  • [0010]
    The normal human retina contains little or no VEGF; however, hypoxia causes upregulation of VEGF production. Disease states characterized by hypoxia-induced VEGF upregulation include CRVO and BRVO. This hypoxia induced upregulation of VEGF can be inhibited pharmacologically. Pe'er J. et al., Vascular endothelial growth factor upregulation in human central retinal vein occlusion, Opthalmology 1998; 105:412-416. It has been demonstrated that anti-VEGF antibodies can inhibit VEGF driven capillary endothelial cell proliferation. Thus, attenuation of the effects of VEGF introduces a rationale for treatment of macular edema from venous occlusive disease.
  • [0011]
    Corticosteroids, a class of substances with anti-inflammatory properties, have been demonstrated to inhibit the expression of the VEGF gene. Nauck M. et al., Induction of vascular endothelial growth factor by platelet-activating factor and platelet-derived growth factor is downregulated by corticosteroids, Am J Resp Cell Mol Biol 1997; 16:398-406. Additionally, corticosteroids can downregulate the induction of VEGF by the pro-inflammatory mediators PDGF and platelet-activating factor (PAF) in a time and dose-dependent manner. Nauck M. et al., Corticosteroids inhibit the expression of the vascular endothelial growth factor gene in human vascular smooth muscle cells, Euro J Pharmacol 1998; 341:309-315. Thus, corticosteroids can to down-regulate VEGF production and reduce breakdown of the blood-retinal barrier. Certain steroids can also have antiangiogenic properties possibly due to attenuation of the effects of VEGF. It should be noted that although certain corticosteroids can apparently down regulate VEGF production there are a number of other physiological mechanisms by which corticosteroids can effect the pathogenesis of an ocular condition, such as macular edema.
  • [0012]
    Triamcinolone
  • [0013]
    Triamcinolone is a corticosteroid and it has been reported that a saline suspension is of triamcinoline (1 mg triamcinolone acetonide in 0.1 ml saline) is non-toxic upon intravitreal injection. McCuen B. et al., The lack of toxicity of intravitreally administered triamcinolone acetonide, Am J Opthalmol 1981; 91:785-788. Intravitreal triamcinolone has been used to treat proliferative vitreoretinopathy (Jonas J. et al., Intravitreal injection of crystalline cortisone as adjunctive treatment of proliferative vitreoretinopathy, Br J Opthalmol 2000; 84:1064-1067), as well as choroidal neovascularization (Challa J. et al., Exudative macular degeneration and intravitreal triamcinolone: 18 month follow up, Aust N Z J Opthalmol 1998; 26:277-281; Penfold P. et al., Exudative macular degeneration and intravitreal triamcinolone: A pilot study, Aust N Z J Opthalmol 1995; 23:293-298, and; Danis R. et al., Intravitreal triamcinolone acetonide in exudative age-related macular degeneration, Retina 2000; 20:244-250).
  • [0014]
    Additionally, European patent application 244 178 A2 (Keller) discloses intravitreal injection of an aqueous solution of dexamethasone and a hyaluronic acid, and a topical triamcinolone suspension for ear treatment is discussed in Chang H. et al., Development of a topical suspension containing three active ingredient, Drug Dev and Ind Pharm, 28(1), 29-39 (2002). Einmahl S. et al, Evaluation of a novel biomaterial in the suprachoroidal space of the rabbit eye, Invest Ophthal & V is Sci 43(5); 1533-1539 (2002) discusses injection of a poly(ortho ester) into the suprachoroidal space, and Einmahl S. et al, Therapeutic applications of viscous and injectable poly(ortho esters), Adv Drug Del Rev 53 (2001) 45-73, discloses that a poly ortho ester polymer containing fluorouracil markedly degrades five days after intravitreal administration. See also U.S. Pat. No. 5,770,589 (Billson) which discusses intravitreal injection of a corticosteroid, such as triamcinolone acetonide. U.S. Pat. No. 5,209,926 (Babcock) discusses ophthalmic use of various amino substituted steroids.
  • [0015]
    Known formulations of triamcinolone clear (diffuses out of and/or is removed by one or more active transport mechanisms) from the vitreous within at most about 90 days, although it has been speculated that with a known formulation (Kenalog) the triamcinolone may be detectable in the vitreous for no more than four months after intravitreal injection. Thus, McCuen B. et al. (1981) supra at page 786 noted that after three months no triamcinolone was visible in any treated eyes. Others have reported that the triamcinolone present in a saline or other aqueous suspension or solution is upon intravitreal administration cleared from the vitreous in about 21-41 days; using opthalmoscopic and spectrophotometric detection means to determine disappearance of the injected triamcinolone, in non-vitrectomized rabbit eyes the average clearance rate of intravitreally triamcinolone (0.5 mg) was 41 days, while in eyes having undergone vitrectomy or combination vitrectomy and lensectomy the average clearance rate was 17 days and 7 days, respectively. Schindler R. et al., The clearance of intravitreal triamcinolone acetonide, Am J Opthalmol 1982; 93:415-417. Using high-performance liquid chromatography (HPLC) complete clearance of intravitreally injected triamcinolone (0.4 mg) in 24 rabbit eyes was observed by 21 days. Scholes G. et al., Clearance of triamcinolone from vitreous, Arch Opthalmol 1985; 103:1567-1569.). Such rapid clearance from the vitreous can necessitate frequent re-administration (re-dosing) in order to effectively treat an ocular condition.
  • [0016]
    A triamcinolone pharmaceutical composition available under the trade name Kenalog® (Bristol-Myers-Squibb, Princeton N.J.) has been widely used off-label to treat various ocular conditions, including by intravitreal administration. Significantly, Kenalog® is approved by the U.S. Food and Drug Administration only for intramuscular or intrabursal use, but not for the treatment of any ocular conditions. Each milliliter (ml) of Kenalog® 40 composition comprises 40 milligrams (mg) of triamcinolone acetonide, sodium chloride as a tonicity agent, 10 mg (0.99%) benzyl alcohol as a preservative, 7.5 mg (0.75%) of carboxymethylcellulose sodium and 0.4 mg (0.04%) of polysorbate 80 as resuspension aids.
  • [0017]
    It has been reported that Kenalog has a 15 day half life in the vitreous with an effect on central macular thickness being observed for up to 140 days after intravitreal injection of the Kenalog. Aubren, F. et al., Pharmacokinetic-Pharmacodynamic modeling of the effect of Triamcinolone Acetonide on Central Macular Thickness in is Patients with Diabetic Macular Edema, Inv Ophth & V is Sci, 45(10); 3435-3441: October 2004. It has also been reported that triamcinolone can be detected in the vitreous up to 93 days after a single intravitreal injection of Kenalog (Beer P. et al., Intraocular concentration and pharmacokinetics of triamcinolone acetonide after a single intravitreal injection, Opthal 110(4); 681-686: April 2003), with the triamcinolone estimated to be potentially detectable in the vitreous for about 4 months. Inoue M. et al., Vitreous concentrations of triamcinolone acetonide in human eyes after intravitreal or subtenon injection, Am J Opth 138(6); 1046-1048: 2004.
  • [0018]
    Noninfectious endophthalmitis have been reported upon intravitreal Kenalog® injection, possibly related to the preservative, excipients and/or resuspension aids present in Kenalog® (Roth D. et al., Noninfectious endophthalmitis associated with intravitreal triamcinolone injection, Arch Opthalmol 2003; 121: 1279-1282; Sutter F. et al., Pseudo-endophthalmitis after intravitreal injection of triamcinolone, Br J Opthalmol 2003; 87:972-974).
  • [0019]
    Additionally, the presence of benzyl alcohol preservative and polysorbate 80 surfactant in Kenalog® can potentially damage or be toxic to sensitive ocular tissues, such as retinal cells, and for this reason clinicians routinely wash the triamcinolone acetonide precipitate (which forms when Kenalog® is left standing) several times with saline to reduce the concentration of these undesirable non-active materials from the formulation. Additionally, methods have been developed to filter out of Kenalog® and from identical formulations such as Kenacort-A the preservative, surfactant, and/or resuspension (suspending agents) aids present in these formulations. Nishimura A. et al., Isolating Triamcinolone acetonide particles for intravitreal use with a porous membrane filter, Retina, vol 23(6); 777-779 (2003). Such washing and/or filtering steps are inconvenient, time consuming, and increase the possibility of microbial or endotoxin contamination that could lead to intraocular infection and inflammation.
  • [0020]
    Significantly, the triamcinolone acetonide in Kenalog® 40 tends to rapidly separate and precipitate from the remainder of the composition. For example, if Kenalog® is left standing for as short a time as about five to ten minutes a substantial separation of a triamcinolone acetonide precipitate from the remainder of the composition occurs. Unfortunately, such rapid settling of the triamcinolone also occurs with other known saline based suspensions of triamcinolone (with or with preservatives and stabilizers). Thus, if the composition is to be injected into the eye it must first be vigorously shaken and used promptly after being so shaken in order to provide a substantially uniform suspension. A substantially uniform suspension (which is not provided by Kenalog or other saline based suspensions of triamcinolone) is required in order to provide a consistent and accurate dose upon administration of the suspension to the eye. In addition, resuspension processing requires the use of the resuspension aids noted above, at least one of which is less than totally desirable for sensitive ocular tissues. At least because of the potential risk of noninfectious endophthalmitis from use of the Kenalog® vehicle, development of a preservative-free triamcinolone formulation for intraocular use to treat an ocular condition (such as a posterior ocular condition) is desirable.
  • [0021]
    Elevated intraocular pressure, that is elevated anterior chamber intraocular pressure, depends on the comparative rates of aqueous production and aqueous drainage, primarily through the trabecular meshwork. Increased intraocular pressure occurs from a variety of mechanisms such as primary or secondary angle-closure glaucoma, primary or secondary open-angle glaucoma, or combined-mechanism glaucoma. If inadequately treated, increased intraocular pressure may result in glaucomatous optic nerve changes and loss of visual field.
  • [0022]
    Known formulations of corticosteroids administered by a topical, systemic or peribulbar route can cause an increase in anterior chamber intraocular pressure. For example, following 4 to 6 weeks of topical corticosteroid administration, 5% of subjects can show an elevation in intraocular pressure of >16 mmHg and 30% of subjects may is show an elevation of 6 to 15 mmHg (Armaly M., Statistical attributes of the steroid hypertensive response in the clinically normal eye, Invest Opthalmol V is Sci 1965; 4:187-197; Becker B,. Intraocular pressure response to topical corticosteroid, Invest Opthalmol V is Sci 1965; 4:198-205). Additionally, intravitreal administration of known formulations of a corticosteroid, such as triamcinolone can also result in increased intraocular pressure (Martidis A. et al., Intravitreal triamcinolone for refractory diabetic macular edema, Opthalmology 2002; 109:920-927; Jonas J. et al., Intravitreal injection of triamcinolone for diffuse diabetic macular edema, Arch Opthalmol 2003; 121:57-61), possibly due to the burst or high release rates of triamcinolone from the known formulations.
  • [0023]
    As well as causing an increase in intraocular pressure, corticosteroids can also cause an increase in cataract formation. Corticosteroid-induced cataracts typically show an axial, posterior subcapsular opacity, which gradually increases in size. Nuclear sclerosis is not a typical lens change from corticosteroids. Topical, systemic and peribulbar corticosteroid administration have all been associated with an increased risk of cataract formation (Butcher J. et al., Bilateral cataracts and glaucoma induced by long term use of steroid eye drops. BMJ 1994; 309-343).
  • [0024]
    The intravitreal administration of known triamcinolone formulations can therefore also be expected to be associated with an increased risk of both elevated intraocular pressure and cataract formation.
  • [0025]
    A further adverse effect from ocular corticosteroid administration can be inflammation. Endophthalmitis is a type of intraocular inflammation that can be due to infection with pathogens such as bacteria of fungi or can be noninfectious. Clinical features include lid edema, conjunctival injection, corneal edema, anterior chamber and vitreous inflammation and hypotonia. Infectious endophthalmitis can occur following an intraocular procedure (i.e. cataract surgery, vitrectomy surgery, intravitreal injection), as a result of systemic infection, as a result of trauma, or occur as a late is feature of conjunctival filtering blebs.
  • [0026]
    The most common dose of triamcinolone used to treat eyes with macular edema associated with diabetes, CRVO or BRVO is 4 mg (Martidis A. et al., Intravitreal triamcinolone for refractory diabetic macular edema, Opthalmology 2002; 109:920-927). The use of 25 mg of triamcinolone has less commonly been used to treat eyes with macular edema (Jonas J. et al., Intraocular injection of crystalline cortisone as adjunctive treatment of diabetic macular edema, Am J Opthalmol 2001; 132:425-427).
  • [0027]
    Thus, there are significant drawbacks and deficiencies with the known triamcinolone formulations used by intravitreal administration to treat an ocular condition, including for example rapid clearance from the vitreous, elevated intraocular pressure, cataract formation, retinal toxicity, and intraocular inflammation, such as endophthalmitis.
  • [0028]
    Hence, a sterile, preservative-free, sustained release triamcinolone preparation is desirable. Additionally, because corticosteroids have known ocular toxicities (as manifested in the occurrence or development of for example elevated IOP, glaucoma and cataract) it is desirable to have a triamcinolone formulation for intraocular (i.e. intravitreal) use which does not result in an increased incidence of elevated IOP, glaucoma, cataract formation and/or intraocular inflammation, or which has, subsequent to intraocular administration of a triamcinolone formulation, a reduced incidence of elevated IOP, glaucoma, cataract formation and/or intraocular inflammation as compared to currently used or known intraocular (i.e. intravitreal) use triamcinolone.
  • DRAWINGS
  • [0029]
    FIG. 1 is a bar graph of observed angiographic leakage (as assessed on a 1-5 grading scale) on the Y-axis versus time of the observation on the X-axis for three groups of rabbit eyes: rabbit control (untreated) eyes, rabbit eyes intravitreally injected with the 1 mg triamcinolone acetonide gel suspension (TAAgs) formulation of Example 8, and rabbit eyes intravitreally injected with the 4 mg TAAgs of Example 9. The grading (scale 1-5) of late-phase angiograms from rabbit eyes was measured over a thirty week period after intravitreal injection of either the 1 mg TAAgs or 4 mg TAAgs. All eyes received intravitreal injection of 500 ng VEGF at each of the time points shown on the X-axis followed by angiography 48 hrs later.
  • [0030]
    FIG. 2 is a bar graph of observed vitreoretinal fluorescence (as area under the curve) on the Y-axis versus time of the observation on the X-axis for the same three groups of rabbit eyes: rabbit control (untreated) eyes, rabbit eyes intravitreally injected with the 1 mg TAAgs, and rabbit eyes intravitreally injected with the 4 mg TAAgs (as in FIG. 1). Scanning vitreal fluorophotometry measurements of VEGF-induced BRB breakdown in rabbit eyes was measured over the same thirty week period after intravitreal injection of the 1 mg or 4 mg TAAgs. As in FIG. 1, all eyes had received intravitreal injection of 500 ng VEGF at the time points shown on the X-axis followed by fluorophotometry 48 hrs later. The area under the fluorescence curve (AUC) was calculated for each eye.
  • [0031]
    FIG. 3 is a bar graph of observed retinal blood vessel caliber and tortuosity (grade) on the Y-axis versus time of the observation on the X-axis for the same rabbit control (untreated) eyes, rabbit eyes intravitreally injected with 1 mg TAAgs or with 4 mg TAAgs (as in FIG. 1). Subjective grading (on a 1-5 scale) of VEGF-induced changes in vessel caliber and tortuosity from fundus images of rabbit eyes was measured over the same thirty week period after intravitreal injection of the 1 or 4 mg TAAgs. As in FIG. 1, all eyes received intravitreal injection of 500 ng VEGF at the indicated time points followed by fundus image capture 48 hrs later.
  • [0032]
    FIG. 4 is a bar graph of observed anterior chamber fluorescence (as area under the curve) on the Y-axis versus time of the observation on the X-axis for the same rabbit control (untreated) eyes, rabbit eyes intravitreally injected with 1 mg TAAgs or with 4 mg TAAgs, (as in FIG. 1). Scanning ocular fluorophotometry of VEGF-induced blood-aqueous barrier breakdown in rabbit eyes was measured over a thirty week period after intravitreal injection of either 1 or 4 mg TAAgs. As in FIG. 1, all eyes received intravitreal injection of 500 ng VEGF at the indicated time points followed by anterior chamber fluorophotometry 48 hrs later. The area under the fluorescence curve (AUC) was calculated for each eye.
  • [0033]
    FIG. 5 is a negative image of a photograph of the eye of a rabbit thirty weeks after intravitreal injection of 50 μL of the Example 94 mg TAAgs formulation. The photograph was taken with an 11.0 megapixel, digital Zeiss FF450 fundus camera coupled to the Zeiss 481 Visupac image capture and analysis system.
  • [0034]
    FIG. 6 is a flow chart which summarizes a preferred manufacturing process for making the triamcinolone formulations of Examples 1 to 9.
  • [0035]
    FIG. 7 consists of three bar graphs showing the size (diameter) in microns α-axis) of triamcinolone acetonide particles in three commercial lots of Kenalog-40 vs the frequency of occurrence of the measured particles diameters. Triamcinolone acetonide particle size diameter and distribution was determined by laser light scattering using a Horiba LA 300 instrument.
  • [0036]
    FIG. 8 consists of four bar graphs (A, B, C and D) showing the size (diameter) in microns (x-axis) of triamcinolone acetonide particles in four lots of the Example 9 (8% Trivaris) formulation vs the frequency of occurrence of the measured particles diameters. The line graph in FIGS. 8A to 8D shows the area under the curve for cummulative (%) triamcinolone acetonide particle size (right hand side y axis). Triamcinolone acetonide particle size diameter and distribution was determined by laser light scattering using a Horiba LA 300 instrument.
  • SUMMARY
  • [0037]
    The present invention provides sterile, preservative-free, sustained release triamcinolone formulations for treating ocular conditions with the desirable characteristics of low ocular toxicities, as manifested in the low or nominal occurrence or development of an elevated IOP, glaucoma, cataract and/or intraocular inflammation.
  • [0038]
    Definitions
  • [0039]
    As used herein, the words or terms set forth below have the following definitions.
  • [0040]
    “About” means that the item, parameter or term so qualified encompasses a range of plus or minus ten percent above and below the value of the stated item, parameter or term.
  • [0041]
    “Administration”, or “to administer” means the step of giving (i.e. administering) a pharmaceutical composition to a subject. The pharmaceutical compositions disclosed herein can be “locally administered”, that is administered at or in the vicinity of the site at which a therapeutic result or outcome is desired. For example to treat an ocular condition (such as for example a macular edema, uveitis or macular degeneration) intravitreal injection or implantation of a sustained release device such as active agent containing polymeric implant can be carried out. “Sustained release” means release of an active agent (such as a triamcinolone) over a period of about seven days or more, while “extended release” means release of an active agent over a period of time of less than about seven days.
  • [0042]
    “Entirely free (i.e. “consisting of” terminology) means that within the detection range of the instrument or process being used, the substance cannot be detected or its presence cannot be confirmed.
  • [0043]
    “Essentially free” (or “consisting essentially of”) means that only trace amounts of the substance can be detected.
  • [0044]
    “Pharmaceutical composition” means a formulation in which an active ingredient (the active agent) can be a steroid, such as a corticosteroid, such as a triamcinolone. The word “formulation” means that there is at least one additional ingredient in the pharmaceutical composition besides the steroid active ingredient. A pharmaceutical composition is therefore a formulation which is suitable for diagnostic or therapeutic administration (i.e. by intraocular injection or by insertion of a depot or implant) to a subject, such as a human patient.
  • [0045]
    “Substantially free” means present at a level of less than one percent by weight of the pharmaceutical composition.
  • [0046]
    All the viscosity values set forth herein were determined at 25° C. (unless another temperature is specified). Additionally, all the viscosity values set forth herein were determined at a shear rate of about 0.1/second (unless another shear rate is specified).
  • [0047]
    The present compositions are highly suitable for intravitreal administration into the posterior segments of eyes without requiring any washing step, while providing for reduced ocular, for example, retinal, damage when used in an eye. The present compositions are advantageously substantially free of added preservative components, for example, contain no benzyl alcohol preservative. In addition, the present compositions advantageously require no resuspension aid or aids. Overall, the present compositions are easily and effectively injectable into the posterior segment of an eye of a human or animal and can be maintained as a substantially uniform suspension for long periods of time, for example, at least about one week or more, without resuspension processing, for example, without requiring shaking or other agitating of the composition to obtain substantial suspension uniformity. In short, is the present compositions and methods provide substantial enhancements and advantages, for example, relative to the prior art Kenalog® 40 composition and methods of using such prior art composition, in the posterior segments of human or animal eyes.
  • [0048]
    In one broad aspect of the present invention, compositions useful for injection into a posterior segment of an eye of a human or animal are provided. Such compositions comprise a corticosteroid component, a viscosity inducing component, and an aqueous carrier component. The corticosteroid component is present in a therapeutically effective amount. The corticosteroid component is present in the compositions in a plurality of particles.
  • [0049]
    The present compositions may include a corticosteroid component in an amount of up to about 25% (w/v) or more of the composition. In one very useful embodiment, the corticosteroid component is present in an amount of at least about 80 mg/ml of composition. Preferably, the corticosteroid component is present in an amount in a range of about 1% to about 10% or about 20% (w/v) of the composition.
  • [0050]
    In one very useful embodiment, the corticosteroid component comprises triamcinolone acetonide. The viscosity inducing component is present in an amount effective in increasing the viscosity of the composition. Any suitable, preferably ophthalmically acceptable, viscosity inducing component may be employed in accordance with the present invention. Many such viscosity inducing components have been proposed and/or used in ophthalmic compositions used on or in the eye. Advantageously, the viscosity inducing component is present in an amount in a range of about 0.5% to about 20% (w/v) of the composition. In one particularly useful embodiment, the viscosity inducing component is a hyaluronic acid polymer component, such as sodium hyaluronate.
  • [0051]
    In one embodiment, the present compositions have a viscosity of at least about 10 cps or at least about 100 cps, preferably at least about 1,000 cps, more preferably at least about 10,000 cps and still more preferably at least about 70,000 cps, for example, up to about 250,000 cps, or about 300,000 cps, at a shear rate of 0.1/second. The present compositions are structured or have make-ups so as to be effectively, for example, manually, injected into a posterior segment of an eye of a human or animal, preferably through a 27 gauge needle, more preferably through a 29 or 30 gauge needle.
  • [0052]
    Without wishing to limit the invention to any particular theory of operation, it is believed that the use of relatively high viscosity compositions, as described herein, provides for effective, and preferably substantially uniform, suspension of the steroid component particles while, at the same time, being injectable into the posterior segment of an eye through conventionally, or even smaller than conventionally, used needles.
  • [0053]
    In one embodiment of the invention, the corticosteroid component is present in a plurality of particles which are substantially uniformly suspended in the composition and remain substantially uniformly suspended in the composition for at least about 1 week, preferably at least about 2 weeks or at least about 1 month, and still more preferably at least about 6 months or at least about 1 year or at least about 2 years, without requiring resuspension processing, that is, without requiring being shaken or otherwise agitated to maintain the corticosteroid component particles substantially uniformly suspended in the composition.
  • [0054]
    Compositions having such substantially uniform suspension of corticosteroid component particles, so as to be able to provide a consistent and accurate dose upon administration to an eye, provide substantial advantages relative to the prior art. In particular, the present compositions may be manufactured, shipped and stored for substantial periods of time without the corticosteroid component particles precipitating is from the remainder of the composition. Having the corticosteroid component particles maintained substantially uniformly suspended in the composition allows the composition to provide long term dosing consistency and accuracy per unit dose amount administered, without any need to resuspend the corticosteroid particles.
  • [0055]
    The aqueous carrier component is advantageously ophthalmically acceptable and may include one or more conventional expedients useful in ophthalmic compositions. For example, the carrier component may include an effective amount of at least one of a preservative component, a tonicity component and a buffer component. In one advantageous embodiment, the present compositions include no added preservative component. This feature reduces or minimizes or even substantially eliminates adverse reactions in the eye which may be caused by or linked to the presence of a preservative component. Although a resuspension component may be employed in accordance with the present invention, in many instances, because of the ability of the present composition to remain a substantially uniform suspension for a long period of time without requiring resuspension processing, the compositions advantageously contain no added resuspension components.
  • [0056]
    Methods of treating posterior segments of the eyes of humans or animals are also disclosed and are included within the scope of the present invention. In general, such methods comprise administering, e.g. injecting a corticosteroid component-containing composition, for example, a composition in accordance with the present intention, to a posterior segment of an eye of a human or animal. Such administering is effective in providing a desired therapeutic effect. The administering step advantageously comprises at least one of intravitreal injecting, subconjunctival injecting, sub-tenon injecting, retrobulbar injecting, suprachoroidal injecting and the like.
  • [0057]
    Our invention encompasses a pharmaceutical composition for treating a posterior ocular condition. The composition can comprise a triamcinolone present in a therapeutically effective amount as a plurality of particles; a viscosity inducing component in an amount effective to increase the viscosity of the composition, and; an aqueous carrier component. The composition can have a viscosity of at least about 10 cps at a shear rate of about 0.1/second and is injectable into the vitreous of a human eye, for example through a 27 gauge needle. By reducing the viscosity of our formulation it can be injected into the vitreous through a 28, 29 or 30 gauge needle.
  • [0058]
    Preferably, the triamcinolone particles of the pharmaceutical composition are substantially uniformly suspended in the composition and the viscosity inducing component is a polymeric hyaluronate.
  • [0059]
    A detailed embodiment within the scope of our invention is a pharmaceutical composition for treating a posterior ocular condition, comprising triamcinolone particles; polymeric hyaluronate, in which the triamcinolone particles are suspended; sodium chloride; sodium phosphate, and water. The pharmaceutical composition can have a viscosity at a shear rate of about 0.1/second of between about 80,000 cps to about 300,000, preferably from about 100,000 cps to about 300,000 cps, and most preferably from about 1280,000 cps to about 225,000 cps. Note that the pharmaceutical composition can have a viscosity at a shear rate of about 0.1/second of between about 80,000 cps and about 300,000 cps, and that when the pharmaceutical composition has a viscosity at a shear rate of about 0.1/second of between about 100,000 cps and about 150,000 cps it can be injected into the vitreous through a 27, 28, 29 or 30 gauge needle. We have found that even with a 300,000 cps our formulations can be injected through a 30 gauge needle due to shear thinning once the formulation is in movement in the syringe. The sodium phosphate present in the pharmaceutical composition can comprise both monobasic sodium phosphate and dibasic sodium phosphate. Additionally, the pharmaceutical composition can comprise between about 2% w/v triamcinolone and about 8% w/v triamcinolone, between about 2% w/v hyaluronate and about 3% w/v hyaluronate, about 0.6% w/v sodium chloride and about 0.03% w/v sodium phosphate to about 0.04% w/v sodium phosphate. Alternately, the pharmaceutical composition of claim 5 can comprise between about is 0.5% w/v hyaluronate and about 6% w/v hyaluronate. If desired the hyaluronate can be heated (see Example 15) to decrease its molecular weight (and therefore its viscosity) in the formulation.
  • [0060]
    The pharmaceutical composition can also comprises between about 0.6% w/v sodium chloride to about 0.9% w/v sodium chloride. Generally, more sodium chloride is used in the formulation as less phosphate is used in the formulation, for example 0.9% sodium chloride can be used if no phosphate is present in the formulation, as in this manner the tonicity of the formulation can be adjusted to obtain the desired isotonicity with physiological fluid. The pharmaceutical composition can comprise between about 0.0% w/v sodium phosphate and 0.1% w/v sodium phosphate. As noted, more phosphate can be used in the formulation if less sodium chloride is present in the formulation so as to obtain a desired pH 7.4 buffering effect.
  • [0061]
    A more detailed embodiment within the scope of our invention is a pharmaceutical composition for treating a posterior ocular condition, the pharmaceutical composition consisting essentially of triamcinolone particles, polymeric hyaluronate, in which polymeric hyaluronate the triamcinolone particles are suspended, sodium chloride, sodium phosphate, and water. The pharmaceutical composition can have a viscosity at a shear rate 0.1/second at 25° C. of between about 128,000 cps and about 225,000 cps and the sodium phosphate present in the pharmaceutical composition can be present as both monobasic sodium phosphate and dibasic sodium phosphate. The most preferable viscosity range is 140,000 to 280,000 cps at a shear rate 0.1/second at 25° C.
  • [0062]
    A further embodiment of our invention is a triamcinolone suspension for treating a posterior ocular condition, consisting of triamcinolone particles, polymeric hyaluronate, in which the triamcinolone particles are suspended, sodium chloride, dibasic sodium phosphate heptahydrate, monobasic sodium phosphate monohydrate, and water, wherein the composition has a viscosity at a shear rate 0.1/second of between about is 128,000 cps and about 225,000 cps.
  • [0063]
    Our invention also includes a method for treating a posterior ocular condition by administering (as by injecting) the pharmaceutical composition of claim 1 to the vitreous of a human or animal, thereby treating the posterior ocular condition. Thus we have invented a method for treating macula edema by administering to the vitreous of a human eye a pharmaceutical composition comprising a triamcinolone, and a hyaluronate, wherein the pharmaceutical composition having a viscosity at a shear rate 0.1/second of between about 128,000 cps and about 225,000 cps.
  • [0064]
    A pharmaceutical composition within the scope of our invention for treating a posterior ocular condition can comprise a triamcinolone present in a therapeutically effective amount as a plurality of particles, a viscosity inducing component in an amount effective to increase the viscosity of the composition, and an aqueous carrier component, wherein the composition has a viscosity of at least about 10 cps at a shear rate of 0.1/second and is injectable into the vitreous of a human eye and wherein the pharmaceutical composition releases the triamcinolone with substantially first order release kinetics over a period of at least about 45 days after the intravitreal injection. This pharmaceutical composition can exhibit reduced generation of intraocular inflammation, no plume effect (that is no wide dispersion of the triamcinolone into the vitreous as soon as the triamcinolone is intravitreally injected), and cohesiveness (as shown by the retention of the form of the triamcinolone gel for 30 weeks or longer after intravitreal injection of the triamcinolone gel formulation) upon intravitreal injection of the pharmaceutical composition.
  • [0065]
    Our invention encompasses a method for treating a posterior ocular condition, the method comprising the step of intravitreal administration of a sustained release pharmaceutical composition implant comprising a triamcinolone present in a therapeutically effective amount as a plurality of particles, a viscosity inducing component in an amount effective to increase the viscosity of the composition, and an is aqueous carrier component, wherein the composition has a viscosity of at least about 10 cps at a shear rate of 0.1/second and is injectable into the vitreous of a human eye, and wherein the posterior ocular condition is treated for up to about 30 weeks by the triamcinolone released from the implant. In this method the pharmaceutical composition can comprise triamcinolone particles, polymeric hyaluronate, in which the triamcinolone particles are suspended, sodium chloride, sodium phosphate, and water. Additionally, the intravitreal administration can be injected through a 27 gauge needle into the vitreous of a human eye, and in an aggregate number of patients practise of the method results in less intraocular inflammation than does practise of the same method with a second pharmaceutical composition which is a saline solution or suspension of a triamcinolone.
  • [0066]
    Our invention also includes a process for making a pharmaceutical composition by (a) mixing triamcinolone particles about 4 microns to about 8 microns in diameter with sodium chloride crystals, and about 35% to about 40% of the total volume of the water (water for injection) used to make the formulation; (b) heating the triamcinolone and sodium chloride mixture to a temperature between about 120° C. and about 140° C., thereby preparing a first part; (c) mixing a sodium phosphate and water, thereby preparing a second part; (d) dissolving sodium hyaluronate with a molecular weight between about 1.0 million Daltons and about 1.9 million Daltons in another about 35% to about 40% of the total water volume used to make the formulation, followed by sterile filtration after the dissolving; (e) lyophilization of the dissolved sodium hyaluronate; (f) reconstitution of the lyophilized, sterile sodium hyaluronate, thereby preparing a third part; and; (g) aseptically combining the first, second and third parts, thereby making a sterile, uniform triamcinolone pharmaceutical composition which is, an opaque white gel suspension suitable for intravitreal injection to treat an ocular condition. Water is added as needed (q.s.) to make the desired gel suspension which is about 80% to about 90% by weight water.
  • [0067]
    Also within the scope of our invention is a pharmaceutical composition for treating a posterior ocular condition, the pharmaceutical composition comprising a plurality of corticosteroid particles mixed with a viscous polymer, wherein the pharmaceutical composition has a viscosity of between about 130,000 cps and about 300,000 cps at a shear rate of about 0.1/second at about 25° C., and the pharmaceutical composition can be injected into the vitreous of a human eye through a 25 to 33 gauge needle. The corticosteroid particles can have a substantially uniform diameter, as shown for example by FIGS. 8A, 8B, 8C and 8D. Additionally, preferably substantially all (i.e. up to 90-97%) of the corticosteroid particles are embedded within the viscous polymer. The corticosteroid can be a triamcinolone and the viscous polymer can be a polymeric hyaluronate or a polymeric hyaluronic acid.
  • [0068]
    An alternate method for treating a posterior ocular condition can comprise the step of injecting into the vitreous of a patient's eye with a posterior ocular condition a viscous pharmaceutical composition comprising a plurality of corticosteroid particles mixed into a viscous polymeric matrix, wherein the pharmaceutical composition has a viscosity of between about 130,000 cps and about 300,000 cps at a shear rate of about 0.1/second at about 25° C., such that about one hour after the intravitreal injection only about 10% or less (or only about 5% or less or only about 3% or less) of the corticosteroid particles are present in the vitreous free of the polymeric matrix.
  • [0069]
    An alternate process for making an intraocular pharmaceutical composition can comprise the step of mixing an aqueous suspension of a plurality of corticosteroid particles and an aqueous solution of a viscous polymeric matrix, so that the resulting pharmaceutical composition has a viscosity of between about 130,000 cps and about 300,000 cps at a shear rate of about 0.1/second at about 25° C. The corticosteroid particles can have a median particle size of between about 4 microns and about 5 microns. By use of this process for making an intraocular pharmaceutical composition the corticosteroid particles can have a stable diameter for at least three months after the pharmaceutical has been made and stored for three months in a syringe placed horizontally at about 25° C. at about 60% relative humidity.
  • [0070]
    Our invention also includes a pharmaceutical composition for treating an articular pathology, the pharmaceutical composition comprising a plurality of corticosteroid particles mixed with a viscous polymer, wherein the pharmaceutical composition has a viscosity of between about 130,000 cps and about 300,000 cps at a shear rate of about 0.1/second at about 25° C.
  • [0071]
    Finally, our invention also includes a method for treating an articular pathology, the method comprising the step of injecting into a joint of a patient with an articular pathology (such as a joint or spine inflammation) a viscous pharmaceutical composition comprising a plurality of corticosteroid particles mixed into a viscous polymeric matrix, wherein the pharmaceutical composition has a viscosity of between about 130,000 cps and about 300,000 cps at a shear rate of about 0.1/second at about 25° C.
  • Description
  • [0072]
    The present invention is based upon our discovery of triamcinolone formulations specifically designed for intravitreal injection to treat various ocular conditions, such a macula edema. Our triamcinolone formulations have numerous superior characteristics and advantages, including the following: (1) the triamcinolone present in our formulations does not rapidly settle out from or precipitate from the formulations. Importantly our formulations have a shelf life of at least two years, meaning that our formulations can be left standing for up to about two years before administration to an eye, and after two years the formulation can still provide a consistent and accurate dose of triamcinolone upon injection to the formulation to an eye; (2) our formulations are free of preservatives and resuspension aids, such as benzyl alcohol and/or a polysorbate; (3) concomitantly, our formulations have a much reduced retinal and photoreceptor toxicity; (4) as well as being sterile and preservative-free our triamcinolone formulations can provide sustained release of therapeutic amounts of the triamcinolone over multi-month periods upon intravitreal injection of such formulations. Thus, our viscous suspension triamcinolone formulations can be characterized as sustained release implants; (5) intravitreal administration of our triamcinolone formulations is not associated with an increased incidence of adverse events such as elevated intra ocular pressure, glaucoma, cataract and/an intraocular inflammation; (6) intravitreal administration of our triamcinolone formulations is not associated with an increased incidence of adverse events such elevated intra ocular pressure, glaucoma, cataract and/an intraocular inflammation as compared to currently used or known intraocular (i.e. intravitreal) use triamcinolone formulations; (7) our formulations permit triamcinolone particles (crystals) to be released (as they solubilize in the viscous fluid of the posterior chamber) from a discrete unitary location, thereby avoiding the plume effect (rapid dispersion) characteristic of aqueous triamcinolone formulations upon intravitreal administration; (8) avoidance of plume formation or rapid dispersion upon intravitreal administration beneficially reduces visual field obscuration; (9) the sustained release characteristic of our formulations reduces the need for intravitreal administration of large drug quantities to achieve a desired therapeutic effect; (10) upon intravitreal administration, the triamcinolone present in our formulations can preferentially be eliminated in posterior direction (that is through the retina and optic nerve) as opposed to elimination through an anterior route (see eg Table 5). This can result in superior treatment of a retinal disease with for example reduced ocular hypertension.
  • [0073]
    Advantage (1) above can be provided by formulating the triamcinolone as a viscous, gel suspension, as opposed to formulating it as an aqueous or saline based formulation. Additionally, advantages (4) and (8) above can be provided by particular characteristics of our formulations, such as suspension of the triamcinolone in one or more particular high molecular weight hydrogel polymers which permit sustained release of the triamcinolone from a biocompatible, biodegradable polymeric matrix, and other implant-like characteristics to the formulations, including substantially zero-order in vivo (i.e. intravitreal) release kinetics (see eg Table 4).
  • [0074]
    The pluming effect occurs when a saline suspension of a triamcinolone (such as Kenalog) is injected into the vitreous. Pluming prevents visualization of the back of the eye (i.e. the retina is obscured) and also reduces the patient's visual field (reduced vision).
  • [0075]
    Generally, the present invention provides compositions useful for placement, preferably by injection, into a posterior segment of an eye of a human or animal. Such compositions in the posterior, e.g., vitreous, of the eye are therapeutically effective against one or more conditions and/or diseases of the posterior of the eye, and/or one or more symptoms of such conditions and/or diseases of the posterior of the eye.
  • [0076]
    It is important to note that while preferably the compositions disclosed herein are preferably administered by intravitreal injection to treat a posterior ocular condition, our compositions (i.e. those of Examples 8 and 9) can also be administered (as by injection) by other routes, such as for example subconjuctival, sub-tenon, periocular, retrobulbar, suprachoroidal, and/or intrascleral to effectively treat an ocular condition. Additionally, a sutured on refillable dome can be placed over the administration site to prevent or to reduce wash out, leaching and/or diffusion of the active agent in a non-preferred direction.
  • [0077]
    Compositions within the scope of our invention can comprise a corticosteroid component; a viscosity inducing component; and an aqueous carrier component. The compositions are advantageously ophthalmically acceptable. One of the important advantages of the present compositions is that they are more compatible with or friendly to the tissues in the posterior segment of the eye, for example, the retina of the eye, relative to compositions previously proposed for intravitreal injection into a posterior segment of an eye, for example, a composition sold under the trademark Kenalog®-40. In particular, the present compositions advantageously are substantially free of added preservative components or include effective preservative components which are more compatible with or friendly to the posterior segment, e.g., is retina, of the eye relative to benzyl alcohol, which is included in the Kenalog®-40 composition as a preservative.
  • [0078]
    In addition, the present compositions preferably include no added resuspension component, such as polysorbate-80, which is included in the Kenalog®-40 composition. Many of the other features of the present compositions, as described elsewhere herein, also render the present compositions more compatible with or friendly to the posterior segments of the eyes into which the compositions are placed relative to prior art compositions, such as Kenalog®-40.
  • [0079]
    As noted above, the present compositions include a corticosteroid component. Such corticosteroid component is present in the compositions in a therapeutically effective amount, that is in an amount effective in providing a desired therapeutic effect in the eye into which the composition is placed. The corticosteroid component is present in the composition in a plurality of particles. Any suitable corticosteroid component may be employed in according to the present invention. Such corticosteroid component advantageously has a limited solubility in water, for example, at 25° C. For example, the corticosteroid component preferably has a solubility in water at 25° C. of less than 10 mg/ml. Of course, the corticosteroid component should be ophthalmically acceptable, that is, should have substantially no significant or undue detrimental effect of the eye structures or tissues. One particularly useful characteristic of the presently useful corticosteroid components is the ability of such component to reduce inflammation in the posterior segment of the eye into which the composition is placed caused by the result of one or more diseases and/or conditions in the posterior segment of the eye.
  • [0080]
    Examples of useful corticosteroid components include, without limitation, cortisone, prednesolone, triamcinolone, triamcinolone acetonide, fluorometholone, dexamethosone, medrysone, loteprednol, derivatives thereof and mixtures thereof. As is used herein, the term “derivative” refers to any substance which is sufficiently structurally similar to the material of which it is identified as a derivative so as to have substantially similar functionality or activity, for example, therapeutic effectiveness, as the material when the substance is used in place of the material. In one very useful embodiment, the corticosteroid component comprises triamcinolone acetonide.
  • [0081]
    The corticosteroid component advantageously is present in an amount of at least about 10 mg per ml of the composition. One important advantage of the present invention is the effective ability of the present compositions to include relatively large amounts or concentrations of the corticosteroid component. Thus, the corticosteroid component may be present in the present compositions in an amount in the range of about 1% or less to about 5% or about 10% or about 20% or about 30% or more (w/v) of the composition. Providing relatively high concentrations or amounts of corticosteroid component in the present compositions is beneficial in that reduced amounts (volumes for injection) of the composition may be required to be placed or injected into the posterior segment of the eye in order to provide the same amount or more corticosteroid component in the posterior segment of the eye relative to compositions, such as Kenalog®-40, which include less than 4% (w/v) of the corticosteroid component. Thus, in one very useful embodiment, the present compositions include more than about 4% (w/v), for example at least about 5% (w/v), to about 10% (w/v) or about 20% (w/v) or about 30% (w/v) of the corticosteroid component. For example, about 50 μL of our Example 8 or 9 formulation provide respectively 2 mg and 4 mg of triamcinolone. This is in contrast to other formulations (such as Kenalog 40) which require 100 μL to provide 4 mg of triamcinolone. Injection of 100 μL or more of a fluid into the vitreous can result in an excess of fluid in the vitreous with elevated intraocular pressure and leakage of the fluid from the vitreous then potentially occurring.
  • [0082]
    The viscosity inducing component is present in an effective amount in increasing, advantageously substantially increasing, the viscosity of the composition. Without is wishing to limit the invention to any particular theory of operation, it is believed that increasing the viscosity of the compositions to values well in excess of the viscosity of water, for example, at least about 100 cps at a shear rate of 0.1/second, compositions which are highly effective for placement, e.g., injection, into the posterior segment of an eye of a human or animal are obtained. Along with the advantageous placement or injectability of the present compositions into the posterior segment, the relatively high viscosity of the present compositions are believed to enhance the ability of the present compositions to maintain the corticosteroid component particles in substantially uniform suspension in the compositions for prolonged periods of time, for example, for as long as 1 to 2 years, without requiring resuspension processing. The relatively high viscosity of the present compositions may also have an additional benefit of at least assisting the compositions to have the ability to have an increased amount or concentration of the corticosteroid component, as discussed elsewhere herein, for example, while maintaining such corticosteroid component in substantially uniform suspension for prolonged periods of time.
  • [0083]
    Advantageously, the present compositions have viscosities of at least about 10 cps or at least about 100 cps or at least about 1000 cps, more preferably at least about 10,000 cps and still more preferably at least about 70,000 cps or more, for example up to about 200,000 cps or about 250,000 cps, or about 300,000 cps or more, at a shear rate of 0.1/second. The present compositions not only have the relatively high viscosity as noted above but also have the ability or are structured or made up so as to be effectively placeable, e.g., injectable, into a posterior segment of an eye of a human or animal, preferably through a 27 gauge needle, or even through a 30 gauge needle.
  • [0084]
    The presently useful viscosity inducing components preferably are shear thinning components in that as the present composition containing such a shear thinning viscosity inducing component is passed or injected into the posterior segment of an eye, for example, through a narrow space, such as 27 gauge needle, under high shear conditions the viscosity of the composition is substantially reduced during such passage. After such passage, the composition regains substantially its pre-injection viscosity so as to maintain the corticosteroid component particles in suspension in the eye.
  • [0085]
    Any suitable viscosity inducing component, for example, ophthalmically acceptable viscosity inducing component, may be employed in accordance with the present invention. Many such viscosity inducing components have been proposed and/or used in ophthalmic compositions used on or in the eye. The viscosity inducing component is present in an amount effective in providing the desired viscosity to the composition. Advantageously, the viscosity inducing component is present in an amount in a range of about 0.5% or about 1.0% to about 5% or about 10% or about 20% (w/v) of the composition. The specific amount of the viscosity inducing component employed depends upon a number of factors including, for example and without limitation, the specific viscosity inducing component being employed, the molecular weight of the viscosity inducing component being employed, the viscosity desired for the present composition being produced and/or used and the like factors, such as shear thinning. The viscosity inducing component is chosen to provide at least one advantage, and preferably multiple advantages, to the present compositions, for example, in terms of each of injectability into the posterior segment of the eye, viscosity, sustainability of the corticosteroid component particles in suspension, for example, in substantially uniform suspension, for a prolonged period of time without resuspension processing, compatibility with the tissues in the posterior segment of the eye into which the composition is to be placed and the like advantages. More preferably, the selected viscosity inducing component is effective to provide two or more of the above-noted benefits, and still more preferably to provide all of the above-noted benefits.
  • [0086]
    The viscosity inducing component preferably comprises a polymeric component and/or at least one viscoelastic agent, such as those materials which are useful in ophthalmic surgical procedures.
  • [0087]
    Examples of useful viscosity inducing components include, but are not limited to, hyaluronic acid (such as a polymeric hyaluronic acid), carbomers, polyacrylic acid, cellulosic derivatives, polycarbophil, polyvinylpyrrolidone, gelatin, dextrin, polysaccharides, polyacrylamide, polyvinyl alcohol, polyvinyl acetate, derivatives thereof and mixtures and copolymers thereof.
  • [0088]
    The molecular weight of the presently useful viscosity inducing components may be in a range of about 10,000 Daltons or less to about 2 million Daltons or more. In one particularly useful embodiment, the molecular weight of the viscosity inducing component is in a range of about 100,000 Daltons or about 200,000 Daltons to about 1 million Daltons or about 1.5 million Daltons. Again, the molecular weight of the viscosity inducing component useful in accordance with the present invention, may vary over a substantial range based on the type of viscosity inducing component employed, and the desired final viscosity of the present composition in question, as well as, possibly one or more other factors.
  • [0089]
    In one very useful embodiment, a viscosity inducing component is a polymeric hyaluronate component, for example, a metal hyaluronate component, preferably selected from alkali metal hyaluronates, alkaline earth metal hyaluronates and mixtures thereof, and still more preferably selected from sodium hyaluronates, and mixtures thereof. The molecular weight of such hyaluronate component (i.e. a polymeric hyaluronic acid) preferably is in a range of about 50,000 Daltons or about 100,000 Daltons to about 1.3 million Daltons or about 2 million Daltons. In one embodiment, the present compositions include a polymeric hyaluronate component in an amount in a range about 0.05% to about 0.5% (w/v). In a further useful embodiment, the hyaluronate component is present in an amount in a range of about 1% to about 4% (w/v) of the composition. In this latter case, the very high polymer viscosity forms a gel that slows particle sedimentation rate to the extent that often no resuspension processing is necessary over the estimated shelf life, for example, at least about 2 years, of the composition. Such a composition may be marketed in pre-filled syringes since the gel cannot be easily removed by a needle and syringe from a bulk container. Pre-filled syringes have the advantages of convenience for the injector and the safety which results from less handling.
  • [0090]
    The aqueous carrier component is advantageously ophthalmically acceptable and may include one or more conventional excipients useful in ophthalmic compositions. The present compositions preferably include a major amount of liquid water. The present compositions may be, and are preferably, sterile, for example, prior to being used in the eye.
  • [0091]
    The present compositions preferably include at least one buffer component in an amount effective to control the pH of the composition and/or at least one tonicity component in an amount effective to control the tonicity or osmolality of the compositions. More preferably, the present compositions include both a buffer component and a tonicity component.
  • [0092]
    The buffer component and tonicity component may be chosen from those which are conventional and well known in the ophthalmic art. Examples of such buffer components include, but are not limited to, acetate buffers, citrate buffers, phosphate buffers, borate buffers and the like and mixtures thereof. Phosphate buffers are particularly useful. Useful tonicity components include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and other sugar alcohols, and other suitable ophthalmically acceptably tonicity component and mixtures thereof.
  • [0093]
    The amount of buffer component employed preferably is sufficient to maintain the pH of the composition in a range of about 6 to about 8, more preferably about 7 to about 7.5. The amount of tonicity component employed preferably is sufficient to provide an osmolality to the present compositions in a range of about 200 to about 400, more preferably about 250 to about 350, mOsmol/kg respectively. Advantageously, the present compositions are substantially isotonic.
  • [0094]
    The present compositions may include one or more other components in amounts effective to provide one or more useful properties and/or benefits to the present compositions. For example, although the present compositions may be substantially free of added preservative components, in other embodiments, the present compositions include effective amounts of preservative components, preferably such components which are more compatible with or friendly to the tissue in the posterior segment of the eye into which the composition is placed than benzyl alcohol. Examples of such preservative components include, without limitation, benzalkonium chloride, chlorhexidine, PHMB (polyhexamethylene biguamide), methyl and ethyl parabens, hexetidine, chlorite components, such as stabilized chlorine dioxide, metal chlorites and the like, other ophthalmically acceptable preservatives and the like and mixtures thereof. The concentration of the preservative component, if any, in the present compositions is a concentration effective to preserve the composition, and is often in a range of about 0.00001% to about 0.05% or about 0.1% (w/v) of the composition.
  • [0095]
    In addition, the present composition may include an effective amount of resuspension component effective to facilitate the suspension or resuspension of the corticosteroid component particles in the present compositions. As noted above, in certain embodiments, the present compositions are free of added resuspension components. In other embodiments of the present compositions effective amounts of resuspension components are employed, for example, to provide an added degree of insurance that the corticosteroid component particles remain in suspension, as desired and/or can be relatively easily resuspended in the present compositions, such resuspension be desired. Advantageously, the resuspension component employed in accordance with the present invention, if any, is chosen to be more compatible with or friendly to the tissue in the posterior segment of the eye into which the composition is placed than polysorbate 80.
  • [0096]
    Any suitable resuspension component may be employed in accordance with the present invention. Examples of such resuspension components include, without limitation, surfactants such as poloxanes, for example, sold under the trademark Pluronic®; tyloxapol; sarcosinates; polyethoxylated castor oils, other surfactants and the like and mixtures thereof.
  • [0097]
    One very useful class of resuspension components are those selected from vitamin derivatives. Although such materials have been previously suggested for use as surfactants in ophthalmic compositions, they have been found to be effective in the present compositions as resuspension components. Examples of useful vitamin derivatives include, without limitation, Vitamin E tocopheryl polyethylene glycol succinates, such as Vitamin E tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS). Other useful vitamin derivatives include, again without limitation, Vitamin E tocopheryl polyethylene glycol succinamides, such as Vitamin E tocopheryl polyethylene glycol 1000 succinamide (Vitamin E TPGSA) wherein the ester bond between polyethylene glycol and succinic acid is replaced by an amide group.
  • [0098]
    The presently useful resuspension components are present, if at all, in the compositions in accordance with the present invention in an amount effective to facilitate suspending the particles in the present compositions, for example, during manufacture of the compositions or thereafter. The specific amount of resuspension component employed may vary over a wide range depending, for example, on the specific resuspension component being employed, the specific composition in which the resuspension component is being employed and the like factors. Suitable concentrations of the resuspension component, if any, in the present compositions are often in a range of about 0.01% to about 5%, for example, about 0.02% or about 0.05% to about 1.0% (w/v) of the composition.
  • [0099]
    The availability of minimally soluble corticosteroid components, such as triamcinolone acetonide, to intraocular tissues may be limited by the dissolution rate for these substances. Slow dissolution is both good and bad for the patient. On the one hand, after a single intravitreal injection of the present composition, the mean elimination half-life for triamcinolone acetonide is advantageously quite long, for example, about 19 days in nonvitrectonized patients and measurable drug levels are detected for up to about 3 months. On the other hand, therapeutic drug levels in the vitreous compartment of the eye may not be achieved for about 1 to about 3 days, due to the slow dissolution rate of the corticosteroid component particles.
  • [0100]
    In one embodiment of the present invention, an effective amount of a solubilizing component is provided in the composition to solubilize a minor amount, that is less than 50%, for example in a range of 1% or about 5% to about 10% or about 20% of the corticosteroid component. For example, the inclusion of a cyclodextrin component, such as β-cyclodextrin, sulfo-butylether β-cyclodextrin (SBE), other cyclodextrins and the like and mixtures thereof, at about 0.5 to about 5.0% (w/v) solubilizes about 1 to about 10% of the initial dose of triamcinolone acetonide. This presolubilized fraction provides a readily bioavailable loading dose, thereby avoiding any delay time in therapeutic effectiveness.
  • [0101]
    The use of such a solubilizing component is advantageous to provide any relatively quick release of the corticosteroid component into the eye for therapeutic effectiveness. Such solubilizing component, of course, should be ophthalmically acceptable or at least sufficiently compatible with the posterior segment of the eye into which the composition is placed to avoid undue damage to the tissue in such posterior segment.
  • [0102]
    The pharmacokinetics of the corticosteroid component, for example, triamcinolone acetonide, following intravitreal administration may involve both the rate of drug dissolution and the rate of drug efflux via the anterior route. For example, following a is single intravitreal injection of a composition containing 4% (w/v) of triamcinolone acetonide, triamcinolone acetonide concentration peaks (monitored in aqueous humor) after several days at thousands of nanograms per mL. This peak (Cmax) is followed by a rapid decrease lasting about 200 hours, and ends in a slow elimination phase with a half-life of about 19 days. Patients typically require repeat dosing, for example about every three months.
  • [0103]
    In one embodiment of the present invention, the compositions further contain sustained release components, for example, polymers (in the form for example of gels and microspheres), such as poly (D,L,-lactide) or poly(D,L-lactide co-glycolide), in amounts effective to reduce local diffusion rates and/or corticosteroid particle dissolution rates. The result is a flatter elimination rate profile with a lower Cmax and a more prolonged therapeutic window, thereby extending the time between required injections for many patients.
  • [0104]
    Any suitable, preferably conditionally acceptable, release component may be employed. Useful examples are set forth above. The sustained release component is preferably biodegradable or bioabsorbable in the eye so that no residue remains over the long term. The amount of the delayed release component included may very over a relatively wide range depending, for example, on the specific sustained release component is being employed, the specific release profile desired and the like factors. Typical amounts of delayed release components, if any, included in the present compositions are in a range of about 0.05 to 0.1 to about 0.5 or about 1 or more percent (w/v) (weight of the ingredient in the total volume of the composition) of the composition.
  • [0105]
    The present compositions can be prepared using suitable blending/processing techniques or techniques, for example, one or more conventional blending techniques. The preparation processing should be chosen to provide the present compositions in is forms which are useful for placement or injection into the posterior segments of eyes of humans or animals. In one useful embodiment a concentration corticosteroid component dispersion is made by combining the corticosteroid component with water, and the excipient (other than the viscosity inducing component) to be included in the final composition. The ingredients are mixed to disperse the corticosteroid component and then autoclaved. Alternatively, the steroid powder may be y-irradiated before addition to the sterile carrier. The viscosity inducing component may be purchased sterile or sterilized by conventional processing, for example, by filtering a dilute solution followed by lyophylization to yield a sterile powder. The sterile viscosity inducing component is combined with water to make an aqueous concentrate. Under aseptic conditions, the concentrated corticosteroid component dispersion can be blended or mixed and added or combined as a slurry to the viscosity inducing component concentrate. Water is added in a quantity sufficient (q.s.) to provide the desired composition and the composition is mixed until homogenous.
  • [0106]
    Methods of using the present composition are provided and are included within the scope of the present invention. In general, such methods comprise administering a composition in accordance with the present invention to a posterior segment of an eye of a human or animal, thereby obtaining a desired therapeutic effect. The administering step advantageously comprises at least one of intravitreal injecting, subconjunctival injecting, sub-tenon injecting, retrobulbar injecting, suprachoroidal injecting and the like. A syringe apparatus including an appropriately sized needle, for example, a 27 gauge needle or a 30 gauge needle, can be effectively used to inject the composition with the posterior segment of an eye of a human or animal.
  • [0107]
    Ocular conditions which can be treated or addressed in accordance with the present invention include, without limitation, the following:
  • [0108]
    Maculopathies/retinal degeneration: macular degeneration, including age related macular degeneration (ARMD), such as non-exudative age related macular degeneration and exudative age related macular degeneration, choroidal neovascularization, retinopathy, including diabetic retinopathy, acute and chronic macular neuroretinopathy, central serous chorioretinopathy, and macular edema, including cystoid macular edema, and diabetic macular edema. Uveitis/retinitis/choroiditis: acute multifocal placoid pigment epitheliopathy, Behcet's disease, birdshot retinochoroidopathy, infectious (syphilis, lyme, tuberculosis, toxoplasmosis), uveitis, including intermediate uveitis (pars planitis) and anterior uveitis, multifocal choroiditis, multiple evanescent white dot syndrome (MEWDS), ocular sarcoidosis, posterior scleritis, serpignous choroiditis, subretinal fibrosis, uveitis syndrome, and Vogt-Koyanagi-Harada syndrome. Vascular diseases/exudative diseases: retinal arterial occlusive disease, central retinal vein occlusion, disseminated intravascular coagulopathy, branch retinal vein occlusion, hypertensive fundus changes, ocular ischemic syndrome, retinal arterial microaneurysms, Coat's disease, parafoveal telangiectasis, hemi-retinal vein occlusion, papillophlebitis, central retinal artery occlusion, branch retinal artery occlusion, carotid artery disease (CAD), frosted branch angitis, sickle cell retinopathy and other hemoglobinopathies, angioid streaks, familial exudative vitreoretinopathy, Eales disease. Traumatic/surgical: sympathetic ophthalmia, uveitic retinal disease, retinal detachment, trauma, laser, PDT, photocoagulation, hypoperfusion during surgery, radiation retinopathy, bone marrow transplant retinopathy. Proliferative disorders: proliferative vitreal retinopathy and epiretinal membranes, proliferative diabetic retinopathy. Infectious disorders: ocular histoplasmosis, ocular toxocariasis, presumed ocular histoplasmosis syndrome (POHS), endophthalmitis, toxoplasmosis, retinal diseases associated with HIV infection, choroidal disease associated with HIV infection, uveitic disease associated with HIV Infection, viral retinitis, acute retinal necrosis, progressive outer retinal necrosis, fungal retinal diseases, ocular syphilis, ocular tuberculosis, diffuse unilateral subacute neuroretinitis, and myiasis. Genetic disorders: retinitis pigmentosa, systemic disorders with associated retinal dystrophies, congenital stationary night blindness, cone dystrophies, Stargardt's disease and fundus flavimaculatus, Bests disease, pattern dystrophy of the retinal pigmented epithelium, X-linked retinoschisis, Sorsby's is fundus dystrophy, benign concentric maculopathy, Bietti's crystalline dystrophy, pseudoxanthoma elasticum. Retinal tears/holes: retinal detachment, macular hole, giant retinal tear. Tumors: retinal disease associated with tumors, congenital hypertrophy of the RPE, posterior uveal melanoma, choroidal hemangioma, choroidal osteoma, choroidal metastasis, combined hamartoma of the retina and retinal pigmented epithelium, retinoblastoma, vasoproliferative tumors of the ocular fundus, retinal astrocytoma, intraocular lymphoid tumors. Miscellaneous: punctate inner choroidopathy, acute posterior multifocal placoid pigment epitheliopathy, myopic retinal degeneration, acute retinal pigment epithelitis and the like.
  • [0109]
    The present methods may comprise a single injection into the posterior segment of an eye or may involve repeated injections, for example over periods of time ranging from about one week or about 1 month or about 3 months to about 6 months or about 1 year or longer.
  • EXAMPLES
  • [0110]
    The following non-limiting Examples are presented to exemplify aspects of the present invention.
  • Examples 1 to 4
  • [0111]
    Four compositions are as follows:
    TABLE 1
    Ingredient Example 1 Example 2 Example 3 Example 4
    Triamcinolone acetonide 2% (w/v) 2% (w/v) 4% (w/v) 4% (w/v)
    Sodium Hyaluronate 0.05% 0.5% 0.05% 0.5%
    (0.6 × 106 DALTONS) (w/v) (w/v) (w/v) (w/v)
    Sodium Phosphate 0.4% 0.4% 0.4% 0.4%
    (w/v) (w/v) (w/v) (w/v)
    Vitamin E-TPGS 0.5% 0.5% 0.0 0.0
    (w/v) (w/v)
    γ-cyclodextrin 0.5% 0.5% 0.0 0.0
    (w/v) (w/v)
    Water for Injection q.s. q.s. q.s. q.s.
    Viscosity at shear rate 20 cps 500 cps 20 cps 500 cps
    0.1/second
  • [0112]
    Each of these compositions is prepared as follows.
  • [0113]
    A concentrated triamcinolone acetonide dispersion is made by combining triamcinolone acetonide with water, Vitamin E-TPGS and γ-cyclodextrin, if any. These ingredients are mixed to disperse the triamcinolone acetonide, and then autoclaved. The sodium hyaluronate may be purchased as a sterile powder or sterilized by filtering a dilute solution followed by lyophylization to yield a sterile powder. The sterile sodium hyaluronate is dissolved in water to make an aqueous concentrate. The concentrated triamcinolone acetonide dispersion is mixed and added as a slurry to the sodium hyaluronate concentrate. Water is added q.s. (quantum sufficit, as much as suffices, in this case as much as is required to prepare the homogenous mixture, dispersion, gel or suspension) and the mixture is mixed until homogenous.
  • [0114]
    Each of these compositions produced a loose flocculation of triamcinolone acetonide that is easily re-suspended by gentle inversion. These compositions can be marketed in small volume pharmaceutical grade glass bottles, and are found to be therapeutically effective against macular edema when injected intravitreally into human eyes.
  • Examples 5 to 7
  • [0115]
    Three compositions are as follows:
    TABLE 2
    Ingredient Example 5 Example 6 Example 7
    Triamcinolone acetonide 2.0% (w/v) 4.0% (w/v) 8.0% (w/v)
    Sodium hyaluronate 3.0% (w/v) 2.5% (w/v) 2.0% (w/v)
    Sodium Phosphate 0.4% (w/v) 0.4% (w/v) 0.4% (w/v)
    Water for Injection q.s. q.s. q.s.
    Viscosity at shear rate 300,000 cps 180,000 cps 100,000 cps
    0.1/second
  • [0116]
    These compositions are prepared in a manner substantially analogous to that set forth in Example 1.
  • [0117]
    The high viscosities of the compositions substantially slows the particle sedimentation rate to an extent that no resuspension processing is necessary or required over the estimated shelf life, e.g., about 2 years, of the compositions. These compositions can be marketed in prefilled syringes since they can not easily be removed by a needle and syringe from a container. However, with the compositions in prefilled syringes, the compositions can be effectively injected into the posterior segment of an eye of a human using a 27 gauge or a 30 gauge needle to provide a desired therapeutic effect in the human eye.
  • [0118]
    The compositions of Examples 5 to 7 employ or contain a sufficient concentration of high molecular weight sodium hyaluronate so as to form a gelatinous plug or drug depot upon intravitreal injection into a human eye. Triamcinolone acetonide particles are, in effect, trapped or held within this viscous plug, so that undesirable pluming does not occur, and the risk of drug particles disadvantageously settling directly on the retinal tissue is substantially reduced, for example, relative to using a composition with a water-like viscosity, such as Kenalog® 40. Since sodium hyaluronate solutions are subject to dramatic shear thinning, these formulations are easily injected through 27 gauge or even 30 gauge needles.
  • Examples 8 and 9
  • [0119]
    Two compositions are as follows:
    TABLE 3
    Ingredient Example 8 Example 9
    Triamcinolone acetonide  2.0% (w/v)  8.0% (w/v)
    Sodium hyaluronate (polymeric)  2.5% (w/v)  2.3% (w/v)
    Sodium chloride 0.63% (w/v) 0.63% (w/v)
    dibasic sodium phosphate, 0.30% (w/v) 0.30% (w/v)
    heptahydrate
    Monobasic sodium phosphate, 0.04% (w/v) 0.04% (w/v)
    monohydrate
    Water for Injection q.s. q.s.
    Viscosity at shear rate 170,000 ± 200,000 ± 25% cps
    0.1/second 25% cps
  • [0120]
    These compositions are prepared in a manner substantially analogous to that set forth in Example 1.
  • [0121]
    The high viscosities of the compositions substantially slows the particle sedimentation rate to an extent that no resuspension processing is necessary or required over the estimated shelf life, e.g., about 2 years, of the compositions. These compositions can be marketed in prefilled syringes since they can not easily be is removed by a needle and syringe from a container. However, with the compositions in prefilled syringes, the compositions can be effectively injected into the posterior segment of an eye of a human using a 27 gauge or a 30 gauge needle to provide a desired therapeutic effect in the human eye.
  • [0122]
    The sodium hyaluronate powders used in these compositions (as well as in the other compositions identified in the Examples herein) have water contents in a range of about 4% to about 20%, preferably about 4% to about 8%, by weight. Differences in the average molecular weight of the hyaluronate used can result in variation in the viscosity of compositions in accordance with the present invention which have the same nominal chemical make-ups. Thus, the viscosities indicated herein should be understood to be target viscosities, with the composition being acceptable for use if the actual viscosity of the composition is within plus or minus (±) about 25% or about 30% or about 35% of the target viscosity.
  • [0123]
    Because each of the compositions set forth in the Examples has a density of about 1 gm/ml, the percentages set forth herein as being based on weight per volume (w/v) can also be considered as being based on weight per weight (w/w).
  • [0124]
    The compositions of Examples 8 and 9 employ or contain a sufficient concentration of high molecular weight (i.e. polymeric) sodium hyaluronate so as to form a gelatinous plug or drug depot upon intravitreal injection into a human eye. Preferably the average molecular weight of the hyaluronate used is less than about 2 million, and more preferably the average molecular weight of the hyaluronate used is between about 1.3 million and 1.6 million. The triamcinolone acetonide particles are, in effect, trapped or held within this viscous plug of hyaluronate, so that undesirable pluming does not occur upon intravitreal injection of the formulation. Thus, the risk of drug particles disadvantageously settling directly on the retinal tissue is substantially reduced, for example, relative to using a composition with a water-like viscosity, such as Kenalog® 40. Since sodium hyaluronate solutions are subject to dramatic shear thinning, these formulations are easily injected through 27 gauge or even 30 gauge needles.
  • [0125]
    The most preferred viscosity range for the Example 8 and 9 formulations is 140,000 cps to 280,000 cps at a shear rate 0.1/second at 25° C.
  • [0126]
    The triamcinolone acetonide used in the formulations set forth herein has the chemical name 9-Fluoro-11,21-dihydroxy-1 6,17-[1-methylethylidenebis(oxy)]pregna-1,4-diene-3,20-dione, and can have the following structure
    Figure US20070224278A1-20070927-C00001
  • [0127]
    The molecular formula of triamcinolone acetonide is C24H31FO6 and its molecular weight is 434.49. The solubility of triamcinolone acetonide in water is about 25.4 μL/mL.
  • [0128]
    The Examples 8 and 9 formulations are prepared as sterile products of a uniform, opaque white dispersion of microfine triamcinolone acetonide particles suspended in a hyaluronate-based polymeric hydrogel, intended for intravitreal injection.
  • [0129]
    The Examples 8 and 9 formulations can be used top treat, for example, macular edema in patients with diabetes, central retinal vein occlusion, and branch retinal vein occlusion. Notable the Examples 8 and 9 formulations are formulated using only excipients that are fully compatible (i.e. non-toxic) to the eye, particularly to the retina. The Examples 8 and 9 formulations (2% (w/w) and 8% (w/w) triamcinolone acetonide, respectively) are buffered at physiological pH with a low concentration of sodium phosphate salts; rendered isotonic with sodium chloride, and use Water for Injection, USP, as the vehicle.
  • [0130]
    A target dosage of 1 mg of the triamcinolone acetonide active agent can be delivered in a 50 mg (approximately 48 μL) injection of the Example 82% (w/w) triamcinolone acetonide gel suspension formulation. A target dosage of 4 mg of the triamcinolone acetonide active agent can be delivered in a 50 mg (approximately 48 μL) injection of the Example 98% (w/w) triamcinolone acetonide gel suspension formulations.
  • [0131]
    As noted, the triamcinolone present in our formulations does not rapidly, or even slowly, settle out from or precipitate from the formulations. Significantly our Example 8 and 9 formulations have a shelf life of at least two years, meaning that these formulations can be left standing (without agitation) for up to about two years before administration to an eye, and after two years the same formulations can still provide a consistent and accurate dose of triamcinolone upon injection to the formulation to an eye. For example, upon preparation (as set froth in Example 15), 50 μL of our 8% formulation provides 4 mg of triamcinolone acetonide, and if left standing for up to about 2 years 50 μL of our 8% formulation stills provides 4 mg±15% of triamcinolone acetonide, thereby meeting the U.S.P. definition of consistent dosage after storage.
  • [0132]
    As noted, the composition of triamcinolone 2% injectable gel suspension (Example 8) is triamcinolone 2.0% (w/w), sodium hyaluronate, sodium chloride, dibasic sodium phosphate (heptahydrate), monobasic sodium phosphate (monohydrate), and water for injection.). The composition of triamcinolone 8% injectable gel suspension (Example 9) is triamcinolone 8.0% (w/w), sodium hyaluronate, sodium chloride, dibasic sodium phosphate (heptahydrate), monobasic sodium phosphate (monohydrate), and water for injection.
  • [0133]
    The triamcinolone acetonide injectable gel suspension we have invented is a viscous suspension of triamcinolone acetonide formulated at concentrations of 8% and 2% with sodium hyaluronate, sodium chloride, dibasic sodium phosphate (heptahydrate), monobasic sodium phosphate (monohydrate), and water for injection (i.e. the formulations of Examples 8 and 9 respectively). The suspensions are prepared to have physiologic pH, and to be isotonic, and preservative-free. The Examples 8 and 9 suspensions can be supplied in single-use glass syringes with fixed 27 gauge needles. The syringes are overfilled to 0.17-0.18 mL, and calibrated to deliver 0.05 mL when primed to a black or blue mark on the barrel of the syringe to thereby provide the 2% and 8% suspensions to deliver 1 mg and 4 mg of triamcinolone, respectively (the pre-filled syringes are made by Allergan, Inc., Irvine, Calif.). These syringes have a shelf life of at least about two years when stored at 2-8° C.
  • Example 10 Ocular and Systemic Pharmacokinetics of a 4% (4 mg) Triamcinolone Acetonide Gel Suspension Formulation upon Intravitreal Injection
  • [0134]
    An experiment was carried out to evaluate the intraocular and systemic pharmacokinetics of triamcinolone acetonide gel suspensions (TAAgs) following intravitreal administration. The formulations used were: (1) 4% w/v (40 mg/mL) triamcinolone acetonide formulated as a high viscosity borate-buffered 2.5% (w/w) hyaluronic acid suspension, and; (2) 16% w/v (160 mg/mL) triamcinolone acetonide formulated as a high viscosity borate-buffered 2.5% (w/w). 100 μL of each formulation was injected into separate rabbit eyes using a 25-gauge needle syringe to provide 4 mg or 16 mg of triamcinolone actinide, respectively. Except as noted the formulations used in this Example 10 were the same as the Example 8 and 9 formulations. For example, the same type of sodium hyaluronate was used in these Example 10 formulations.
  • [0135]
    Following a single intravitreal injection (New Zealand albino rabbits) of 100 μL of the 4% w/v triamcinolone acetonide formulation (4 mg triamcinolone acetonide), aqueous humor, vitreous humor, retina and plasma were collected on days 1, 3, 10, 17, 31 and 45 and analyzed for triamcinolone acetonide by liquid chromatography tandem mass spectrometry. In vitreous humor, the maximal triamcinolone acetonide concentration (Cmax) was 385 μg/g on Day 10. The relatively constant concentrations (i.e. sustained release) of triamcinolone acetonide were observed from Day 1 to Day 45. (Tables 4 and 5) Therefore, the TAAgs formulation delivers a relatively stable concentration (i.e. approximately zero-order release kinetics) of triamcinolone acetonide to the retina over at least 45-day period following single intravitreal injection.
  • [0136]
    Table 4 also shows that the ratio of the amount of triamcinolone acetonide present in the vitreous to the amount of triamcinolone acetonide present in the aqueous chamber can be greater than 1000:1 at all time points.
  • [0137]
    Table 5 shows that ratio of the total amount of triamcinolone acetonide present in the vitreous over the 45 day study period to the total amount of triamcinolone acetonide present in the aqueous humor over the 45 day study period can be greater than about 5,000:1.
    TABLE 4
    Triamcinolone acetonide concentration in aqueous humor,
    retina and vitreous humor after a single intravitreal injection
    of a 4% triamcinolone acetonide formulation in albino rabbits
    Triamcinolone Acetonide (μg/mL or μg/g)
    Timepoint (Day) Aqueous Humor Vitreous Humor
    1 0.319 382
    3 0.200 335
    10 0.052 385
    17 0.033 338
    31 0.014 185
    45 0.011 222
  • [0138]
    TABLE 5
    Pharmacokinetic parameters of triamcinolone acetonide
    in ocular tissues after a single intravitreal injection of 4%
    triamcinolone acetonide formulation in albino rabbits
    Cmax AUC0-45day
    Treatment (μg/mL or μg/g) (μg · day/mL or μg · day/g)
    Vitreous Humor
    4% Triamcinolone 385 12500
    Acetonide Injectable
    Aqueous Humor
    4% Triamcinolone 0.319 2.36
    Acetonide Injectable
  • [0139]
    Following intravitreal administration of the 4% TAAgs formulation in albino rabbits, triamcinolone acetonide was absorbed into the systemic circulation with mean plasma Cmax of 15.8 ng/mL at 1 day postdose. Between days 2 and 45, plasma levels drop to 7 and 1 ng/mL, respectively. Thus, our the triamcinolone acetonide gel suspension formulations are free of excipients with known ocular toxicity, and through sustained release from the gel delivers prolonged levels of triamcinolone acetonide to the vitreous and retina.
  • Example 11 Triamcinolone Gel Suspensions to Treat Ocular Conditions
  • [0140]
    Introduction
  • [0141]
    As set forth herein, we have invented triamcinolone acetonide gel suspensions (TAAgs) and their use to treat various ocular conditions, including macular edema, such as macular edema associated with diabetes and/or a retinal vein occlusion, (branch or central), and to maintain or to improve visual acuity. Our TAAgs formulations can contain a polymeric hyaluronic acid.
  • [0142]
    The blood-aqueous barrier (“BAB”) is a membrane of the capillary bed of the ciliary body of the eye that influences or controls two-way transfer of fluids between the aqueous chamber of the eye and the blood. The BAB acts as an anatomical mechanism to reduce or prevent exchange of materials between the chambers of the eye and the blood.
  • [0143]
    The blood-retinal barrier (“BRB”) is composed of specialized nonfenestrated tightly-joined (tight junction) retinal epithelium and adjacent retinal blood vessel endothelium cells that forming a transport barrier for certain substances between the retinal capillaries and the retinal tissue. BRB breakdown is symptomatic of various retinal ocular conditions, including reduced visual acuity, macular edema, macula degeneration, retinal swelling, and other retinopathies, including diabetic retinopathy.
  • [0144]
    This experiment was designed to assess efficacy and duration of action of particular TAAgs polymeric hyaluronic acid formulations injected intravitreally to treat break down (deterioration) of the blood-aqueous barrier (“BAB”) and of the blood-retinal barrier (“BRB”) in mammal eyes. Generally, a reduced BRB breakdown is a is desirable condition or state, as it indicates a stabilized or more normal or more healthy retina (tightened barrier). On the other hand, where in a model system a BAB breakdown is induced, it is considered a positive or beneficial result if upon intravitreal administration of a steroid, such as a corticosteroid or an anti-inflammatory steroid into an eye with BAB breakdown, an improvement of the BAB breakdown is not observed. Failure of BAB breakdown to be reduced or repaired is an indication that the steroid intravitreally administered has not in significant quantity made it's way (i.e. by diffusion and/or by an active transport mechanism) to the aqueous (or anterior) chamber (“AC”) of the eye. It is known that AC presence of various steroids can cause increased intraocular (i.e. aqueous humor) pressure (elevated IOP is symptomatic of glaucoma) and/or cataract generation.
  • SUMMARY
  • [0145]
    The experiment was carried out using intravitreal injection of either a 1 mg or 4 mg triamcinolone acetonide gel suspension (TAAgs) (the Example 8 and 9 formulations, respectively) in a rabbit model of VEGF-mediated blood-aqueous barrier (BAB) and blood-retinal barrier (BRB) breakdown. The model system used is set forth in Edelman et al., Corticosteroids inhibit VEGF-induced vascular leakage in a rabbit model of blood-retinal and blood-aqueous barrier breakdown, Exp Eye Res 2005 February; 80(2):249-58, although instead of intravitreal injection of a triamcinolone acetonide saline suspension, the formulation of Examples 8 and 9 above were used in this experiment.
  • [0146]
    BAB breakdown was measured by anterior chamber fluorophotometry. BRB breakdown was measured by vitreal fluorophotometry and subjective grading of fluorescein angiograms. In addition, VEGF-induced changes in vessel caliber and tortuosity (AVC-T) were assessed by subjective scoring of fundus images. The equipment and procedures used to obtain anterior chamber fluorophotometry, vitreal fluorophotometry, fluorescein angiograms, and fundus images were as set forth in Edelman (2005) supra.
  • [0147]
    The results obtained in this experiment can be summarized as follows:
  • [0000]
    1. intravitreal 1 mg TAAgs had no effect on VEGF-induced BAB at any time point as compared to control eyes.
  • [0000]
    2. intravitreal 1 mg TAAgs significantly inhibited VEGF-induced BRB and AVC-T through at least 6 weeks.
  • [0000]
    3. intravitreal 4 mg TAAgs did not significantly inhibit VEGF-induced BAB breakdown at 10, 22, and 30 weeks.
  • [0148]
    4. intravitreal 4 mg TAAgs significantly blocked VEGF-induced angiographic BRB breakdown for at least about 14 weeks, fluorophotometric BRB breakdown for at least about 22 weeks, and ΔVC-T for at least about 14 weeks, and in at least some rabbit eyes for up to at least about 30 weeks.
  • [0149]
    Methods
  • [0150]
    Female Dutch Belt rabbits (5 to 6 months old) were randomly assigned to a no treatment group (control; n=12 eyes), to a group to receive intravitreal injection of 1 mg TAAgs (n=8 eyes), or to a group to receive intravitreal injection of 4 mg TAAgs (n=10 eyes). 50 μL of the 2% or 8% (Example 8 and Example 9 formulations respectively) TAAgs formulations were intravitreally injected into eyes of the later two groups on Day 1. Since the VEGF responses are transient and return to baseline by one week (See Edelman et al.(2005), supra), the TAAgs duration of action was determined by injecting VEGF intravitreally at multiple times points over a 10 week for 1 mg TAAgs and over a 30 week for the 4 mg TAAgs. Thus, the VEGF was injected intravitreally at 2 weeks, 6 weeks and 10 weeks after study initiation for the 1 mg TAAgs study rabbits. The VEGF was injected intravitreally at 2 weeks, 6 weeks and 10 weeks, 14 weeks, 22 weeks, and 30 weeks after study initiation for the 4 mg TAAgs is study rabbits.
  • [0151]
    Drug (FAAgs) Injection
  • [0152]
    General anesthesia was initiated by isoflurane inhalation and the ocular surface was anesthetized with 1-2 drops of 1% proparacaine. Rabbits were then placed on a heated pad, covered with a sterile drape, and both eyes were treated with Betadine for 30 seconds and rinsed with sterile saline. 50 μL of the 1 mg or 4 mg TAAgs formulations (the Example 8 and 9 formulations, respectively) were administered via their original glass syringes and 27 gauge needle, and each syringe was calibrated to the blue line prior to injection). The syringe needle was inserted about 3 mm posterior to the limbus and aimed inferior and posterior. After injection, the needle was removed and the eye was checked for leakage.
  • [0153]
    Rabbit Model of VEGF-Induced Vasculopathologies
  • [0154]
    The Edelman (2005) A model of BRB and BAB breakdown was used to determine the pharmacologic duration of action after intravitreal injection of 1 and 4 mg TAAgs. Rabbits were placed on a heated pad, covered with a sterile drape, and 500 ng of recombinant human vascular endothelial growth factor (165 amino acid variant; VEGF165, obtained from R & D Systems, Minneapolis, Minn.) in 50 μL sterile phosphate buffered saline was injected intravitreally into all eyes via a 27G needle.
  • [0155]
    Forty-Eight hours after VEGF injection, eyes were dilated with 10% phenylephrine HCl and 1% cyclopentolate HCl. Anesthesia was induced via subcutaneous injection of 50 mg/kg ketamine and 10 mg/kg xylazine. Once anesthetized, the rabbit fundus was visualized with a Zeiss retinal camera and fundus images were obtained and stored on a personal computer. Sodium fluorescein was administered intravenously (11.75 mg/kg) and late phase angiograms were obtained after 5-10 min. Fifty minutes after fluorescein injection BRB and BAB integrity were measured using scanning ocular fluorophotometry (Fluorotron Master).
  • [0156]
    Fundus images were graded on a scale of 1 (normal) to 5 (maximal blood vessel dilation and tortuosity) by three masked observers. Retinal fluorescein leakage was scored from angiograms read by masked observers on a scale of 1 (no fluorescein leakage=normal) to 5 (maximum fluorescein leakage).
  • [0157]
    Angiogram and fundus image scores were compared with an unpaired non-parametric Wilcoxon Rank Sum/Mann-Whitney U-Test. Fluorophotometric measurements (area under the curve) were analyzed with a two tailed Students t-test. P-values≦0.05 are determined to be significant.
  • [0158]
    Results
  • [0159]
    2% TAAgs: 1 mg dose
  • [0000]
    1. Effect on blood-retinal barrier (BRB) breakdown. Subjective grading of angiograms (FIG. 1) or vitreal fluorophotometry (FIG. 2) shows that VEGF-induced BRB breakdown was suppressed in eyes treated with 1 mg TAAgs through at least about six weeks.
  • [0000]
    2. Effect on changes in retinal vessel caliber-tortuosity (ΔVC-T). Subjective grading of fundus images (FIG. 3) shows that VEGF-induced ΔVC-T was suppressed in eyes treated with 1 mg TAAgs through at least about six weeks.
  • [0000]
    3. Effect on blood-aqueous barrier (BAB) breakdown. Anterior chamber fluorophotometry shows that the extent of VEGF-induced BAB breakdown was not suppressed in rabbit eyes treated with the 1 mg TAAgs for at least at about 10 weeks (FIG. 4).
  • [0000]
    8% TAAgs: 4 mg Dose
  • [0160]
    1. Effect on BRB breakdown. Subjective grading of angiograms (FIG. 1) or is vitreal fluorophotometry (FIG. 2) shows that VEGF-induced BRB breakdown was suppressed in eyes treated with 4 mg TAAgs for between about fourteen weeks (FIG. 1) and twenty weeks (FIG. 2).
  • [0161]
    2. Effect on ΔVC-T. Subjective grading of fundus images (FIG. 3) shows that VEGF-induced ΔVC-T was clearly suppressed in all eyes treated with 4 mg TAAgs for at least fourteen weeks, and for some rabbits through twenty two to thirty weeks (210 days or about 7.5 months).
  • [0000]
    3. Effect on BAB breakdown. Anterior chamber fluorophotometry (FIG. 4) shows that the extent of VEGF-induced BAB breakdown was not significantly suppressed at 10, 22, and 30 weeks.
  • [0162]
    These results showed significant inhibition of VEGF-induced BRB responses for at least six weeks with intravitreal 1 mg TAAgs (FIGS. 1-3), and for at least 30 weeks with intravitreal 4 mg TAAgs (FIG. 3). Note that FIG. 5 (a negative image of a photograph of the eye of a rabbit in this Example 11 thirty weeks after intravitreal injection of 50 μL of the 4 mg TAAgs formulation) shows that our TAAgs. formulation can remain intact in the vitreous for a prolonged period. In FIG. 5 item A is the intact, single object (bolus) intravitreal 4 mg, 50 μL TAA gel suspension 30 weeks after intravitreal injection. B is the vitreous chamber and C is a light reflection artifact.
  • [0163]
    Thus, based upon a demonstrated therapeutic effect for as long as thirty weeks after intravitreal injection of a TAAgs formulation, which TAAgs which remains intact in the vitreous for the same period, our TAAgs formulation can be characterized as a sustained release, biocompatible, biodegradable implant.
  • [0164]
    Thus, the results from this experiment demonstrate that intravitreal administration of a TAAgs formulation can be used to treat a retinal disease or condition (such as a retinal disease or condition which includes BRB breakdown or deterioration) with no or is little diffusion of drug to the anterior chamber (as determined for example by the Example 10 data, and by the lack of or of a reduced effect on BAB breakdown set forth in this Example 11). It can therefore be concluded that our TAAgs formulations can be used to advantageously treat a retinal disease or condition with, for example, little or no IOP elevation (with reduced incidence of glaucoma therefore) and with no or little inducement of cataract formation or intraocular inflammation.
  • [0165]
    Our TAAgs formulations have numerous novel and advantageous characteristics making them well suited for the treatment of ocular conditions, such as posterior ocular conditions, such as macular edema, such as diabetic macula edema. For example our TAAgs formulation (for example the Examples 8 and 9 formulations) do not contain any preservatives or excipients such as an alcohol (such as a benzyl alcohol) or a polysorbate (such as a polysorbate 80). Thus our TAAgs formulations have a reduced retinal toxicity.
  • [0166]
    Additionally, our TAAgs formulations have superior depot and release characteristics. Intravitreal injection of an aqueous (i.e. in saline) solution of a triamcinolone provides active agent which quickly (in a matter of hours) diffuses out of the retina. Our TAAgs formulations have a longer duration of intravitreal therapeutic activity because therapeutic amounts of the triamcinolone can diffuse out of the gel over a period of thirty weeks or more. Thus, use of a suspending agent such as a polymeric hyaluronate can provide the consistency permitting substantially zero order kinetics release of the triamcinolone form the hyaluronate, proving thereby both an extended duration of effect of the triamcinolone and reduced levels and therefore a reduced effect of the triamcinolone upon the anterior chamber of the eye and a reduced systemic exposure to the active agent.
  • [0167]
    Our invention comprises triamcinolone acetonide injectable gel suspensions formulated viscous suspensions of triamcinolone acetonide at concentrations of, for example, 8% and 2% with sodium hyaluronate, sodium chloride, dibasic sodium phosphate (heptahydrate), monobasic sodium phosphate (monohydrate), and water for injection. The triamcinolone acetonide injectable gel suspensions are preferably at physiologic pH, isotonic, and preservative-free. Triamcinolone acetonide injectable gel suspensions within the scope of our invention can be supplied in single-use glass syringes with fixed 27 gauge needles. The syringes can be overfilled to 0.17-0.18 mL, and calibrated to deliver 0.05 mL when primed to a black mark on the barrel of the syringe to thereby deliver, for example, 2% and 8% suspensions of 1 mg and 4 mg of triamcinolone, respectively. Our triamcinolone acetonide injectable gel suspensions can be defined as implants which upon injection (i.e. implantation) into the vitreous provided sustained release (i.e. over a period of up to seven months or longer) from the compact gel bolus injected.
  • [0168]
    Our triamcinolone acetonide injectable gel suspensions are preferably not used as visualizing agents, for example in conjunction with a vitrectomy (see eg U.S. Pat. No. 6,395,294) because the viscous, gel nature of our formulations prevents them for rapidly spreading out within the vitreous, as is required for a vitreal visualization agent (such as for example triptan vision blue, or water or saline based triamcinolone solutions or formulation, such as Kenalog®). A lower molecular weight hyaluronate with triamcinolone acetonide can be used for visualization (for example with a viscosity at a shear rate of about 0.1/second of less than about 90,000 cps, such as for example about 1,000 to 10,000 cps), whereas the higher molecular weight hyaluronate of Examples 8 and 9 are preferred for use as in situ forming vitreous implants.
  • Example 12 Treatment of Macular Edema with Intravitreal Triamcinolone Acetonide Suspension
  • [0169]
    A 64 year old obese female patient with symptoms of diabetes presents with vision loss due to macula edema with central retinal vein occlusion and/or branch retinal vein occlusion. She receives intravitreal injection of 4 mg of a high viscosity triamcinolone acetonide (polymeric hyaluronate based) suspension, such as the Example 9 formulation.
  • [0170]
    Twelve months after injection she demonstrates an improved best corrected visual acuity of fifteen or more letters from baseline as determined using the Early Treatment of Diabetic Retinopathy Study (ETDRS) visual acuity chart.
  • Example 13 Treatment of a Posterior Ocular Condition with Intravitreal Triamcinolone Acetonide Suspension
  • [0171]
    Patients with a posterior ocular condition (such as a macular edema, uveitis, or macular degeneration) can be treated by intravitreal injection of 1 mg or 4 mg of a high viscosity triamcinolone acetonide gel (polymeric hyaluronate based) suspension, such as the Example 8 or Example 9 formulation. Alternately, the formulation can be administered by subconjunctival injection to treat the posterior ocular condition. These patients can demonstrate twelve months after injection an improved best corrected visual acuity of fifteen or more letters from baseline as determined using the Early Treatment of Diabetic Retinopathy Study (ETDRS) visual acuity chart.
  • [0172]
    In clinical studies being carried out for the treatment of macula edema, participated in, or supervised by the inventors or their colleagues over one thousands patients have received intravitreal injection of the Example 8 or Example 9 formulations. Yet the incidence of aseptic endophthalmitis in these numerous patients has been 0%. This is striking when one notes that the incidence of endophthalmitis upon intravitreal injection of Kenalog is about 1% to 2%.
  • [0173]
    Thus, it is important to note that the desired therapeutic result (maintained or improved vision) can be obtained with little or no incidence of intraocular inflammation. Without wishing to be bound by theory we can postulate reasons for this exceptional result. Macrophages are involved with the removal of particulate material from the body through phagocytosis. However, particles of large morphology and irregular is geometry can be toxic to macrophages and lead to cell death. The death of macrophages can lead to release of pro-inflammatory cytokines that cause both acute and chronic inflammation. Clinical examples of toxicity from particles include gouty arthritis, where urate crystals that range from 5 to 20 microns cause a debilitating arthritis. Helliwell P., Use of an objective measure of articular stiffness to record changes in fingerjoints after intra-articular injection of corticosteroid, Ann Rheum Dis 1997; 56:71-73. Macrophages are injured when phagocytosing the urate crystals and this initiates the inflammatory response. When patients are treated with medication that reduces macrophage activity, such as colchicine, this leads to a dramatic improvement in the arthritis. Another example of joint inflammation related to particles is ‘crystal-induced synovitis,’ where 1-2% of patients that receive intra-articular injections of Lederspan, Kenalog, or other corticosteroid depot formulation, develop a post-injection exacerbation of the joint inflammation. McCarty D., et al., Inflammatory reaction after intrasynovial injection of microcrystalline adrenocorticosteroid esters, Arthritis and Rheumatism, 7(4); 359-367 (1964). The particles in these formulations, which are on the average over 10 microns and have irregular morphology, are very similar to the urate crystals in joint of patients with gout. Significantly, in our formulations the triamcinolone particles (crystals) are not available to and/or are substantially ignored by macrophages due to the aggregation (suspension) of the triamcinolone particles in the high molecular weight hyaluronate used in our formulations. The fact that our triamcinolone formulations are in situ forming implants can also limit the exposure of whole or individual triamcinolone crystals to sensitive ocular tissues, concomitantly thereby limiting macrophage activation and hence also limiting or preventing an intraocular inflammatory response. It is important to note that with our formulation the particular high viscosity hyaluronic acid polymer chosen maintains the triamcinolone crystals in a collective matrix that acts as a sustained-release reservoir which decrease the need for frequent repeat injections. Thus, our formulation forms a cohesive agglomerate upon intravitreal injection. The reduced surface area of such an agglomerate facilitates provision and maintenance of a lower release rate of the triamcinolone, as compared to much larger surface area saline suspension of a triamcinolone (such as Kenalog). The cohesiveness of our formulation is exemplified by the fact that the formulation maintains its internal consistency (i.e. its shape after injection) for at least about 30 weeks after intravitreal injection (see FIG. 5).
  • [0174]
    Additionally, the compositions of our invention are preferably formulated with hyaluronic acid, a material known for its anti-inflammatory abilities. Dea I. et al., Hyaluronic acid: a novel, double helical molecule, Science, 1973 Feb. 9; 1 79(73):560-2.).
  • [0175]
    Furthermore, the absence of preservatives and/or stabilizers (such as benzyl alcohol and polysorbate 80) in our formulation reduces the retinal toxicity of our formulations as compared to formulations which contain one or more preservatives and/or stabilizers.
  • [0176]
    The combination of these five factors (lack of injury to macrophages, low availability of the triamcinolone crystal to macrophages, use of a biocompatible polymer, use of a high viscosity biocompatible polymer, and absence of preservatives and stabilizers provides an optimal ophthalmic delivery system which limits the incidence of post-injection aseptic endophthalmitis.
  • [0177]
    A preferred embodiment of our invention can be the Example 8 and 9 formulations in which the average diameter of the triamcinolone particles present in the formulations is less than 10 microns and preferably less than 5 microns, and additionally with a uniform (spherical) morphology. It has been shown in the pulmonary literature that micronized particles of corticosteroids, <10 microns, and preferably <5 microns, are less injurious to macrophages, and have the potential for less inflammation. (Robert A. Freitas Jr., Nanomedicine, Volume IIA: Biocompatibility, Landes Bioscience, Georgetown, Tex., 2003). Thus, preparing our formulations with a is median triamcinolone particle size of <5 microns and with uniform shape provides formulation which are even more biocompatible in the vitreous and with less propensity to cause intraocular inflammation.
  • Example 14 Six Month Ocular and Systemic Pharmacokinetics of Triamcinolone Acetonide Following Intravitreal Injection of 2% (1 mg) and 8% (4 mg) Triamcinolone Acetonide Injectable Gel Suspension Formulations in Rabbit Eves
  • [0178]
    An experiment was carried out to compare the ocular and systemic pharmacokinetics of triamcinolone acetonide (TA) following a single unilateral intravitreal injection of 2% (1 mg) and 8% (4 mg) TA injectable gel suspensions in new Zealand white rabbit eyes. These suspensions are the TA formulations of Examples 8 and 9, respectively.
  • [0179]
    Seventy-two female New Zealand White rabbits were obtained from Harlan (Indianapolis, Ind.). The rabbits were specific pathogen free (SPF), 17-18 weeks old and weighed 2.58-3.15 kg at the time of dosing. The seventy-two female rabbits were intravitreally injected with one of two TA doses (2% or 8%) and ocular and systemic pharmacokinetics monitored. Rabbits (four per group) were sacrificed on days 2, 4, 11, 32, 64, 92, 121, 151 and 183 for aqueous humor (AH), vitreous humor (VH) and plasma drug levels determined at each such time point at each of these three physiological locations. Samples were quantified using validated LC-MS/MS methods with assay range for TA of 0.2-20 ng/mL in plasma, 1-500 ng/mL in AH and 0.4-100 pg/mL in VH.
  • [0180]
    This study was a single treatment, parallel design, with 18 treatment groups and non-serial samples collected from each animal, as shown by Table 6.
    TABLE 6
    Study Design
    Euthanasia and
    Number of Treatment (Right Eye Only) Necropsy
    Group Rabbits (Day 1 = Day of intravitreal injection) TA Dosed (Day)
    A 4 2% (1 mg) Triamcinolone Gel Suspension 1 mg 2
    B 4 2% (1 mg) Triamcinolone Gel Suspension 1 mg 4
    C 4 2% (1 mg) Triamcinolone Gel Suspension 1 mg 11
    D 4 2% (1 mg) Triamcinolone Gel Suspension 1 mg 32
    E 4 2% (1 mg) Triamcinolone Gel Suspension 1 mg 64
    F 4 2% (1 mg) Triamcinolone Gel Suspension 1 mg 92
    G 4 2% (1 mg) Triamcinolone Gel Suspension 1 mg 121
    H 4 2% (1 mg) Triamcinolone Gel Suspension 1 mg 151
    I 4 2% (1 mg) Triamcinolone Gel Suspension 1 mg 183
    J 4 8% (4 mg) Triamcinolone Gel Suspension 4 mg 2
    K 4 8% (4 mg) Triamcinolone Gel Suspension 4 mg 4
    L 4 8% (4 mg) Triamcinolone Gel Suspension 4 mg 11
    M 4 8% (4 mg) Triamcinolone Gel Suspension 4 mg 32
    N 4 8% (4 mg) Triamcinolone Gel Suspension 4 mg 64
    O 4 8% (4 mg) Triamcinolone Gel Suspension 4 mg 92
    P 4 8% (4 mg) Triamcinolone Gel Suspension 4 mg 121
    Q 4 8% (4 mg) Triamcinolone Gel Suspension 4 mg 151
    R 4 8% (4 mg) Triamcinolone Gel Suspension 4 mg 183
  • [0181]
    The seventy-two rabbits received a single unilateral (right eye) intravitreal injection of either 2% (1 mg) or 8% (4 mg) TA gel suspension. On day 1 each rabbit received an intravitreal injection into the midvitreous region through the dorsotemporal quadrant of the right eye, approximately 2-3 mm posterior to the limbus. For each injection, the needle of a pre-filled syringe (2% and 8% TA pre-filled syringes) was introduced through the dorsotemporal quadrant of the eye, approximately 2-3 mm posterior to the limbus, with the bevel of the needle directed downward and posteriorly to avoid the lens. 50 μL of either the 2% or 8% formulation was injected in a single bolus at a location roughly in the center of the vitreous.
  • [0182]
    There were no drug-related effects on body weight and mortality. Following a single intravitreal injection of either 2 or 8% TA gel suspension, TA was detected in the is AH, VH and plasma at the earliest timepoint of Day 2. No contralateral diffusion of TA to the untreated eyes was detected in AH. The AH mean maximal concentrations (Cmax) for 2% and 8% TA gel suspension were 27.6 ng/mL (Day 2) and 29.5 ng/mL (Day 11), respectively. The AH drug levels for the 2% and 8% dose were detectable up to Day 32 (4.15 ng/mL) and Day 151 (3.55 ng/mL), respectively. The area under the AH concentration time curve (AUC0-tlast) was dose-dependent for the 2% (328 ng-day/mL) and 8% (1311 ng-day/mL) gel suspension with half-life (t1/2) of 12.4 and 94.1 days, respectively.
  • [0183]
    Following intravitreal injection of 2% and 8% TA gel suspension, VH concentration of TA declined from 444 pg/g (57.6% dose remaining) at 2 days postdose to 22.1 μg/g (3.4% dose remaining) by 32 days post dose and 1460 μg/g (51.2% dose remaining) at 2 days to 33 μg/g (1.3% dose remaining) by 151 days post dose, respectively. No contralateral diffusion of TA to the untreated eyes was detected in VH at all timepoints except for the 8% dose on Day 2 (0.306 pg/g). The AUC0-tlast for the 2% and 8% doses were 3410 pg-day/g and 68800 pg-day/g, respectively. The t1/2 for the 2% and 8% doses were 8.57 and 32.8 days, respectively. This 33 day half life is significantly greater than the 15 day half life reported for a saline suspension of TA (such as is Kenalog) in the vitreous (Aubren (2004), supra). The 33 day half life can be expected to increase significantly to a half life of about 50-60 days in the VH of pathological and/or vitrectomized eyes.
  • [0184]
    The plasma Cmax (Day 2) for the 2% and 8% doses were 4.12 ng/mL and 3.59 ng/mL, respectively. Plasma TA was detected for the 2 and 8% dose up to Day 11 and Day 64, respectively. The AUC0-tlast for the 2% and 8% doses were 18.1 ng-day/mL and 83.6 ng-day/mL, respectively. The t12 for the 2% and 8% doses were 3.11 and 16.2 days, respectively.
  • [0185]
    Significantly (as noted above), TA was detected in the VH for the 2% (1 mg) and 8% (4 mg) TA gel suspension for up to 1 and 5 months postdose, respectively. The systemic exposure to TA following intravitreal injection was low and is expected to be relatively safe compared to systemic exposure of oral TA. Thus, it can be concluded that at least our 8% TA gel suspension can release TA into the vitreous over at least a 5 month (151 day) period, in the manner therefore of an in situ forming sustained release implant.
  • Example 15 Method for Making Injectable Triamcinolone Acetonide Gel Suspension Formulations
  • [0186]
    Preferred methods were developed for making the formulations of Examples 1 to 9.
  • [0187]
    The triamcinolone formulations are made as sterile, uniform, opaque white gel suspensions suitable for intraocular (such as intravitreal) injection. The manufacturing process involves two main stages: 1) sterile suspension bulk compounding and 2) aseptic filling. The bulk product manufacture includes preparations of three separate parts, followed by aseptic combination of these three parts. The aseptic filling operation is conducted in a class 100 environment, and the sterile bulk product may be filled into pre-sterilized ready-to-use syringes.
  • [0188]
    Micronized triamcinolone acetonide, USP, was purchased from Pfizer, Inc., Kalamazoo Mi. Typical and most useful particle sizes for this drug are 4-8 microns in diameter. Sodium hyaluronate powder was purchased from Hyaluron, Woburn, Mass. Typical and most useful molecular weights for this polymer are 1.0 to 1.9 million Daltons. When used, SBE7-β-cyclodextrin (Captisol®) was obtained from CyDex, Inc., Overland Park, Kans.
  • [0189]
    Part I is prepared in a main batch vessel that has capabilities of bulk heat sterilization and viscous fluid mixing. First, water for injection (WFI) at 40% of batch size is charged into the vessel and sodium chloride is dissolved. Triamcinolone powder is then added and dispersed with strong agitation. The suspension is heated and sterilized at above 121° C. for a sufficient time period by steam passing through the jacket of the vessel. After the bulk heat cycle is completed, the suspension is cooled down to room temperature.
  • [0190]
    Part II is prepared in an open vessel equipped with a top entering, variable speed mixer. First, WFI at 10% of batch size is charged into the vessel. Sodium phosphate salts and, optionally, a β-cyclodextrin derivative is added and dissolved. If necessary, the pH of the solution is adjusted with 1 N sodium hydroxide and/or 1 N hydrochloric acid. When a beta cyclodextrin is used in the formulation is can be dissolved along with the phosphate salts in this part II.
  • [0191]
    Part III is prepared in a Class 100 environment through a series of aseptic procedures. First, sodium hyaluronate is dissolved in WFI at dilute concentration, e.g., 0.2% w/w. The solution is sterile-filtered and sodium hyaluronate powder is recovered through bulk lyophilization. Finally, the sodium hyaluronate powder is reconstituted with sterile WFI at 50% of batch size.
  • [0192]
    Sterile bulk suspension is compounded by aseptically combining (mixing) the three parts. First, Part II solution is filtered into sterile Part I in the main batch vessel using a 0.2 micron sterilizing grade filter. Part III is then aseptically transferred into the main batch vessel. Finally, the bulk is blended (mixed) under low shear conditions to achieve uniformity. The final bulk suspension is held in a controlled area before aseptic filling.
  • [0193]
    Aseptic filling operations are performed in a Class 100 environment. Sterile bulk suspension is first filtered through a clarification screen into a sterile holding container. The bulk is then transferred to the filling machine and filled into pre-sterilized syringes. The filled units are transferred to the packaging area for application of tamper-evident seals, labeling and cartoning.
  • [0194]
    The pharmaceutical manufacturing process of this Example 15 for making triamcinolone sterile suspensions is illustrated by the FIG. 6 process flow chart.
  • [0195]
    Although not shown in FIG. 6, after Part III has been made (and before the lyophilization step is applied to Part III), Part III can be heated at between about 120° C. and about 130° C. for between about 25-35 minutes. Doing so both sterilizes the hyaluronate and can reduce the initial 1 million to 1.9 million Daltons molecular weight of the hyaluronate used in our formulation by about 20% to about 30% (i.e. to between about 0.7 million to about 1.3 million Daltons), thereby permitting use of a higher (i.e. 30 gauge) gauge injection needle.
  • Example 16 Low Immunogenicity, Stable Intraocular Triamcinolone Compositions
  • [0196]
    We carried out further experiments with the formulation of Example 9, a pharmaceutical composition comprising 8% triamcinolone acetonide in polymeric hyaluronic acid, referred to herein by the trade name Trivaris or Trivaris 8%. The findings set forth herein apply as well to the Example 8 formulation (Trivaris 2%). We confirmed the low immunogenicity or anti-inflammatory nature of Trivaris and determined that upon intraocular administration substantially all the Trivaris triamcinolone acetonide particles are embedded within the polymeric matrix of the hyaluronic acid and that Trivaris is storage stable.
  • [0197]
    Sterile endophthalmitis is an inflammatory response that can exacerbate macular edema, cause retinal detachment, and lead to vision loss. Sterile endophthalmitis can occur upon intravitreal injections of prior, known triamcinolone acetonide (TA) formulations. For example, sterile endophthalmitis has been reported with aqueous (low viscosity) TA formulations, such as Kenalog-40, that contain the preservative benzyl alcohol. Significantly, sterile endophthalmitis has also been reported with intravitreal injection of preservative free TA formulations so the presence of the preservative in Kenalog-40 may not be the primary cause of the cases of sterile endophthalmitis it can cause.
  • [0198]
    A major factor associated with the inflammatory reaction characteristic of sterile endophthalmitis can be the drug particle burden in the vitreous cavity, as evidenced by the plume effect, which occurs upon intravitreal injection of an aqueous (low viscosity) TA formulation. Thus, individual drug particles are recognized by macrophages resident in the vitreous as they attempt to phagocytose free floating drug particles. Phagocytosis leads to cytokine release and both neutrophils and macrophages are thereby recruited to the vitreous cavity. The enormous numbers of indigestible drug particles released into the vitreous by a aqueous TA formulation (with or without a preservative) can be lethal to macrophages and neutrophils, causing these cells die and release lysosomal contents, oxidative enzymes, and more proinflammatory cytokines. This results in an acceleration of the inflammatory reaction and hence the clinical manifestations of sterile endophthalmitis.
  • [0199]
    Due to their higher density triamcinolone acetonide drug particles injected into the is vitreous agglomerate into consolidated drug depots within the first week following intravitreal injection. Therefore, the risk of sterile endophthalmitis occurring is generally within the 48 hour period after intravitreal injection as this is the time when the macrophages have greatest access to the still free floating, individual drug particles.
  • [0200]
    Three lots of Kenalog-40 were examined (see FIG. 7) and it was determined that the TA particles in Kenalog can be as large as 80 microns, with high particles size variability. The heterogeneous population of drug particles in Kenalog-40 ranging in size from about 2 to about 80 microns can be injurious to phagocytes since larger and irregularly shaped drug particles are poorly ingested by such cells resulting in phagocyte cell death. This toxic inflammatory reaction to corticosteroid crystals has also been observed following intra-articular injections where an inflammatory joint reaction occurs within 48 hours after injection is called crystal synovitis. Other more remote causes of sterile endophthalmitis with use of intravitreal corticosteroid formulations include the presence of endotoxins, extraneous particles and/or excipients in the formulation and the formulation having a pH less than 5 or greater than pH 8.
  • [0201]
    The particles size distribution of four lots of Trivaris was also examined. As shown by FIGS. 8A to 8D, the median TA particles size in Trivaris was between about 4 microns and 5 microns and 90% of the TA particles in Trivaris had a diameter of 10 microns or less. FIG. 8 also shows that about 40% of the Trivaris TA particles had a diameter between about 4 microns and about 8 microns and that about 60% of the Trivaris TA particles had a diameter between about 3.5 microns and about 9 microns.
  • [0202]
    The TA particle size distribution data in FIGS. 7 and 8 was obtained by light scattering using a Horiba LA 300 instrument. The line graph in FIGS. 8A, B, C and 8D shows the cummulative TA particle size % (area under the curve) (right hand side Y axis). Trivaris is a viscous TA formulation in which the TA drug particles are embedded in and coated by the polymeric matrix of the hyaluronic acid (HA) to thereby form a viscoelastic hydrogel with a viscosity of between about 130 k and about 300 k centipoises (cps) at a shear rate of about 0.1/second at 25° C. Significantly, the TA drug particle sizes in Trivaris are deliberately uniform in distribution with a median particle size ranging from about 4 to about 6 microns. This hydrogel formulation of Trivaris can be injected through a hypodermic (syringe) needle having a needle gauge as small as 33 gauge.
  • [0203]
    The HA in Trivaris creates a physical barrier to free movement of the embedded TA drug particles, thereby reducing the potential for free floating TA particle exposure in the vitreous and resulting macrophage activation. Importantly, HA is recognized by scavenging intravitreal macrophages as a native (non-immunogenic) because there is a high concentration of HA naturally present in the vitreous humor. Thus coating the TA drug particles with HA renders the injected Trivaris formulation non-antigenic, lowering the potential of the TA drug particles to instigate an inflammatory response. Use of HA encapsulation as an ‘immunologic disguise’ is used in a similar fashion by some streptococcus bacterial species to evade detection and phagocytosis by macrophages and increasing the virulence of the organism. Importantly, the hydrogel formulation of Trivaris permits the TA particles to become free drug as the TA is solubilized (dissolves) in the vitreous, thereby permitting the solubilized TA to enter solution in the vitreous and then diffuse or be actively transported to the retina to treat a retinal disease or condition. The close proximity of the TA drug particles in the Trivaris HA hydrogel allows for controlled and rapid agglomeration of the TA particles as the HA gradually diffuses over time out of the depot formed upon intravitreal Trivaris injection.
  • [0204]
    An additional experiment was carried out to determine free TA particle exposure and pupillary obscuration in patients receiving either intravitreal Kenalog-40 or Trivaris. Thus a fundus photography evaluation of patients was performed one hour after each is patient had received an intravitreal injection of 4 mg of either Kenalog-40 (n=4) or Trivaris (n=3). A 48 μL (50 mg) injection of the Example 98% formulation (Trivaris 8%) provided the 4 mg of TA. Note that about 100 μL of the Kenalog-40 was required to provide 4 mg of TA. The required greater (double) volume of Kenalog-40 to obtain the same amount of injected TA can by itself cause deleterious effects (such as acute elevation of intraocular pressure leading to central retnal artery occlusion) due to the limited normal intravitreal volume. As shown by Table 7 it was determined that about 83% of the TA particles were floating free in the vitreous after the Kenalog injections, whereas only about 6% of the TA particles were free floating in the patients injected with Trivaris. Significantly, therefore about 84% of the Trivaris TA particles were upon intravitreal injection embedded within the HA. Additionally, the pupil was obscured with drug particles in a mean of 29.8% of the patients who received Kenalog, versus only a 1.7% pupil obscuration by TA particles in the patients who had received Trivaris.
  • [0205]
    Hence, Trivaris has minimal free TA drug particle exposure and pupil obscuration, compared with Kenalog, following intravitreal injection.
  • [0206]
    The low numbers of drug particles in an unbound state following injection of Trivaris can be expected to reduce activation of scavenging macrophages compared with other TA suspensions, such as Kenalog-40, where the majority of the TA particles are upon intravitreal injection exposed to macrophages and inflammatory consequences can then ensue. The effectiveness of the Trivaris formulation to reduce the inflammatory potential has been observed in recent clinical trials. In over 1000 patients in phase 3 clinical trials that have received injections of Trivaris formulation, some multiple times, there have been no reported cases of sterile endophthalmitis. The consolidation of the drug particles in the Trivaris HA hydrogel, with a clear view through the pupillary axis, also enables immediate recovery of vision after injection & enables PDT, thermal laser and diagnostic procedures to be performed.
  • [0207]
    A further experiment was carried out to examine the stability of the TA particles in Trivaris. We determined that the TA drug particles in the HA hydrogel suspension of is Trivaris were remarkably stable, with minimal crystal agglomeration or degradation during extended storage. Thus, 0.5 mL glass syringes were filled with 0.2 mL of the Example 9 formulation. The filled syringes were stored horizontally at 25° C. in 60% relative humidity. Upon syringe filling (time zero), at 5 weeks, at 6 weeks and after three months of storage, TA particle size was determined using laser light scattering with Horiba LA 300 instrument, after dilution of a Trivaris sample in distilled water just prior to the light scattering analysis. 90th percentile of volume-weighted size distribution data from three different lots showed that at time zero 90% of the TA particles had a diameter of 11 microns or less, at +5 weeks and at +6 weeks 90% of the TA particles still had a diameter of about 11 microns or less. Finally at +3 months 90% of the TA particles still had a diameter of about 13 microns or less. These results mean that even with prolonged storage the TA particles remain suspended in the HA and undergo neither substantial agglomeration or degradation. Hence, even after prolonged storage Trivaris retains its syringability without needle occlusion.
  • [0208]
    In addition to limiting particle exposure, the HA of Trivaris has additional inherent anti-inflammatory properties. Hyaluronic acid inhibits movement of macrophages, down regulates the production of proinflammatory cytokines and chemokines in models and human diseases, scavenges oxygen free radicals, and inhibits matrix metalloproteinases. Trivaris can include additional features to minimize an inflammatory reaction upon intravitreal injection, such as preparing Trivaris to have a pH between 6 and 7 range, and strict endotoxin and extraneous particle control.
  • [0209]
    Furthermore, the uniform population of micronized TA particles in Trivaris (see FIG. 7) provides a predictable ocular TA release pharmacokinetics with increased TA vitreous half-life.
  • [0210]
    The Example 8 and 9 Trivaris formulations can also be used as an injectable pharmaceutical composition to treat various articular (joints and spine) pathologies while at the same time reducing the potential for occurrence of post-injection inflammation (crystal synovitis).
  • [0211]
    In summary, the Trivaris formulation creates a physical barrier to free movement of drug particles to reduce the potential for particle exposure, macrophage activation, and the potential for sterile endophthalmitis. The consolidation of the TA drug particles in the HA hydrogel enables immediate recovery of vision after injection & enables PDT, thermal laser and diagnostic procedures to be performed. Incorporating a uniform population of micronized TA particles in the formulation facilitates management by macrophages when outside of the drug depot, but also leads to predictable ocular pharmacokinetics with an increased vitreous half-life. Trivaris is supplied in pre-loaded syringes with little or no endotoxin and extraneous particle content, to thereby further limit post-injection inflammation. Trivaris does not contain benzyl alcohol or any other preservatives thereby reducing toxicity to retinal cells.
    TABLE 7
    Photographic evaluation in patients following an intravitreal injection of
    Kenalog-40 or Trivaris 8%
    Free Posterior
    particles Consolidated PoleView Pupil
    Subject Kenalog-40 Trivaris exposed % depot % obscuration* Obscuration**
    1 X 80 20  2+ 10
    2 X 95 5  1+ 30
    3 X 5 95 0 0
    4 X 10 90 0 0
    5 X 75 25 0 4
    6 X 3 97 0 5
    7 X 80 20  3+ 75
    TOTALS
    Kenalog 4 82.5 17.5  +1.5 29.8
    Mean (SD) (8.7) (8.7)   (1.29) (32.1)
    Trivaris Mean 3 6.0 94.0 0 1.7
    (SD) (3.6) (3.6) (2.9)

    *graded as Vitreous Haze (SUN Criteria) 0 through 4+

    **grade as % of pupillary area (dilated) obscured by drug as measured with the red reflex photo
  • [0212]
    While this invention has been described with respect to various specific examples and embodiments, it is to be understood that the invention is not limited thereto. For example, the corticosteroid formulations set forth herein can be used to treat conditions including articular pathologies, such as rheumatoid and osteoarthritis, and spinal conditions, such as facet arthritis, and the treatment of chronic pain by epidural or spinal root injections of a formulation such as a Trivaris formulation
  • [0213]
    Additionally, although preferably the polymeric hyaluronate in Trivaris is a non-cross linked hyaluronate (so as to obtain, upon application of force to the plunger of the syringe used to administer Trivaris, a high shear rate and hence relative ease of injection of Trivaris through a 27-33 gauge needle), the hyaluronate can alternately be is a cross linked hyaluronate (to form a true hydrogel therefore) with a significantly lower viscosity (i.e. with a viscosity of about 5,000 cps at a shear rate of about 0.1/second at about 25° C.). Such a cross-linked hyaluronate can have the same or similar excellent corticosteroid suspension property of Trivaris, and have the additional advantage of longer residency (i.e. biodegradable at a slower rate) of the hyaluronate in the vitreous, with resulting prolonged nominal immunogenicity of such a cross-linked hyaluronate formulation in the vitreous, due to a longer period of intravitreal (or intraocular) retention of the corticosteroid particles in the polymeric matrix of the cross-linked hyaluronate.
  • [0214]
    Furthermore, besides hyaluronate other cross-linked polymers can be used, such as for example a polycarbophil.
  • [0215]
    All references, articles, publications, patents and applications set forth above are incorporated herein by reference in their entireties.

Claims (15)

  1. 1. A pharmaceutical composition for treating a posterior ocular condition, the pharmaceutical composition comprising:
    (a) a plurality of corticosteroid particles mixed with;
    (b) a viscous polymer, wherein the pharmaceutical composition has a viscosity of between about 130,000 cps and about 300,000 cps at a shear rate of about 0.1/second at about 25° C., and the pharmaceutical composition can be injected into the vitreous of a human eye through a 25 to 33 gauge needle.
  2. 2. The pharmaceutical composition of claim 1, wherein the corticosteroid particles have a substantially uniform diameter.
  3. 3. The pharmaceutical composition of claim 1, wherein substantially all the corticosteroid particles are embedded within the viscous polymer.
  4. 4. The pharmaceutical composition of claim 1, wherein the corticosteroid is a triamcinolone.
  5. 5. The pharmaceutical composition of claim 1, wherein the viscous polymer is a polymeric hyaluronate or a polymeric hyaluronic acid.
  6. 6. A pharmaceutical composition for treating a posterior ocular condition, the composition comprising:
    (a) a plurality of triamcinolone particles with a substantially uniform diameter, and;
    (b) a viscous polymeric hyaluronate or polymeric hyaluronic acid, wherein the pharmaceutical composition has a viscosity of between about 130,000 cps and about 300,000 cps at a shear rate of about 0.1/second at about 25° C. and can be injected into the vitreous of a human eye through a 25 to 33 gauge needle, wherein the triamcinolone particles are mixed with the viscous polymer substantially all the corticosteroid particles are embedded within and coated by the viscous polymeric hyaluronate or a polymeric hyaluronic acid.
  7. 7. A method for treating a posterior ocular condition, the method comprising the step of injecting into the vitreous of a patient's eye with a posterior ocular condition a viscous pharmaceutical composition comprising a plurality of corticosteroid particles mixed into a viscous polymeric matrix, wherein the pharmaceutical composition has a viscosity of between about 130,000 cps and about 300,000 cps at a shear rate of about 0.1/second at about 25° C., such that about one hour after the intravitreal injection only about 10% or less of the corticosteroid particles are present in the vitreous free of the polymeric matrix.
  8. 8. The method of claim 7, wherein about one hour after the intravitreal injection only about 5% or less of the corticosteroid particles are present in the vitreous free of the is polymeric matrix.
  9. 9. The method of claim 7, wherein about one hour after the intravitreal injection only about 3% or less of the corticosteroid particles are present in the vitreous free of the polymeric matrix.
  10. 10. A process for making an intraocular pharmaceutical composition, the method comprising the step of mixing an aqueous suspension of a plurality of corticosteroid particles and an aqueous solution of a viscous polymeric matrix, so that the resulting pharmaceutical composition has a viscosity of between about 130,000 cps and about 300,000 cps at a shear rate of about 0.1/second at about 25° C.
  11. 11. The process of claim 10, wherein the corticosteroid particles have a median particle size of between about 4 microns and about 5 microns.
  12. 12. The process of claim 10, wherein the corticosteroid particles have a stable diameter for at least three months after the pharmaceutical has been made and stored for three months in a syringe placed horizontally at about 25° C. at about 60% relative humidity.
  13. 13. The pharmaceutical composition made by the method of claim 10.
  14. 14. A pharmaceutical composition for treating an articular pathology, the pharmaceutical composition comprising:
    (a) a plurality of corticosteroid particles mixed with;
    (b) a viscous polymer, wherein the pharmaceutical composition has a viscosity of between about 130,000 cps and about 300,000 cps at a shear rate of about 0.1/second at about 25° C.,
  15. 15. A method for treating an articular pathology, the method comprising the step of is injecting into a joint of a patient with an articular pathology a viscous pharmaceutical composition comprising a plurality of corticosteroid particles mixed into a viscous polymeric matrix, wherein the pharmaceutical composition has a viscosity of between about 130,000 cps and about 300,000 cps at a shear rate of about 0.1/second at about 25° C.
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Cited By (37)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090036403A1 (en) * 2007-07-30 2009-02-05 Allergan, Inc. Tunably Crosslinked Polysaccharide Compositions
US20100028437A1 (en) * 2008-08-04 2010-02-04 Lebreton Pierre F Hyaluronic Acid-Based Gels Including Lidocaine
US20100098772A1 (en) * 2008-10-21 2010-04-22 Allergan, Inc. Drug delivery systems and methods for treating neovascularization
US20100278897A1 (en) * 2009-05-01 2010-11-04 Allergan, Inc. Intraocular bioactive agent delivery system with molecular partitioning system
WO2010132730A2 (en) * 2009-05-14 2010-11-18 Surmodics Pharmaceuticals, Inc. Hyaluronic acid (ha) injection vehicle
WO2011075481A1 (en) 2009-12-16 2011-06-23 Allergan, Inc. Intracameral devices for sustained delivery
US20110182966A1 (en) * 2010-01-22 2011-07-28 Allergan, Inc. Intracameral sustained release therapeutic agent implants
US20110224164A1 (en) * 2010-03-12 2011-09-15 Allergan Industrie, Sas Fluid compositions for improving skin conditions
US20110229574A1 (en) * 2010-03-22 2011-09-22 Allergan, Inc. Polysaccharide and protein-polysaccharide cross-linked hydrogels for soft tissue augmentation
US8128960B2 (en) 2008-03-11 2012-03-06 Alcon Research, Ltd. Low viscosity, highly flocculated triamcinolone acetonide suspensions for intravitreal injection
US8338375B2 (en) 2007-05-23 2012-12-25 Allergan, Inc. Packaged product
US8338388B2 (en) 2003-04-10 2012-12-25 Allergan, Inc. Cross-linking of low-molecular weight and high-molecular weight polysaccharides, preparation of injectable monophase hydrogels, polysaccharides and hydrogels obtained
US8394783B2 (en) 2007-11-30 2013-03-12 Allergan, Inc. Polysaccharide gel formulation having multi-stage bioactive agent delivery
US8394782B2 (en) 2007-11-30 2013-03-12 Allergan, Inc. Polysaccharide gel formulation having increased longevity
US20130136780A1 (en) * 2007-11-30 2013-05-30 Allergan, Inc. Crosslinked polysaccharide gel compositions for medical and cosmetic applications
US20130150410A1 (en) * 2008-07-21 2013-06-13 The Regents Of The University Of California Controlled Release Ion Channel Modulator Compositions and Methods for the Treatment of Otic Disorders
EP2606828A1 (en) * 2011-12-20 2013-06-26 Angioclinic AG Hyaluronic acid and its use for treating venous insufficiency and varicose veins
US8697044B2 (en) 2007-10-09 2014-04-15 Allergan, Inc. Crossed-linked hyaluronic acid and collagen and uses thereof
US8697057B2 (en) 2010-08-19 2014-04-15 Allergan, Inc. Compositions and soft tissue replacement methods
US8771745B2 (en) 2008-10-27 2014-07-08 Allergan, Inc. Prostaglandin and prostamide drug delivery systems and intraocular therapeutic uses thereof
US8883139B2 (en) 2010-08-19 2014-11-11 Allergan Inc. Compositions and soft tissue replacement methods
US8889123B2 (en) 2010-08-19 2014-11-18 Allergan, Inc. Compositions and soft tissue replacement methods
US8946192B2 (en) 2010-01-13 2015-02-03 Allergan, Inc. Heat stable hyaluronic acid compositions for dermatological use
US9005605B2 (en) 2010-08-19 2015-04-14 Allergan, Inc. Compositions and soft tissue replacement methods
CN104667287A (en) * 2013-11-27 2015-06-03 山东博士伦福瑞达制药有限公司 Eye-use composition for treating posterior chamber new vessel hyperplasia and application of eye-use composition
US9050336B2 (en) 2007-12-12 2015-06-09 Allergan, Inc. Botulinum toxin formulation
WO2015095772A3 (en) * 2013-12-20 2015-08-13 Emory University Formulations and methods for targeted ocular delivery of therapeutic agents
US9114188B2 (en) 2010-01-13 2015-08-25 Allergan, Industrie, S.A.S. Stable hydrogel compositions including additives
US9149422B2 (en) 2011-06-03 2015-10-06 Allergan, Inc. Dermal filler compositions including antioxidants
US9228027B2 (en) 2008-09-02 2016-01-05 Allergan Holdings France S.A.S. Threads of Hyaluronic acid and/or derivatives thereof, methods of making thereof and uses thereof
US9241829B2 (en) 2011-12-20 2016-01-26 Abbott Medical Optics Inc. Implantable intraocular drug delivery apparatus, system and method
US9265761B2 (en) 2007-11-16 2016-02-23 Allergan, Inc. Compositions and methods for treating purpura
US9393263B2 (en) 2011-06-03 2016-07-19 Allergan, Inc. Dermal filler compositions including antioxidants
US9408797B2 (en) 2011-06-03 2016-08-09 Allergan, Inc. Dermal filler compositions for fine line treatment
US9572800B2 (en) 2012-11-08 2017-02-21 Clearside Biomedical, Inc. Methods and devices for the treatment of ocular diseases in human subjects
US9788995B2 (en) 2006-05-02 2017-10-17 Georgia Tech Research Corporation Methods and devices for drug delivery to ocular tissue using microneedle
US9795711B2 (en) 2011-09-06 2017-10-24 Allergan, Inc. Hyaluronic acid-collagen matrices for dermal filling and volumizing applications

Families Citing this family (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060073208A1 (en) * 2004-10-01 2006-04-06 Allergan, Inc. Cosmetic neurotoxin compositions and methods
US20090148527A1 (en) * 2007-12-07 2009-06-11 Robinson Michael R Intraocular formulation
US9161970B2 (en) 2007-12-12 2015-10-20 Allergan, Inc. Dermal filler
US20120251615A1 (en) * 2008-01-18 2012-10-04 Horst Kief Agent for intra-articular injection
US20090202645A1 (en) * 2008-02-08 2009-08-13 Acme Drugs S.R.L. Intrasynovial formulations of stanozolol
US20110118206A1 (en) * 2008-08-04 2011-05-19 Allergan Industrie, Sas Hyaluronic acid based formulations
US8273725B2 (en) * 2009-09-10 2012-09-25 Genzyme Corporation Stable hyaluronan/steroid formulation
US20110171311A1 (en) * 2010-01-13 2011-07-14 Allergan Industrie, Sas Stable hydrogel compositions including additives
US20110171286A1 (en) * 2010-01-13 2011-07-14 Allergan, Inc. Hyaluronic acid compositions for dermatological use
RU2012145811A (en) * 2010-03-29 2014-05-10 Евоник Корпорейшн Compositions and methods for improved retention of the pharmaceutical composition at the site of local administration
US20120142628A1 (en) * 2010-12-07 2012-06-07 Allergan, Inc. Methods for treating crepitus
CN102988406B (en) * 2011-09-16 2016-03-02 中国医药大学 For inhibiting inflammation pharmaceutical compositions and kits
EP2606896B1 (en) * 2011-12-23 2014-08-27 AAP Implantate AG Sterile emulsion containing hyaluronate and glucocorticoid, and use of such emulsion in the treatment of inflammatory joint disorders
US9833460B2 (en) 2013-01-23 2017-12-05 Semnur Pharmaceuticals, Inc. Pharmaceutical formulation
JP6208261B2 (en) 2013-02-05 2017-10-04 パーデュー、ファーマ、リミテッド、パートナーシップPurdue Pharma L.P. Tampering resistant pharmaceutical preparations

Citations (93)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US385887A (en) * 1888-07-10 Chables sumnbr tainter
US4008864A (en) * 1974-02-18 1977-02-22 Nils Gustav Yngve Torphammar Locking mechanism for a safety belt
US4014335A (en) * 1975-04-21 1977-03-29 Alza Corporation Ocular drug delivery device
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
US4158005A (en) * 1975-02-10 1979-06-12 Interx Research Corporation Intermediates useful in the synthesis of optically active m-acyloxy-α-[(methylamino)methyl]benzyl alcohols
US4186184A (en) * 1977-12-27 1980-01-29 Alza Corporation Selective administration of drug with ocular therapeutic system
US4190642A (en) * 1978-04-17 1980-02-26 Alza Corporation Ocular therapeutic system for dispensing a medication formulation
US4200098A (en) * 1978-10-23 1980-04-29 Alza Corporation Osmotic system with distribution zone for dispensing beneficial agent
US4327725A (en) * 1980-11-25 1982-05-04 Alza Corporation Osmotic device with hydrogel driving member
US4383992A (en) * 1982-02-08 1983-05-17 Lipari John M Water-soluble steroid compounds
US4425346A (en) * 1980-08-01 1984-01-10 Smith And Nephew Associated Companies Limited Pharmaceutical compositions
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
US4649151A (en) * 1982-09-27 1987-03-10 Health Research, Inc. Drugs comprising porphyrins
US4656186A (en) * 1985-04-30 1987-04-07 Nippon Petrochemicals Co., Ltd. Tetrapyrrole therapeutic agents
US4668506A (en) * 1985-08-16 1987-05-26 Bausch & Lomb Incorporated Sustained-release formulation containing and amino acid polymer
US4675338A (en) * 1984-07-18 1987-06-23 Nippon Petrochemicals Co., Ltd. Tetrapyrrole therapeutic agents
US4727064A (en) * 1984-04-25 1988-02-23 The United States Of America As Represented By The Department Of Health And Human Services Pharmaceutical preparations containing cyclodextrin derivatives
US4920104A (en) * 1988-05-16 1990-04-24 Medchem Products, Inc. Sodium hyaluronate composition
US4935498A (en) * 1989-03-06 1990-06-19 Board Of Regents, The University Of Texas System Expanded porphyrins: large porphyrin-like tripyrroledimethine-derived macrocycles
US4981871A (en) * 1987-05-15 1991-01-01 Abelson Mark B Treatment of ocular hypertension with class I calcium channel blocking agents
US4997652A (en) * 1987-12-22 1991-03-05 Visionex Biodegradable ocular implants
US5002962A (en) * 1988-07-20 1991-03-26 Health Research, Inc. Photosensitizing agents
US5017579A (en) * 1986-02-14 1991-05-21 Sanofi Use of aminoalkoxyphenyl derivatives for reducing and/or controlling excessive intraocular pressure
US5019400A (en) * 1989-05-01 1991-05-28 Enzytech, Inc. Very low temperature casting of controlled release microspheres
US5034413A (en) * 1989-07-27 1991-07-23 Allergan, Inc. Intraocular pressure reducing 9,11-diacyl prostaglandins
US5089509A (en) * 1988-09-15 1992-02-18 Allergan, Inc. Disubstituted acetylenes bearing heteroaromatic and heterobicyclic groups having retinoid like activity
US5093349A (en) * 1988-07-20 1992-03-03 Health Research Inc. Photosensitizing agents
US5100431A (en) * 1990-09-27 1992-03-31 Allergan, Inc. Single stitch suture needle and method
US5106615A (en) * 1986-10-14 1992-04-21 Shabtay Dikstein Eyedrops having non-newtonian rheological properties
US5128326A (en) * 1984-12-06 1992-07-07 Biomatrix, Inc. Drug delivery systems based on hyaluronans derivatives thereof and their salts and methods of producing same
US5190966A (en) * 1988-07-06 1993-03-02 Health Research, Inc. Purified hematoporphyrin dimers and trimers useful in photodynamic therapy
US5198460A (en) * 1988-07-20 1993-03-30 Health Research Inc. Pyropheophorbides and their use in photodynamic therapy
US5209926A (en) * 1990-06-12 1993-05-11 Insite Vision Incorporated Aminosteroids for ophthalmic use
US5300114A (en) * 1992-05-04 1994-04-05 Allergan, Inc. Subconjunctival implants for ocular drug delivery
US5324519A (en) * 1989-07-24 1994-06-28 Atrix Laboratories, Inc. Biodegradable polymer composition
US5324718A (en) * 1992-07-14 1994-06-28 Thorsteinn Loftsson Cyclodextrin/drug complexation
US5332582A (en) * 1990-06-12 1994-07-26 Insite Vision Incorporated Stabilization of aminosteroids for topical ophthalmic and other applications
US5378475A (en) * 1991-02-21 1995-01-03 University Of Kentucky Research Foundation Sustained release drug delivery devices
US5487897A (en) * 1989-07-24 1996-01-30 Atrix Laboratories, Inc. Biodegradable implant precursor
US5494901A (en) * 1993-01-05 1996-02-27 Javitt; Jonathan C. Topical compositions for the eye comprising a β-cyclodextrin derivative and a therapeutic agent
US5501856A (en) * 1990-11-30 1996-03-26 Senju Pharmaceutical Co., Ltd. Controlled-release pharmaceutical preparation for intra-ocular implant
US5504074A (en) * 1993-08-06 1996-04-02 Children's Medical Center Corporation Estrogenic compounds as anti-angiogenic agents
US5516522A (en) * 1994-03-14 1996-05-14 Board Of Supervisors Of Louisiana State University Biodegradable porous device for long-term drug delivery with constant rate release and method of making the same
US5597897A (en) * 1991-06-21 1997-01-28 Genetics Institute, Inc. Pharmaceutical formulations of osteogenic proteins
US5707643A (en) * 1993-02-26 1998-01-13 Santen Pharmaceutical Co., Ltd. Biodegradable scleral plug
US5717030A (en) * 1994-04-08 1998-02-10 Atrix Laboratories, Inc. Adjunctive polymer system for use with medical device
US5747061A (en) * 1993-10-25 1998-05-05 Pharmos Corporation Suspension of loteprednol etabonate for ear, eye, or nose treatment
US5766242A (en) * 1993-11-15 1998-06-16 Oculex Pharmaceuticals, Inc. Biocompatible ocular implants
US5770589A (en) * 1993-07-27 1998-06-23 The University Of Sydney Treatment of macular degeneration
US5776699A (en) * 1995-09-01 1998-07-07 Allergan, Inc. Method of identifying negative hormone and/or antagonist activities
US5780044A (en) * 1994-04-08 1998-07-14 Atrix Laboratories, Inc. Liquid delivery compositions
US5869079A (en) * 1995-06-02 1999-02-09 Oculex Pharmaceuticals, Inc. Formulation for controlled release of drugs by combining hydrophilic and hydrophobic agents
US5877207A (en) * 1996-03-11 1999-03-02 Allergan Sales, Inc. Synthesis and use of retinoid compounds having negative hormone and/or antagonist activities
US5882682A (en) * 1991-12-27 1999-03-16 Merck & Co., Inc. Controlled release simvastatin delivery device
US5906920A (en) * 1995-08-29 1999-05-25 The Salk Institute For Biological Studies Methods for the detection of ligands for retinoid X receptors
US5913884A (en) * 1996-09-19 1999-06-22 The General Hospital Corporation Inhibition of fibrosis by photodynamic therapy
US5919970A (en) * 1997-04-24 1999-07-06 Allergan Sales, Inc. Substituted diaryl or diheteroaryl methanes, ethers and amines having retinoid agonist, antagonist or inverse agonist type biological activity
US5922773A (en) * 1992-12-04 1999-07-13 The Children's Medical Center Corp. Glaucoma treatment
US6051576A (en) * 1994-01-28 2000-04-18 University Of Kentucky Research Foundation Means to achieve sustained release of synergistic drugs by conjugation
US6066675A (en) * 1996-09-13 2000-05-23 The Regents Of The University Of California Method for treatment of retinal diseases
US6074661A (en) * 1997-08-11 2000-06-13 Allergan Sales, Inc. Sterile bioerodible occular implant device with a retinoid for improved biocompatability
US6217869B1 (en) * 1992-06-09 2001-04-17 Neorx Corporation Pretargeting methods and compounds
US6217895B1 (en) * 1999-03-22 2001-04-17 Control Delivery Systems Method for treating and/or preventing retinal diseases with sustained release corticosteroids
US6225303B1 (en) * 1994-03-14 2001-05-01 Massachusetts Eye And Ear Infirmary Use of green porphyrins to treat neovasculature in the eye
US6258319B1 (en) * 1989-10-26 2001-07-10 Cerus Corporation Device and method for photoactivation
US6261583B1 (en) * 1998-07-28 2001-07-17 Atrix Laboratories, Inc. Moldable solid delivery system
US6357568B1 (en) * 2000-09-27 2002-03-19 Shou Mao Chen Structure for protecting a luggage shell
US6369116B1 (en) * 1995-06-02 2002-04-09 Oculex Pharmaceuticals, Inc. Composition and method for treating glaucoma
US6387409B1 (en) * 1998-03-30 2002-05-14 Rtp Pharma Inc. Composition and method of preparing microparticles of water-insoluble substances
US6395294B1 (en) * 2000-01-13 2002-05-28 Gholam A. Peyman Method of visualization of the vitreous during vitrectomy
US6403649B1 (en) * 1992-09-21 2002-06-11 Allergan Sales, Inc. Non-acidic cyclopentane heptanoic acid,2-cycloalkyl or arylalkyl derivatives as therapeutic agents
US6407079B1 (en) * 1985-07-03 2002-06-18 Janssen Pharmaceutica N.V. Pharmaceutical compositions containing drugs which are instable or sparingly soluble in water and methods for their preparation
US20020094998A1 (en) * 2000-11-01 2002-07-18 Burke James A. Methods and compositions for treatment of ocular neovascularization and neural injury
US6537568B2 (en) * 1997-08-11 2003-03-25 Allergan, Inc. Implant device with a retinoid for improved biocompatibility
US20030060763A1 (en) * 2000-01-06 2003-03-27 Penfold Philip Leslie Guide means for intraocular injection
US20030069286A1 (en) * 2001-05-31 2003-04-10 Bardeen Sciences Co., Llc Hypotensive lipid and timolol compositions and methods of using same
US6565874B1 (en) * 1998-10-28 2003-05-20 Atrix Laboratories Polymeric delivery formulations of leuprolide with improved efficacy
US6565871B2 (en) * 1994-12-02 2003-05-20 Elan Drug Delivery Ltd. Solid dose delivery vehicle and methods of making same
US6573280B2 (en) * 1997-06-30 2003-06-03 Allergan, Inc. Calcium blockers to treat proliferative vitreoretinopathy
US6595945B2 (en) * 2001-01-09 2003-07-22 J. David Brown Glaucoma treatment device and method
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
US20040054374A1 (en) * 2002-09-18 2004-03-18 David Weber Methods and apparatus for delivery of ocular implants
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
US6713268B2 (en) * 2001-06-26 2004-03-30 Allergan, Inc. Methods of identifying ocular hypotensive compounds having reduced hyperpigmentation
US6723353B2 (en) * 1998-09-02 2004-04-20 Allergan, Inc. Preserved cyclodextrin-containing compositions
US20040077562A1 (en) * 2000-11-15 2004-04-22 Chandavarkar Mohan A. Combination drug
US6726918B1 (en) * 2000-07-05 2004-04-27 Oculex Pharmaceuticals, Inc. Methods for treating inflammation-mediated conditions of the eye
US20050101582A1 (en) * 2003-11-12 2005-05-12 Allergan, Inc. Compositions and methods for treating a posterior segment of an eye
US20060009498A1 (en) * 2004-07-12 2006-01-12 Allergan, Inc. Ophthalmic compositions and methods for treating ophthalmic conditions
US20060141049A1 (en) * 2003-11-12 2006-06-29 Allergan, Inc. Triamcinolone compositions for intravitreal administration to treat ocular conditions

Family Cites Families (109)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US621583A (en) * 1899-03-21 Ledger balance-indicator
US3396081A (en) 1965-03-17 1968-08-06 Etapharm Chem Pharm Lab Ges M Hyaluronic acid preparation and method of producing same
US4052505A (en) 1975-05-30 1977-10-04 Alza Corporation Ocular therapeutic system manufactured from copolymer
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
US4063064A (en) 1976-02-23 1977-12-13 Coherent Radiation Apparatus for tracking moving workpiece by a laser beam
US4057619A (en) 1975-06-30 1977-11-08 Alza Corporation Ocular therapeutic system with selected membranes for administering ophthalmic drug
US4285987A (en) 1978-10-23 1981-08-25 Alza Corporation Process for manufacturing device with dispersion zone
US4303637A (en) 1980-04-04 1981-12-01 Alza Corporation Medication indicated for ocular hypertension
US4281654A (en) 1980-04-07 1981-08-04 Alza Corporation Drug delivery system for controlled ocular therapy
US4396625A (en) 1980-05-13 1983-08-02 Sumitomo Chemical Company, Limited Treatment of glaucoma or ocular hypertension and ophthalmic composition
US4304765A (en) 1980-10-14 1981-12-08 Alza Corporation Ocular insert housing steroid in two different therapeutic forms
US4478818A (en) 1982-12-27 1984-10-23 Alza Corporation Ocular preparation housing steroid in two different therapeutic forms
JPS58126435U (en) 1982-02-19 1983-08-27
US5166331A (en) 1983-10-10 1992-11-24 Fidia, S.P.A. Hyaluronics acid fractions, methods for the preparation thereof, and pharmaceutical compositions containing same
US4693885A (en) 1984-07-18 1987-09-15 Nippon Petrochemicals Co., Ltd. Tetrapyrrole therapeutic agents
US4636524A (en) 1984-12-06 1987-01-13 Biomatrix, Inc. Cross-linked gels of hyaluronic acid and products containing such gels
FR2577509B1 (en) 1985-02-21 1987-05-07 Nirvana Espar Systems Sa Mast sailing boat
US5099013A (en) 1985-03-12 1992-03-24 Biomatrix, Inc, Hylan preparation and method of recovery thereof from animal tissues
US4713448A (en) 1985-03-12 1987-12-15 Biomatrix, Inc. Chemically modified hyaluronic acid preparation and method of recovery thereof from animal tissues
CN85102921B (en) 1985-04-05 1988-06-08 菲地亚有限公司 Method of making pharmaceutical hyaluronic acid components and medical therefrom
EP0244178A3 (en) 1986-04-28 1989-02-08 Iolab, Inc Intraocular dosage compositions and method of use
US4959217A (en) 1986-05-22 1990-09-25 Syntex (U.S.A.) Inc. Delayed/sustained release of macromolecules
US4863457A (en) 1986-11-24 1989-09-05 Lee David A Drug delivery device
DE3871639D1 (en) * 1987-07-23 1992-07-09 Philips Nv A display cell.
DE3802158A1 (en) 1987-08-11 1989-02-23 Hoechst Ag A device for application of implants
JPH02112A (en) * 1987-09-18 1990-01-05 Ethicon Inc Gel compound containing growth factor
DE3734223A1 (en) 1987-10-09 1989-04-20 Boehringer Ingelheim Kg An implantable, biodegradable drug-release system
US4853224A (en) 1987-12-22 1989-08-01 Visionex Biodegradable ocular implants
US4865846A (en) 1988-06-03 1989-09-12 Kaufman Herbert E Drug delivery system
US4968715A (en) 1988-07-06 1990-11-06 Health Research, Inc. Use of purified hematoporphyrin trimers in photodynamic therapy
ES2186670T3 (en) 1988-09-06 2003-05-16 Pharmacia Ab Prostaglandin derivatives for the treatment of glaucoma or ocular hypertension.
US5702716A (en) 1988-10-03 1997-12-30 Atrix Laboratories, Inc. Polymeric compositions useful as controlled release implants
US5457183A (en) 1989-03-06 1995-10-10 Board Of Regents, The University Of Texas System Hydroxylated texaphyrins
US5098443A (en) 1989-03-23 1992-03-24 University Of Miami Method of implanting intraocular and intraorbital implantable devices for the controlled release of pharmacological agents
US5171741A (en) 1989-04-21 1992-12-15 Health Research, Inc. Bacteriochlorophyll-a derivatives useful in photodynamic therapy
US5173504A (en) 1989-04-21 1992-12-22 Health Research, Inc. Bacteriochlorophyll-a derivatives useful in photodynamic therapy
US5077049A (en) 1989-07-24 1991-12-31 Vipont Pharmaceutical, Inc. Biodegradable system for regenerating the periodontium
US6271216B1 (en) 1989-07-24 2001-08-07 Allergan Stable solution of hyaluronate in a balanced salt medium
US4981715A (en) * 1989-08-10 1991-01-01 Microelectronics And Computer Technology Corporation Method of patterning electroless plated metal on a polymer substrate
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
US5075115A (en) 1990-04-02 1991-12-24 Fmc Corporation Process for polymerizing poly(lactic acid)
US5232844A (en) 1990-05-15 1993-08-03 New York Blood Center Photodynamic inactivation of viruses in cell-containing compositions
US5256408A (en) 1990-06-12 1993-10-26 Insite Vision Incorporated Aminosteroids for ophthalmic use
US5143724A (en) 1990-07-09 1992-09-01 Biomatrix, Inc. Biocompatible viscoelastic gel slurries, their preparation and use
US5492936A (en) 1990-11-30 1996-02-20 Allergan, Inc. Bimodal molecular weight hyaluronate formulations and methods for using same
US5552160A (en) 1991-01-25 1996-09-03 Nanosystems L.L.C. Surface modified NSAID nanoparticles
US5356629A (en) 1991-07-12 1994-10-18 United States Surgical Corporation Composition for effecting bone repair
US5169638A (en) 1991-10-23 1992-12-08 E. R. Squibb & Sons, Inc. Buoyant controlled release powder formulation
US5656297A (en) 1992-03-12 1997-08-12 Alkermes Controlled Therapeutics, Incorporated Modulated release from biocompatible polymers
WO1993021172A1 (en) 1992-04-09 1993-10-28 Rotta Research Laboratorium S.P.A. Basic derivatives of glutamic acid and aspartic acid as gastrin or cholecystokinin antagonists
US5655832A (en) 1992-04-16 1997-08-12 Tir Technologies, Inc. Multiple wavelength light processor
US5244914A (en) 1992-04-27 1993-09-14 American Cyanamid Company Stable porfimer sodium compositions and methods for their manufacture
US5688819A (en) 1992-09-21 1997-11-18 Allergan Cyclopentane heptanoic acid, 2-cycloalkyl or arylalkyl derivatives as therapeutic agents
US5285887A (en) * 1992-11-23 1994-02-15 Interroll Holding A. G. Accumulating conveyor and control system
US5385887A (en) 1993-09-10 1995-01-31 Genetics Institute, Inc. Formulations for delivery of osteogenic proteins
DE4403326C1 (en) 1994-02-03 1995-06-22 Hans Reinhard Prof Dr Koch An intraocular lens assembly for astigmatism
US5466233A (en) 1994-04-25 1995-11-14 Escalon Ophthalmics, Inc. Tack for intraocular drug delivery and method for inserting and removing same
US6270492B1 (en) 1994-09-09 2001-08-07 Cardiofocus, Inc. Phototherapeutic apparatus with diffusive tip assembly
US5576311A (en) 1994-11-30 1996-11-19 Pharmos Corporation Cyclodextrins as suspending agents for pharmaceutical suspensions
US5565188A (en) 1995-02-24 1996-10-15 Nanosystems L.L.C. Polyalkylene block copolymers as surface modifiers for nanoparticles
US5958954A (en) 1995-09-01 1999-09-28 Allergan Sales, Inc. Synthesis and use of retinoid compounds having negative hormone and/or antagonist activities
US6645945B1 (en) * 1996-03-05 2003-11-11 Depuy Acromed, Inc. Method of treating diseased, injured or abnormal cartilage with hyaluronic acid and growth factors
CA2258920C (en) * 1996-06-21 2003-12-02 Fidia S.P.A. Autocross-linked hyaluronic acid and related pharmaceutical compositions for the treatment of arthropathies
US6270749B1 (en) 1996-12-11 2001-08-07 Pharmacyclics, Inc. Use of Texaphyrin in ocular diagnosis and therapy
US5913970A (en) * 1997-01-16 1999-06-22 Eastman Chemical Company Stabilized non-polymeric acetoacetate esters that promote adhesion to metallic and oxidized substrates
US6274614B1 (en) 1997-02-11 2001-08-14 Qlt Inc. Methods, compositions and articles for reducing or preventing the effects of inflammation
US6271220B1 (en) 1998-03-11 2001-08-07 Allergan Sales, Inc. Anti-angiogenic agents
EP1100366B1 (en) 1998-07-09 2009-04-15 Curelight Medical Ltd Apparatus and method for efficient high energy photodynamic therapy of acne vulgaris and seborrhea
EP1104302A4 (en) 1998-07-10 2006-08-09 Retmed Pty Ltd Prophylactic treatments of neovascularisation in macular degeneration
US20040152664A1 (en) 1998-09-02 2004-08-05 Allergan, Inc. Prednisolone compositions
US6143314A (en) 1998-10-28 2000-11-07 Atrix Laboratories, Inc. Controlled release liquid delivery compositions with low initial drug burst
WO2000030532A1 (en) 1998-11-20 2000-06-02 University Of Connecticut Generic integrated implantable potentiostat telemetry unit for electrochemical sensors
US6482854B1 (en) 1999-03-25 2002-11-19 Massachusetts Eye And Ear Infirmary Glaucoma treatment
US6290713B1 (en) 1999-08-24 2001-09-18 Thomas A. Russell Flexible illuminators for phototherapy
US6317616B1 (en) 1999-09-15 2001-11-13 Neil David Glossop Method and system to facilitate image guided surgery
US6331313B1 (en) 1999-10-22 2001-12-18 Oculex Pharmaceticals, Inc. Controlled-release biocompatible ocular drug delivery implant devices and methods
US6461631B1 (en) 1999-11-16 2002-10-08 Atrix Laboratories, Inc. Biodegradable polymer composition
US6319273B1 (en) 1999-12-16 2001-11-20 Light Sciences Corporation Illuminating device for treating eye disease
CA2398901C (en) 2000-02-10 2010-11-16 Massachusetts Eye And Ear Infirmary Methods and compositions for treating conditions of the eye
CA2414780A1 (en) 2000-07-13 2002-01-24 Tugrul T. Kararli Ophthalmic formulation of a selective cyclooxygenase-2 inhibitory drug
US20020198174A1 (en) 2001-05-07 2002-12-26 Allergan Sales, Inc. Disinfecting and solubilizing steroid compositions
EP1404370A2 (en) 2001-06-08 2004-04-07 Novartis AG Ophthalmic compositions comprising hyaluronic acid
JP2005508336A (en) 2001-09-27 2005-03-31 アラーガン、インコーポレイテッドAllergan,Incorporated Kinase inhibitors as a 3- (aryl) methylene-1,3-dihydro -2h- indol-2-ones
JP2005511576A (en) 2001-11-09 2005-04-28 アイテック・ファーマシューティカルズ A method of treating ocular neovascular disease
US6960346B2 (en) 2002-05-09 2005-11-01 University Of Tennessee Research Foundation Vehicles for delivery of biologically active substances
US20040137059A1 (en) 2003-01-09 2004-07-15 Thierry Nivaggioli Biodegradable ocular implant
WO2004069280A1 (en) 2003-02-06 2004-08-19 Cipla Ltd Pharmaceutical inclusion complexes containing a steroid and optionally an antibacterial agent
EP1670480A4 (en) 2003-02-20 2007-10-10 Alcon Inc Use of steroids to treat ocular disorders
JP2006518769A (en) 2003-02-21 2006-08-17 サン・ファーマシューティカル・インダストリーズ・リミテッドSun Pharmaceutical Industries Limited Stable ophthalmic composition
CN1852700A (en) * 2003-09-23 2006-10-25 爱尔康公司 Triamcinolone acetonide and anecortave acetate formulations for injection
WO2006043965A1 (en) 2004-10-14 2006-04-27 Allergan, Inc. Therapeutic ophthalmic compositions containing retinal friendly excipients and related methods
CN100548271C (en) 2004-01-20 2009-10-14 阿勒根公司 Compositions for localized therapy of the eye, comprising preferably triamcinolone acetonide and hyaluronic acid
US20050244463A1 (en) 2004-04-30 2005-11-03 Allergan, Inc. Sustained release intraocular implants and methods for treating ocular vasculopathies
US7771742B2 (en) 2004-04-30 2010-08-10 Allergan, Inc. Sustained release intraocular implants containing tyrosine kinase inhibitors and related methods
US8425929B2 (en) 2004-04-30 2013-04-23 Allergan, Inc. Sustained release intraocular implants and methods for preventing retinal dysfunction
US20050244466A1 (en) 2004-04-30 2005-11-03 Allergan, Inc. Photodynamic therapy in conjunction with intraocular implants
US8119154B2 (en) 2004-04-30 2012-02-21 Allergan, Inc. Sustained release intraocular implants and related methods
US20050244461A1 (en) 2004-04-30 2005-11-03 Allergan, Inc. Controlled release drug delivery systems and methods for treatment of an eye
US20050244478A1 (en) 2004-04-30 2005-11-03 Allergan, Inc. Anti-excititoxic sustained release intraocular implants and related methods
US20050244458A1 (en) 2004-04-30 2005-11-03 Allergan, Inc. Sustained release intraocular implants and methods for treating ocular neuropathies
US20050244462A1 (en) 2004-04-30 2005-11-03 Allergan, Inc. Devices and methods for treating a mammalian eye
US7799336B2 (en) 2004-04-30 2010-09-21 Allergan, Inc. Hypotensive lipid-containing biodegradable intraocular implants and related methods
US7589057B2 (en) 2004-04-30 2009-09-15 Allergan, Inc. Oil-in-water method for making alpha-2 agonist polymeric drug delivery systems
US20050244465A1 (en) 2004-04-30 2005-11-03 Allergan, Inc. Drug delivery systems and methods for treatment of an eye
US20050244471A1 (en) 2004-04-30 2005-11-03 Allergan, Inc. Estradiol derivative and estratopone containing sustained release intraocular implants and related methods
US20070298073A1 (en) 2006-06-23 2007-12-27 Allergan, Inc. Steroid-containing sustained release intraocular implants and related methods
US8802128B2 (en) 2006-06-23 2014-08-12 Allergan, Inc. Steroid-containing sustained release intraocular implants and related methods

Patent Citations (99)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US385887A (en) * 1888-07-10 Chables sumnbr tainter
US4008864A (en) * 1974-02-18 1977-02-22 Nils Gustav Yngve Torphammar Locking mechanism for a safety belt
US4088864A (en) * 1974-11-18 1978-05-09 Alza Corporation Process for forming outlet passageways in pills using a laser
US4158005A (en) * 1975-02-10 1979-06-12 Interx Research Corporation Intermediates useful in the synthesis of optically active m-acyloxy-α-[(methylamino)methyl]benzyl alcohols
US4014335A (en) * 1975-04-21 1977-03-29 Alza Corporation Ocular drug delivery device
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
US4190642A (en) * 1978-04-17 1980-02-26 Alza Corporation Ocular therapeutic system for dispensing a medication formulation
US4200098A (en) * 1978-10-23 1980-04-29 Alza Corporation Osmotic system with distribution zone for dispensing beneficial agent
US4425346A (en) * 1980-08-01 1984-01-10 Smith And Nephew Associated Companies Limited Pharmaceutical compositions
US4327725A (en) * 1980-11-25 1982-05-04 Alza Corporation Osmotic device with hydrogel driving member
US4383992A (en) * 1982-02-08 1983-05-17 Lipari John M Water-soluble steroid compounds
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
US5028621A (en) * 1982-09-27 1991-07-02 Health Research, Inc. Drugs comprising porphyrins
US4649151A (en) * 1982-09-27 1987-03-10 Health Research, Inc. Drugs comprising porphyrins
US4932934A (en) * 1982-09-27 1990-06-12 Health Research, Inc. Methods for treatment of tumors
US4521210A (en) * 1982-12-27 1985-06-04 Wong Vernon G Eye implant for relieving glaucoma, and device and method for use therewith
US4727064A (en) * 1984-04-25 1988-02-23 The United States Of America As Represented By The Department Of Health And Human Services Pharmaceutical preparations containing cyclodextrin derivatives
US4675338A (en) * 1984-07-18 1987-06-23 Nippon Petrochemicals Co., Ltd. Tetrapyrrole therapeutic agents
US5128326A (en) * 1984-12-06 1992-07-07 Biomatrix, Inc. Drug delivery systems based on hyaluronans derivatives thereof and their salts and methods of producing same
US4656186A (en) * 1985-04-30 1987-04-07 Nippon Petrochemicals Co., Ltd. Tetrapyrrole therapeutic agents
US6407079B1 (en) * 1985-07-03 2002-06-18 Janssen Pharmaceutica N.V. Pharmaceutical compositions containing drugs which are instable or sparingly soluble in water and methods for their preparation
US4668506A (en) * 1985-08-16 1987-05-26 Bausch & Lomb Incorporated Sustained-release formulation containing and amino acid polymer
US5017579A (en) * 1986-02-14 1991-05-21 Sanofi Use of aminoalkoxyphenyl derivatives for reducing and/or controlling excessive intraocular pressure
US5106615A (en) * 1986-10-14 1992-04-21 Shabtay Dikstein Eyedrops having non-newtonian rheological properties
US4981871A (en) * 1987-05-15 1991-01-01 Abelson Mark B Treatment of ocular hypertension with class I calcium channel blocking agents
US4997652A (en) * 1987-12-22 1991-03-05 Visionex Biodegradable ocular implants
US4920104A (en) * 1988-05-16 1990-04-24 Medchem Products, Inc. Sodium hyaluronate composition
US5190966A (en) * 1988-07-06 1993-03-02 Health Research, Inc. Purified hematoporphyrin dimers and trimers useful in photodynamic therapy
US5314905A (en) * 1988-07-20 1994-05-24 Health Research, Inc. Pyropheophorbides conjugates and their use in photodynamic therapy
US5198460A (en) * 1988-07-20 1993-03-30 Health Research Inc. Pyropheophorbides and their use in photodynamic therapy
US5002962A (en) * 1988-07-20 1991-03-26 Health Research, Inc. Photosensitizing agents
US5093349A (en) * 1988-07-20 1992-03-03 Health Research Inc. Photosensitizing agents
US5089509A (en) * 1988-09-15 1992-02-18 Allergan, Inc. Disubstituted acetylenes bearing heteroaromatic and heterobicyclic groups having retinoid like activity
US4935498A (en) * 1989-03-06 1990-06-19 Board Of Regents, The University Of Texas System Expanded porphyrins: large porphyrin-like tripyrroledimethine-derived macrocycles
US5019400A (en) * 1989-05-01 1991-05-28 Enzytech, Inc. Very low temperature casting of controlled release microspheres
US5324519A (en) * 1989-07-24 1994-06-28 Atrix Laboratories, Inc. Biodegradable polymer composition
US5487897A (en) * 1989-07-24 1996-01-30 Atrix Laboratories, Inc. Biodegradable implant precursor
US5034413A (en) * 1989-07-27 1991-07-23 Allergan, Inc. Intraocular pressure reducing 9,11-diacyl prostaglandins
US6258319B1 (en) * 1989-10-26 2001-07-10 Cerus Corporation Device and method for photoactivation
US5332582A (en) * 1990-06-12 1994-07-26 Insite Vision Incorporated Stabilization of aminosteroids for topical ophthalmic and other applications
US5209926A (en) * 1990-06-12 1993-05-11 Insite Vision Incorporated Aminosteroids for ophthalmic use
US5100431A (en) * 1990-09-27 1992-03-31 Allergan, Inc. Single stitch suture needle and method
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
US5882682A (en) * 1991-12-27 1999-03-16 Merck & Co., Inc. Controlled release simvastatin delivery device
US5300114A (en) * 1992-05-04 1994-04-05 Allergan, Inc. Subconjunctival implants for ocular drug delivery
US6217869B1 (en) * 1992-06-09 2001-04-17 Neorx Corporation Pretargeting methods and compounds
US5324718A (en) * 1992-07-14 1994-06-28 Thorsteinn Loftsson Cyclodextrin/drug complexation
US6403649B1 (en) * 1992-09-21 2002-06-11 Allergan Sales, Inc. Non-acidic cyclopentane heptanoic acid,2-cycloalkyl or arylalkyl derivatives as therapeutic agents
US5922773A (en) * 1992-12-04 1999-07-13 The Children's Medical Center Corp. Glaucoma treatment
US5494901A (en) * 1993-01-05 1996-02-27 Javitt; Jonathan C. Topical compositions for the eye comprising a β-cyclodextrin derivative and a therapeutic agent
US5707643A (en) * 1993-02-26 1998-01-13 Santen Pharmaceutical Co., Ltd. Biodegradable scleral plug
US5770589A (en) * 1993-07-27 1998-06-23 The University Of Sydney Treatment of macular degeneration
US5504074A (en) * 1993-08-06 1996-04-02 Children's Medical Center Corporation Estrogenic compounds as anti-angiogenic agents
US5747061A (en) * 1993-10-25 1998-05-05 Pharmos Corporation Suspension of loteprednol etabonate for ear, eye, or nose treatment
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
US5516522A (en) * 1994-03-14 1996-05-14 Board Of Supervisors Of Louisiana State University Biodegradable porous device for long-term drug delivery with constant rate release and method of making the same
US6225303B1 (en) * 1994-03-14 2001-05-01 Massachusetts Eye And Ear Infirmary Use of green porphyrins to treat neovasculature in the eye
US5780044A (en) * 1994-04-08 1998-07-14 Atrix Laboratories, Inc. Liquid delivery compositions
US5717030A (en) * 1994-04-08 1998-02-10 Atrix Laboratories, Inc. Adjunctive polymer system for use with medical device
US6565871B2 (en) * 1994-12-02 2003-05-20 Elan Drug Delivery Ltd. Solid dose delivery vehicle and methods of making same
US20030095995A1 (en) * 1995-06-02 2003-05-22 Vernon Wong Formulation for controlled release of drugs by combining hydrophilic 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
US5906920A (en) * 1995-08-29 1999-05-25 The Salk Institute For Biological Studies Methods for the detection of ligands for retinoid X receptors
US5776699A (en) * 1995-09-01 1998-07-07 Allergan, Inc. Method of identifying negative hormone and/or antagonist activities
US5877207A (en) * 1996-03-11 1999-03-02 Allergan Sales, Inc. Synthesis and use of retinoid compounds having negative hormone and/or antagonist activities
US6066675A (en) * 1996-09-13 2000-05-23 The Regents Of The University Of California Method for treatment of retinal diseases
US5913884A (en) * 1996-09-19 1999-06-22 The General Hospital Corporation Inhibition of fibrosis by photodynamic therapy
US5919970A (en) * 1997-04-24 1999-07-06 Allergan Sales, Inc. Substituted diaryl or diheteroaryl methanes, ethers and amines having retinoid agonist, antagonist or inverse agonist type biological activity
US6573280B2 (en) * 1997-06-30 2003-06-03 Allergan, Inc. Calcium blockers to treat proliferative vitreoretinopathy
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
US6387409B1 (en) * 1998-03-30 2002-05-14 Rtp Pharma Inc. Composition and method of preparing microparticles of water-insoluble substances
US6261583B1 (en) * 1998-07-28 2001-07-17 Atrix Laboratories, Inc. Moldable solid delivery system
US6723353B2 (en) * 1998-09-02 2004-04-20 Allergan, Inc. Preserved cyclodextrin-containing compositions
US6565874B1 (en) * 1998-10-28 2003-05-20 Atrix Laboratories Polymeric delivery formulations of leuprolide with improved efficacy
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
US20030060763A1 (en) * 2000-01-06 2003-03-27 Penfold Philip Leslie Guide means for intraocular injection
US6395294B1 (en) * 2000-01-13 2002-05-28 Gholam A. Peyman Method of visualization of the vitreous during vitrectomy
US6726918B1 (en) * 2000-07-05 2004-04-27 Oculex Pharmaceuticals, Inc. Methods for treating inflammation-mediated conditions of the eye
US6357568B1 (en) * 2000-09-27 2002-03-19 Shou Mao Chen Structure for protecting a luggage shell
US20020094998A1 (en) * 2000-11-01 2002-07-18 Burke James A. Methods and compositions for treatment of ocular neovascularization and neural injury
US20040077562A1 (en) * 2000-11-15 2004-04-22 Chandavarkar Mohan A. Combination drug
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
US6595945B2 (en) * 2001-01-09 2003-07-22 J. David Brown Glaucoma treatment device and method
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
US20030069286A1 (en) * 2001-05-31 2003-04-10 Bardeen Sciences Co., Llc Hypotensive lipid and timolol compositions and methods of using same
US6713268B2 (en) * 2001-06-26 2004-03-30 Allergan, Inc. Methods of identifying ocular hypotensive compounds having reduced hyperpigmentation
US20040054374A1 (en) * 2002-09-18 2004-03-18 David Weber Methods and apparatus for delivery of ocular implants
US6899717B2 (en) * 2002-09-18 2005-05-31 Allergan, Inc. Methods and apparatus for delivery of ocular implants
US20060141049A1 (en) * 2003-11-12 2006-06-29 Allergan, Inc. Triamcinolone compositions for intravitreal administration to treat ocular conditions
US20050101582A1 (en) * 2003-11-12 2005-05-12 Allergan, Inc. Compositions and methods for treating a posterior segment of an eye
US20060009498A1 (en) * 2004-07-12 2006-01-12 Allergan, Inc. Ophthalmic compositions and methods for treating ophthalmic conditions

Cited By (75)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8563532B2 (en) 2003-04-10 2013-10-22 Allergan Industrie Sas Cross-linking of low-molecular weight and high-molecular weight polysaccharides, preparation of injectable monophase hydrogels, polysaccharides and hydrogels obtained
US8338388B2 (en) 2003-04-10 2012-12-25 Allergan, Inc. Cross-linking of low-molecular weight and high-molecular weight polysaccharides, preparation of injectable monophase hydrogels, polysaccharides and hydrogels obtained
US9788995B2 (en) 2006-05-02 2017-10-17 Georgia Tech Research Corporation Methods and devices for drug delivery to ocular tissue using microneedle
US8338375B2 (en) 2007-05-23 2012-12-25 Allergan, Inc. Packaged product
US20090036403A1 (en) * 2007-07-30 2009-02-05 Allergan, Inc. Tunably Crosslinked Polysaccharide Compositions
US8318695B2 (en) 2007-07-30 2012-11-27 Allergan, Inc. Tunably crosslinked polysaccharide compositions
US8703118B2 (en) 2007-10-09 2014-04-22 Allergan, Inc. Crossed-linked hyaluronic acid and collagen and uses thereof
US8697044B2 (en) 2007-10-09 2014-04-15 Allergan, Inc. Crossed-linked hyaluronic acid and collagen and uses thereof
US9265761B2 (en) 2007-11-16 2016-02-23 Allergan, Inc. Compositions and methods for treating purpura
US8394784B2 (en) 2007-11-30 2013-03-12 Allergan, Inc. Polysaccharide gel formulation having multi-stage bioactive agent delivery
US8513216B2 (en) 2007-11-30 2013-08-20 Allergan, Inc. Polysaccharide gel formulation having increased longevity
US8394783B2 (en) 2007-11-30 2013-03-12 Allergan, Inc. Polysaccharide gel formulation having multi-stage bioactive agent delivery
US8853184B2 (en) 2007-11-30 2014-10-07 Allergan, Inc. Polysaccharide gel formulation having increased longevity
US8394782B2 (en) 2007-11-30 2013-03-12 Allergan, Inc. Polysaccharide gel formulation having increased longevity
US20130136780A1 (en) * 2007-11-30 2013-05-30 Allergan, Inc. Crosslinked polysaccharide gel compositions for medical and cosmetic applications
US9050336B2 (en) 2007-12-12 2015-06-09 Allergan, Inc. Botulinum toxin formulation
US8128960B2 (en) 2008-03-11 2012-03-06 Alcon Research, Ltd. Low viscosity, highly flocculated triamcinolone acetonide suspensions for intravitreal injection
US8211880B2 (en) 2008-03-11 2012-07-03 Alcon Research, Ltd. Low viscosity, highly flocculated triamcinolone acetonide suspensions for intravitreal injection
US20130150410A1 (en) * 2008-07-21 2013-06-13 The Regents Of The University Of California Controlled Release Ion Channel Modulator Compositions and Methods for the Treatment of Otic Disorders
US9089518B2 (en) 2008-08-04 2015-07-28 Allergan Industrie Sas Hyaluronic acid-based gels including lidocaine
US20100028437A1 (en) * 2008-08-04 2010-02-04 Lebreton Pierre F Hyaluronic Acid-Based Gels Including Lidocaine
US8357795B2 (en) 2008-08-04 2013-01-22 Allergan, Inc. Hyaluronic acid-based gels including lidocaine
US9089517B2 (en) 2008-08-04 2015-07-28 Allergan Industrie Sas Hyaluronic acid-based gels including lidocaine
US9089519B2 (en) 2008-08-04 2015-07-28 Allergan Industrie Sas Hyaluronic acid-based gels including lidocaine
US9238013B2 (en) 2008-08-04 2016-01-19 Allergan Industrie, Sas Hyaluronic acid-based gels including lidocaine
US8450475B2 (en) 2008-08-04 2013-05-28 Allergan, Inc. Hyaluronic acid-based gels including lidocaine
US9358322B2 (en) 2008-08-04 2016-06-07 Allergan Industrie Sas Hyaluronic acid-based gels including lidocaine
US8822676B2 (en) 2008-08-04 2014-09-02 Allergan Industrie, Sas Hyaluronic acid-based gels including lidocaine
US9228027B2 (en) 2008-09-02 2016-01-05 Allergan Holdings France S.A.S. Threads of Hyaluronic acid and/or derivatives thereof, methods of making thereof and uses thereof
US9861570B2 (en) 2008-09-02 2018-01-09 Allergan Holdings France S.A.S. Threads of hyaluronic acid and/or derivatives thereof, methods of making thereof and uses thereof
US20100098772A1 (en) * 2008-10-21 2010-04-22 Allergan, Inc. Drug delivery systems and methods for treating neovascularization
US8771745B2 (en) 2008-10-27 2014-07-08 Allergan, Inc. Prostaglandin and prostamide drug delivery systems and intraocular therapeutic uses thereof
US20100278897A1 (en) * 2009-05-01 2010-11-04 Allergan, Inc. Intraocular bioactive agent delivery system with molecular partitioning system
WO2010132730A2 (en) * 2009-05-14 2010-11-18 Surmodics Pharmaceuticals, Inc. Hyaluronic acid (ha) injection vehicle
US20100291027A1 (en) * 2009-05-14 2010-11-18 Jason Campbell Hyaluronic acid (ha) injection vehicle
WO2010132730A3 (en) * 2009-05-14 2011-01-06 Surmodics Pharmaceuticals, Inc. Hyaluronic acid (ha) injection vehicle
WO2011075481A1 (en) 2009-12-16 2011-06-23 Allergan, Inc. Intracameral devices for sustained delivery
US9114188B2 (en) 2010-01-13 2015-08-25 Allergan, Industrie, S.A.S. Stable hydrogel compositions including additives
US8946192B2 (en) 2010-01-13 2015-02-03 Allergan, Inc. Heat stable hyaluronic acid compositions for dermatological use
US9855367B2 (en) 2010-01-13 2018-01-02 Allergan Industrie, Sas Heat stable hyaluronic acid compositions for dermatological use
US9655991B2 (en) 2010-01-13 2017-05-23 Allergan Industrie, S.A.S. Stable hydrogel compositions including additives
US9333160B2 (en) 2010-01-13 2016-05-10 Allergan Industrie, Sas Heat stable hyaluronic acid compositions for dermatological use
US9504696B2 (en) 2010-01-22 2016-11-29 Allergan, Inc. Intracameral sustained release therapeutic agent implants
US20110182966A1 (en) * 2010-01-22 2011-07-28 Allergan, Inc. Intracameral sustained release therapeutic agent implants
US8647659B2 (en) 2010-01-22 2014-02-11 Allergan, Inc. Intracameral sustained release therapeutic agent implants
US9125840B2 (en) 2010-03-12 2015-09-08 Allergan Industrie Sas Methods for improving skin conditions
US20110224164A1 (en) * 2010-03-12 2011-09-15 Allergan Industrie, Sas Fluid compositions for improving skin conditions
US9585821B2 (en) 2010-03-12 2017-03-07 Allergan Industrie Sas Methods for making compositions for improving skin conditions
US8921338B2 (en) 2010-03-12 2014-12-30 Allergan Industrie, Sas Fluid compositions for improving skin conditions
US8586562B2 (en) 2010-03-12 2013-11-19 Allergan Industrie, Sas Fluid compositions for improving skin conditions
US8691279B2 (en) 2010-03-22 2014-04-08 Allergan, Inc. Polysaccharide and protein-polysaccharide cross-linked hydrogels for soft tissue augmentation
US9480775B2 (en) 2010-03-22 2016-11-01 Allergan, Inc. Polysaccharide and protein-polysaccharide cross-linked hydrogels for soft tissue augmentation
US20110229574A1 (en) * 2010-03-22 2011-09-22 Allergan, Inc. Polysaccharide and protein-polysaccharide cross-linked hydrogels for soft tissue augmentation
US9012517B2 (en) 2010-03-22 2015-04-21 Allergan, Inc. Polysaccharide and protein-polysaccharide cross-linked hydrogels for soft tissue augmentation
US8697057B2 (en) 2010-08-19 2014-04-15 Allergan, Inc. Compositions and soft tissue replacement methods
US8889123B2 (en) 2010-08-19 2014-11-18 Allergan, Inc. Compositions and soft tissue replacement methods
US9005605B2 (en) 2010-08-19 2015-04-14 Allergan, Inc. Compositions and soft tissue replacement methods
US8883139B2 (en) 2010-08-19 2014-11-11 Allergan Inc. Compositions and soft tissue replacement methods
US9149422B2 (en) 2011-06-03 2015-10-06 Allergan, Inc. Dermal filler compositions including antioxidants
US9408797B2 (en) 2011-06-03 2016-08-09 Allergan, Inc. Dermal filler compositions for fine line treatment
US9962464B2 (en) 2011-06-03 2018-05-08 Allergan, Inc. Dermal filler compositions including antioxidants
US9393263B2 (en) 2011-06-03 2016-07-19 Allergan, Inc. Dermal filler compositions including antioxidants
US9737633B2 (en) 2011-06-03 2017-08-22 Allergan, Inc. Dermal filler compositions including antioxidants
US9821086B2 (en) 2011-09-06 2017-11-21 Allergan, Inc. Hyaluronic acid-collagen matrices for dermal filling and volumizing applications
US9795711B2 (en) 2011-09-06 2017-10-24 Allergan, Inc. Hyaluronic acid-collagen matrices for dermal filling and volumizing applications
CN104010578A (en) * 2011-12-20 2014-08-27 血管诊疗公司 Hyaluronic acid and use for treating venous insufficiency and varicose veins
WO2013092860A3 (en) * 2011-12-20 2013-12-05 Angioclinic Ag Hyaluronic acid and its use for treating venous insufficiency and varicose veins
EP2606828A1 (en) * 2011-12-20 2013-06-26 Angioclinic AG Hyaluronic acid and its use for treating venous insufficiency and varicose veins
US9730887B2 (en) 2011-12-20 2017-08-15 Angioclinic Ag Hyaluronic acid and its use for treating venous insufficiency and varicose veins
US9241829B2 (en) 2011-12-20 2016-01-26 Abbott Medical Optics Inc. Implantable intraocular drug delivery apparatus, system and method
US9572800B2 (en) 2012-11-08 2017-02-21 Clearside Biomedical, Inc. Methods and devices for the treatment of ocular diseases in human subjects
US9931330B2 (en) 2012-11-08 2018-04-03 Clearside Biomedical, Inc. Methods and devices for the treatment of ocular diseases in human subjects
US9636332B2 (en) 2012-11-08 2017-05-02 Clearside Biomedical, Inc. Methods and devices for the treatment of ocular diseases in human subjects
CN104667287A (en) * 2013-11-27 2015-06-03 山东博士伦福瑞达制药有限公司 Eye-use composition for treating posterior chamber new vessel hyperplasia and application of eye-use composition
WO2015095772A3 (en) * 2013-12-20 2015-08-13 Emory University Formulations and methods for targeted ocular delivery of therapeutic agents

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