WO2006117666A2 - Dosage forms, pharmaceutical compositions and methods for sub-tenon delivery - Google Patents

Dosage forms, pharmaceutical compositions and methods for sub-tenon delivery Download PDF

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Publication number
WO2006117666A2
WO2006117666A2 PCT/IB2006/001158 IB2006001158W WO2006117666A2 WO 2006117666 A2 WO2006117666 A2 WO 2006117666A2 IB 2006001158 W IB2006001158 W IB 2006001158W WO 2006117666 A2 WO2006117666 A2 WO 2006117666A2
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WO
WIPO (PCT)
Prior art keywords
formula
compound
tenon
sub
mammal
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PCT/IB2006/001158
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French (fr)
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WO2006117666A3 (en
Inventor
Channing Rodney Beals
Wesley Warren Day
Deborah Anne Khalil
Karen Jean Klamerus
Susan Renee Raber
Baldo Scassellati-Sorzolini
Samuel Hyman Zwillich
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Pfizer Inc.
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Publication of WO2006117666A2 publication Critical patent/WO2006117666A2/en
Publication of WO2006117666A3 publication Critical patent/WO2006117666A3/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents

Definitions

  • the present invention relates to drug delivery, and in particular to pharmaceutical compositions, dosage forms, and methods for the delivery of pharmaceutically active agents to the back of the eye. More particularly, the present invention relates to dosage forms of pharmaceutical compositions and methods for sub-Tenon delivery of pharmaceutically active agents to the posterior segment of the eye proximate the macula.
  • posterior segment disease is to a significant extent limited by the difficulty in delivering effective doses of drugs to target tissues in the posterior eye.
  • Four approaches may be used to deliver drugs to the posterior segment including topical, systemic, intraocular, and periocular (including sub-Tenon, subconjunctival, and retrobulbar) delivery.
  • Topically applied drugs may enter the eye by crossing the conjunctiva and then diffusing through the sclera, but this approach typically does not yield therapeutic drug levels in the posterior vitreous, retina, or choroids.
  • systemic administration can deliver drugs to the posterior of the eye, the large systemic doses necessary are often associated with significant side effects.
  • Intravitreal injections provides the most direct approach to delivering drugs to the tissues of the posterior segment, and therapeutic tissue drug levels can be achieved, however, the inherent potential side effects of retinal detachment, hemorrhage, endophthalmitis, and cataract remain, and the often required frequent injections are not always well tolerated by the patient. Furthermore, drugs injected directly into the vitreous are rapidly eliminated. Intravitreal sustained-release devices have been used to avoid repeated injections. These devices, however, require intraocular surgery, must be replaced periodically, and have potential side effects similar to those associated with intravitreal injection. Periocular drug delivery using sub-Tenon, subconjunctival or retrobulbal injections, and placement of sustained-release devices provides alternate routes for delivering drugs to the posterior tissues of the eye. This approach to drug delivery is safer and less invasive than intravitreal injection and also offers the potential for localized, sustained-release drug delivery.
  • Drug delivery by this vector ideally would be transscleral and thus could take advantage of the large surface area of the sclera.
  • the average 17-cm 2 surface area of the sclera accounts for 95% of the total surface area of the globe and provides a significantly larger avenue for drug diffusion to the inside of the eye than the 1-cm 2 surface area of the cornea.
  • regional differences in scleral thickness could be used to further optimize transscleral drug diffusion if sustained-release delivery devices or systems could be placed in regions where scleral permeability was greatest.
  • the sclera for example, is 1.0 mm thick near the optic nerve and an average of 0.53 mm thick at the corneoscleral limbus and thins to an average of 0.39 mm at the equator, where it can be as thin as 0.1 mm in a significant number of eyes. Further, an increasing body of evidence suggests that the sclera is quite permeable to a wide range of solutes and holds significant potential for posterior segment drug delivery.
  • the present invention relates to indazole compounds, pharmaceutical compositions containing such compounds, and methods of using such compounds to mediate and/or inhibit the activity of certain protein kinases for the treatment of disease states associated with angiogenesis and/or cellular proliferation including neovascular ocular diseases such as age-related macular degeneration. More particularly, the present invention relates to dosage forms of such compounds and compositions for sub-Tenon delivery to the posterior segment of the eye proximate the macula.
  • Indazole compounds useful in the compositions, dosage forms and methods described herein are disclosed in U.S. Patent Nos. 6,531,491; 6,534,524; and 6,869,962; U.S. Patent Application Nos. 10/737,655 and 10/796226; and U.S. Provisional Patent Application No. 60/620,394, the disclosures of each are hereby incorporated by reference in their entirety for all purposes. In particular, these patents and applications disclose compounds having Formula I 1
  • the compounds of Formula I, Il and III are tyrosine kinase inhibitors intended for the treatment of age-related macular degeneration. Typically, these compounds are formulated as compositions of sterile suspensions and administered to the back of the posterior segment of the eye proximate the macula via sub-Tenon injection. Currently, formulations of these compounds are being developed for Phase III studies and subsequent commercialization.
  • the therapeutically effective dose of the compounds of Formula I, Il or III may be administered to the mammal via sub-Tenon, intraocular, systemic or topical delivery.
  • the therapeutically effective dose of the compounds of Formula I 1 Il or III may be administered to one or both eyes at the same time or at different intervals.
  • the invention provides dosage forms comprising a compound of Formula I, Il or III or a pharmaceutically acceptable salt or solvate thereof, wherein the compound of Formula I 1 Il or III is from about 1 ⁇ g to about 1 ,500 ⁇ g. 6 001158
  • the invention provides dosage forms, wherein the dosage form further comprises one or more pharmaceutically acceptable excipients.
  • the invention provides dosage forms, wherein the compound of Formula I, Il or III is from about 50 ⁇ g to about 1 ,000 ⁇ g. In another aspect, the invention provides dosage forms, wherein the compound of Formula I, Il or III is from about 100 ⁇ g to about 600 ⁇ g.
  • the invention provides dosage forms, wherein the compound of Formula I, Il or III is about 1 ⁇ g.
  • the invention provides dosage forms, wherein the compound of Formula I, Il or III is about 50 ⁇ g.
  • the invention provides dosage forms, wherein the compound of Formula I, Il or III is about 100 ⁇ g.
  • the invention provides dosage forms, wherein the compound of Formula I, Il or III is about 150 ⁇ g. In another aspect, the invention provides dosage forms, wherein the compound of Formula I, Il or III is about 300 ⁇ g.
  • the invention provides dosage forms, wherein the compound of Formula I, Il or III is about 600 ⁇ g.
  • the invention provides dosage forms, wherein the compound of Formula I, Il or III is about 1 ,000 ⁇ g.
  • the invention provides dosage forms, wherein the compound of Formula I, Il or III is about 1,500 ⁇ g.
  • the invention provides methods for treating ocular diseases in a mammal, comprising administering to the mammal a composition comprising a therapeutically effective amount of a compound of Formula I, Il or III or a pharmaceutically acceptable salt or solvate thereof, wherein the therapeutically effective amount is about 1 ⁇ g to about 1,500 ⁇ g.
  • the invention provides methods for treating ocular diseases in a mammal, wherein the composition further comprises one or more pharmaceutically acceptable excipients.
  • the invention provides methods for treating ocular diseases in a mammal, wherein the composition is administered by sub-Tenon delivery to the eye.
  • the invention provides methods for treating ocular diseases in a mammal, wherein the ocular disease is selected from age related macular degeneration (AMD) including nonexudative (Dry AMD) and exudative (Wet AMD), choroidal neovascularization, retinopathies such as diabetic retinopathy and retinopathy of prematurity, diabetic macular edema, retinitis, uveitis, cystoid macular edema, glaucoma, and other diseases or conditions of the posterior segment of the eye.
  • AMD age related macular degeneration
  • Wet AMD exudative
  • retinopathies such as diabetic retinopathy and retinopathy of prematurity
  • diabetic macular edema retinitis
  • uveitis cystoid macular edema
  • cystoid macular edema cystoid macular edema
  • glaucoma glaucoma
  • the invention provides methods for treating ocular diseases in a mammal, wherein the therapeutically effective amount is from about 100 ⁇ g to about 600 ⁇ g-
  • the invention provides methods for treating ocular diseases in a mammal, wherein the therapeutically effective amount is about 1 ⁇ g.
  • the invention provides methods for treating ocular diseases in a mammal, wherein the therapeutically effective amount is about 50 ⁇ g.
  • the invention provides methods for treating ocular diseases in a mammal, wherein the therapeutically effective amount is about 100 ⁇ g.
  • the invention provides methods for treating ocular diseases in a mammal, wherein the therapeutically effective amount is about 150 ⁇ g. In another aspect, the invention provides methods for treating ocular diseases in a mammal, wherein the therapeutically effective amount is about 300 ⁇ g.
  • the invention provides methods for treating ocular diseases in a. mammal, wherein the therapeutically effective amount is about 600 ⁇ g.
  • the invention provides methods for treating ocular diseases in a mammal, wherein the therapeutically effective amount is about 1 ,000 ⁇ g.
  • the invention provides methods for treating ocular diseases in a mammal, wherein the therapeutically effective amount is about 1,500 ⁇ g.
  • the invention provides methods for treating ocular diseases in a mammal, wherein the therapeutically effective amount is about 50 ⁇ g/eye to about 600 ⁇ g/eye.
  • the invention provides methods for treating ocular diseases in a mammal, wherein the therapeutically effective amount is about 150 ⁇ g/eye.
  • the invention provides methods for treating ocular diseases in a mammal, wherein the composition is administered 12 times/year. In another aspect, the invention provides methods for treating ocular diseases in a mammal, wherein the composition is administered 4 times/year.
  • the invention provides methods for treating ocular diseases in a mammal, wherein the composition is administered 3 times/year.
  • the invention provides methods for treating ocular diseases in a mammal, wherein the composition is administered 2 times/year.
  • the invention provides methods for treating ocular diseases in a mammal, wherein the composition is administered 1 time/year.
  • the invention provides methods for stabilizing visual acuity in a mammal, comprising administering the dosage forms of the invention. In another aspect, the invention provides methods for improving visual acuity in a mammal, comprising administering the dosage forms of the invention.
  • the invention provides methods for preventing ocular diseases, comprising administering the dosage forms of the invention. In another aspect, the invention provides methods for preventing ocular diseases, wherein the ocular disease is ocular neovascularization.
  • the invention provides methods for treating cancer in a mammal, comprising administering to the mammal a composition comprising a therapeutically effective amount of a compound of Formula I 1 Il or III or a pharmaceutically acceptable salt or solvate thereof, wherein the compound of Formula I, Il or III is from about 1 ⁇ g to about 1 ,500 ⁇ g.
  • the invention provides methods for treating cancer, wherein the composition further comprises one or more pharmaceutically acceptable excipients.
  • the invention provides pharmaceutical compositions, comprising a pharmaceutically active agent having Formula I 1 Il or III, or a pharmaceutically acceptable salt or solvate thereof; one or more excipients; and one or more buffers, wherein the tonicity and pH of the composition are adjusted to physiological conditions; and wherein the composition is for sub-Tenon delivery to the posterior segment of the eye proximate the macula.
  • the invention provides pharmaceutical compositions, wherein one or more excipients is a flocculating agent.
  • the invention provides pharmaceutical compositions, wherein the flocculating agent is about 0.001% to about 10% benzalkonium chloride.
  • the invention provides pharmaceutical compositions, wherein the flocculating agent is about 0.02% benzalkonium chloride; and the tonicity of the composition is adjusted to physiological conditions with about 4.5% mannitol.
  • the invention provides pharmaceutical compositions, wherein the buffer is about a 10 mM PBS buffer.
  • the invention provides pharmaceutical compositions, comprising from about 0.01 mg/mL to about 2 mg/mL of a pharmaceutically active agent having Formula I, Il or III. In another aspect, the invention provides pharmaceutical compositions, comprising from about 0.1 mg/mL to about 1.2 mg/mL of a pharmaceutically active agent having Formula I 1 Il or III; about 0.02% benzalkonium chloride; about 10 mM PBS buffer; and the tonicity of the composition is adjusted to physiological conditions with about 4.5% mannitol. In another aspect, the invention provides pharmaceutical compositions, wherein the flocculating agent is about 0.001% to about 10% docusate sodium.
  • the invention provides pharmaceutical compositions, comprising about 0.005% docusate sodium; and the tonicity of the composition is adjusted to physiological conditions with about 0.9% NaCI.
  • the invention provides pharmaceutical compositions, wherein the buffer is about a 10 mM PBS buffer.
  • the invention provides pharmaceutical compositions, comprising from about 0.01 mg/mL to about 2 mg/mL of a pharmaceutically active agent having Formula I, Il or III.
  • the invention provides pharmaceutical compositions, comprising from about 0.1 mg/mL to about 1.2 mg/mL of a pharmaceutically active agent having Formula I, Il or III; about 0.005% docusate sodium; about 10 mM PBS buffer; and the tonicity of the composition is adjusted to physiological conditions with about 0.9% NaCI.
  • the invention provides pharmaceutical compositions, wherein the flocculating agent is about 0.001% to about 10% sodium lauryl sulfate.
  • the invention provides pharmaceutical compositions, comprising about 0.01% sodium lauryl sulfate; and the tonicity of the composition is adjusted to physiological conditions with about 4% mannitol and about 0.2% MgCI.
  • the invention provides pharmaceutical compositions, wherein the buffer is about a 10 mM PBS buffer.
  • the invention provides pharmaceutical compositions, comprising from about 0.01 mg/mL to about 2 mg/mL of a pharmaceutically active agent having Formula I, Il or III.
  • the invention provides pharmaceutical compositions, comprising from about 0.1 mg/mL to about 1.2 mg/mL of a pharmaceutically active agent having Formula I, Il or III; about 0.01% sodium lauryl sulfate; about 10 mM PBS buffer; and the tonicity of the composition is adjusted to physiological conditions with about 4% mannitol and about 0.2% MgCI.
  • the invention provides pharmaceutical compositions, wherein the pharmaceutically active agent is an angiogenesis inhibitor.
  • the invention provides pharmaceutical compositions, wherein the angiogenesis inhibitor is an inhibitor of a protein kinase receptor. In another aspect, the invention provides pharmaceutical compositions, wherein the protein kinase receptor is a VEGF receptor.
  • the invention provides methods for sub-Tenon delivery of pharmaceutical compositions to the posterior of the eye proximate the macula, comprising a pharmaceutically active agent having Formula I, Il or III, or a pharmaceutically acceptable salt or solvate thereof; one or more excipients; and one or more buffers, wherein the tonicity and pH of the composition are adjusted to physiological conditions.
  • the invention provides methods for sub-Tenon delivery of pharmaceutical compositions, wherein one or more excipients is a flocculating agent.
  • the invention provides methods for sub-Tenon delivery of pharmaceutical compositions, wherein the flocculating agent is about 0.001% to about 10% benzalkonium chloride.
  • the invention provides methods for sub-Tenon delivery of pharmaceutical compositions, comprising about 0.02% benzalkonium chloride; and the tonicity of the composition is adjusted to physiological conditions with about 4.5% mannitol.
  • the invention provides methods for sub-Tenon delivery of pharmaceutical compositions, wherein the buffer is about a 10 mM PBS buffer. In another aspect, the invention provides methods for sub-Tenon delivery of pharmaceutical compositions, comprising from about 0.01 mg/mL to about 2 mg/mL of a pharmaceutically active agent having Formula I 1 Il or III.
  • the invention provides methods for sub-Tenon delivery of pharmaceutical compositions, comprising from about 0.1 mg/mL to about 1.2 mg/mL of a pharmaceutically active agent having Formula I 1 Il or III; about 0.02% benzalkonium chloride; about 10 mM PBS buffer; and the tonicity of the composition is adjusted to physiological conditions with about 4.5% mannitol.
  • the invention provides methods for sub-Tenon delivery of pharmaceutical compositions, wherein the flocculating agent is about 0.001% to about 10% docusate sodium.
  • the invention provides methods for sub-Tenon delivery of pharmaceutical compositions, comprising about 0.005% docusate sodium; and the tonicity of the composition is adjusted to physiological conditions with about 0.9% NaCI.
  • the invention provides methods for sub-Tenon delivery of pharmaceutical compositions, wherein the buffer is about a 10 mM PBS buffer.
  • the invention provides methods for sub-Tenon delivery of pharmaceutical compositions, comprising from about 0.01 mg/mL to about 2 mg/mL of a pharmaceutically active agent having Formula I, Il or III.
  • the invention provides methods for sub-Tenon delivery of pharmaceutical compositions, comprising from about 0.1 mg/mL to about 1.2 mg/mL of a pharmaceutically active agent having Formula I, Il or III; about 0.005% docusate sodium; about 10 mM PBS buffer; and the tonicity of the composition is adjusted to physiological conditions with about 0.9% NaCI.
  • the invention provides methods for sub-Tenon delivery of pharmaceutical compositions, wherein the flocculating agent is about 0.001% to about 10% sodium lauryl sulfate.
  • the invention provides methods for sub-Tenon delivery of pharmaceutical compositions, comprising about 0.01% sodium lauryl sulfate; and the tonicity of the composition is adjusted to physiological conditions with about 4% mannitol and about 0.2% MgCI.
  • the invention provides methods for sub-Tenon delivery of pharmaceutical compositions, wherein the buffer is about a 10 mM PBS buffer. In another aspect, the invention provides methods for sub-Tenon delivery of pharmaceutical compositions, comprising from about 0.01 mg/mL to about 2 mg/mL of a pharmaceutically active agent having Formula I 1 Il or III.
  • the invention provides methods for sub-Tenon delivery of pharmaceutical compositions, comprising from about 0.1 mg/mL to about 1.2 mg/mL of a pharmaceutically active agent having Formula I 1 Il or III; about 0.01% sodium lauryl sulfate; about 10 mM PBS buffer; and the tonicity of the composition is adjusted to physiological conditions with about 4% mannitol and about 0.2% MgCI.
  • the invention provides methods for sub-Tenon delivery of pharmaceutical compositions, wherein the pharmaceutically active agent is an angiogenesis inhibitor.
  • the invention provides methods for sub-Tenon delivery of pharmaceutical compositions, wherein the angiogenesis inhibitor is an inhibitor of a protein kinase receptor.
  • the invention provides methods for sub-Tenon delivery of pharmaceutical compositions, wherein the protein kinase receptor is a VEGF receptor.
  • stabilization of visual acuity or “stabilizing visual acuity”, unless otherwise indicated, means that at one year or longer, there is a loss of less than 15 letters, or alternatively, a loss of less than 3 lines, of visual acuity from baseline as measured by the visual acuity charts used in the Early Treatment Diabetic Retinopathy Study (ETDRS charts). ETDRS charts are discussed in the American Journal Of Ophthalmology 94:91-96, 1982, by Ferris, F. L. et al., the disclosure of which is hereby incorporated by reference in its entirety for all purposes.
  • the terms “improvement of visual acuity” or “improving visual acuity”, unless otherwise indicated, means that within one year, there is a gain of 15 or more letters, or alternatively, a gain of 3 or more lines, of visual acuity from baseline as measured by the ETDRS chart.
  • prevention of ocular neovascular i zation means to stop the progression of nonexudative age related macular degeneration (dry AMD) to exudative age related macular degeneration (wet AMD), as measured by techniques well known in the art such as fluorescein angiograms and/or color fundus photographs.
  • treating means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
  • treatment refers to the act of treating as “treating” is defined immediately above.
  • the phrase "pharmaceutically acceptable salt(s)" includes salts of acidic or basic groups, which may be present in a compound.
  • Compounds that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.
  • the acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edislyate, estolate, esylate, ethylsuccinate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylsulfate,
  • the subject invention also includes isotopically-labelled compounds, which are identical to those recited in Formula I, Il and III, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 CI, respectively.
  • Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
  • Certain isotopically-labelled compounds of the present invention, for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • lsotopically labelled compounds of Formula I, Il or III of this invention can generally be prepared by carrying out the procedures described for the non-labelled compound by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.
  • Fig. 1 is a schematic illustration of the eye.
  • FIG. 1 schematically illustrates a human eye 10.
  • Eye 10 has a cornea 12, a lens 14, a sclera 16, a choroid 18, a retina 20, and an optic nerve 22.
  • the anterior segment 24 of eye 10 generally includes the portions of eye 10 anterior of line 25, whereas the posterior segment 26 of eye 10 generally includes the portions of eye 10 posterior of line 25.
  • Retina 20 is physically attached to choroid 18 in a circumferential manner proximate pars plana 28.
  • Retina 20 has a macula 30 located slightly lateral to optic nerve 22.
  • the macula 30 is comprised primarily of retinal cones and is the region of maximum visual acuity in retina 20.
  • a Tenon's capsule or Tenon's membrane 34 is disposed on sclera 16.
  • a conjunctiva 36 covers a short area of the globe of eye 10 posterior to limbus 32 (the bulbar conjunctiva) and folds up (the upper cul-de- sac) or down (the lower cul-de-sac) to cover the inner areas of upper eyelid 35 and lower eyelid 37, respectively.
  • Conjunctiva 36 is disposed on top of Tenon's capsule 34.
  • Sclera 16 and Tenon's capsule 34 define the exterior surface of the globe of eye 10.
  • AMD age related macular degeneration
  • dry AMD nonexudative
  • wet AMD exudative
  • CME cystoid macular edema
  • a specific quantity of an ophthalmically acceptable pharmaceutically active agent is directly delivered onto the outer surface of sclera 16 and below Tenon's capsule 34 to form a depot 38.
  • a depot 38 is deposited directly onto the outer surface of sclera 16, below Tenon's capsule 34, and generally above macula 30.
  • Periocular delivery of substances to the posterior tissues of the eye is well known by those of skill in the art.
  • U.S. Patent No. 6,413,245 describes instruments useful for sub-Tenon delivery of a drug, and is hereby incorporated by reference in its entirety for all purposes.
  • the present invention provides dosage forms of the compounds of Formula I 1 Il and III, pharmaceutical compositions thereof, and methods for sub-Tenon delivery, in which the compounds and/or compositions are administered to the posterior-segment of the eye proximate the macula.
  • the compositions described herein further include various excipients and buffers that are safe and non-irritating to delicate eye tissues.
  • compositions are useful for treating severe vision loss from age-related macular degeneration and other diseases affecting the posterior segment of the eye, such as choroidal neovascularization, diabetic retinopathy, glaucoma, and retinitis pigmentosa.
  • the inventive compositions used to form drug depot 38 may include one or more pharmaceutically active agents, in addition to one or more non-active excipients as described herein.
  • pharmaceutically active agents useful in the inventive compositions includes anti-infectives, including, without limitation, antibiotics, antivirals, and antifungals; antiallergenic agents and mast cell stabilizers; steroidal and nonsteroidal anti-inflammatory agents (such as nepafenac); cyclooxygenase inhibitors, including, without limitation, Cox I and Cox Il inhibitors; combinations of anti-infective and anti-inflammatory agents; decongestants; anti-glaucoma agents, including, without limitation, adrenergics, beta-adrenergic blocking agents, alpha-adrenergic agonists, parasypathomimetic agents, cholinesterase inhibitors, carbonic anhydrase inhibitors, and prostaglandins; combinations of anti-glaucoma agents; antioxidants; nutritional supplements; drugs for the treatment of cyst
  • a compound of the present invention is delivered in a pharmaceutically acceptable ophthalmic vehicle such that the compound is maintained in contact with the ocular surface for a sufficient time period to allow the compound to penetrate the cornea and/or sclera and internal regions of the eye, including, for example, the anterior chamber, posterior chamber, vitreous body, aqueous humor, vitreous humor, cornea, iris/ciliary's, lens, choroid/retina and sclera.
  • the pharmaceutically acceptable ophthalmic vehicle may be an ointment, vegetable oil, or an encapsulating material.
  • a compound of the invention may also be injected directly into the vitreous humor or aqueous humor.
  • a compound may be also be administered by well known, acceptable methods, such as sub-Tenon and/or subconjunctival injections.
  • the macula is comprised primarily of retinal cones and is the region of maximum visual acuity in the retina.
  • a Tenon's capsule or Tenon's membrane is disposed on the sclera.
  • a conjunctiva covers a short area of the globe of the eyeposterior to the limbus (the bulbar conjunctiva) and folds up (the upper cul-de-sac) or down (the lower cul-de-sac) to cover the inner areas of the upper eyelid and lower eyelid, respectively.
  • the conjunctiva is disposed on top of Tenon's capsule.
  • the sclera and Tenon's capsule define the exterior surface of the globe of the eye.
  • AMD age related macular degeneration
  • Wet exudative
  • retinopathies such as diabetic retinopathy, retinopathy of prematurity
  • CME cystoid macular edema
  • glaucoma and other diseases or conditions of the posterior segment of the eye
  • AMD age related macular degeneration
  • Dry nonexudative
  • W exudative
  • CME CME
  • the compounds may be formulated as a depot preparation. Such long-acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) intramuscular injection or by the above mentioned sub-Tenon or intravitreal injection.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • the compounds may be prepared for topical administration in saline (combined with any of the preservatives and antimicrobial agents commonly used in ocular preparations), and administered in eyedrop form.
  • the solution or suspension may be prepared in its pure form and administered several times daily.
  • the present compositions, prepared as described above, may also be administered directly to the cornea.
  • the composition is prepared with a muco- adhesive polymer that binds to cornea.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion-exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • a pharmaceutical carrier for hydrophobic compounds is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase.
  • the cosolvent system may be a VPD co-solvent system.
  • VPD is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant polysorbate 80, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.
  • the VPD cosolvent system (VPD:5W) contains VPD diluted 1:1 with a 5% dextrose in water solution. This co-solvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon systemic administration. Naturally, the proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics.
  • co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of polysorbate 80; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g. polyvinyl pyrrolidone; and other sugars or polysaccharides may be substituted for dextrose.
  • other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity.
  • the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.
  • sustained-release materials have been established and are known by those skilled in the art.
  • Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days.
  • additional strategies for protein stabilization may be employed.
  • compositions also may comprise suitable solid- or gel-phase carriers or excipients.
  • suitable solid- or gel-phase carriers or excipients include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
  • Some of the compounds of the invention may be provided as salts with pharmaceutically compatible counter ions.
  • Pharmaceutically compatible salts may be formed with many acids, including hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free-base forms.
  • the preparation of preferred compounds of the present invention is described in detail in the following examples, but the artisan will recognize that the chemical reactions described may be readily adapted to prepare a number of other compounds of the invention.
  • the synthesis of non-exemplified compounds according to the invention may be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by changing to other suitable reagents known in the art, or by making routine modifications of reaction conditions.
  • other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of the invention.
  • the compounds of Formula I, Il and III are tyrosine kinase inhibitors intended for the treatment of age-related macular degeneration.
  • these compounds are formulated as compositions of sterile suspensions and administered via sub-Tenon injection.
  • a suspension formulation of these compounds is being developed for Phase III studies and subsequent commercialization.
  • the compound particles sediment into the annulus between the glass and stopper and are relatively difficult to resuspend. This is due in part to the tight packing of the micron-sized compound particles on these surfaces. This sedimentation results in a decreased potency of the product following resuspension by hand shaking. A drop in potency is not observed for vials stored upright.
  • Another approach to facilitate resuspension of particles from the glass stopper annulus is to induce the particles to form loosely structured floes (aggregates) in which inter particle attraction is maximized in the secondary energy minimum desbribed by DLVO theory.
  • Formulation-based approaches that induce particles into a secondary energy minimum balance Van-der-Waals attractive forces with either a steric repulsive force or an electrostatic repulsive force, or a combination of the two Generally, flocculation efficiency increases with increasing particle concentration. Controlled flocculation by steric repulsion is achieved by adsorbing large molecules (aqueous or liquid) to the particles surface. Flocculating agents can be neutral polymers such as methylcellulose or surface-active agents such as polyvinyl alcohol. With such agents, increasing molecular weight of the molecule increases the repulsion force. In contrast, flocculation controlled by electrostatic repulsion is achieved by adsorbing ionic molecules to the particles surface.
  • Such flocculating agents are cationic surfactants such as benzalkonium chloride, docusate sodium, sodium lauryl sulfate and the like. Increasing concentration of these ionic surfactants increases the repulsive force. If adsorption of the surfactant to the particle surface is maximal, then increasing the concentration of surfactant further has no effect on the repulsive force.
  • Flocculated formulations are also easier to resuspend because the floes do not pack as tightly on surfaces as individual particles. For example, hand shaking these vials can break up the floes thereby rendering the formulation acceptable for injection.
  • attainment of optimal conditions for the formation of loosely structured floes are facilitated by a clear mechanistic understanding of floe formataion and a comprehensive flocculation evaluation strategy.
  • Various techniques utilizing a variety of flocculating agents have been developed to create and optimize the flocculation process. Many of the agents described have been shown to be minimally toxic at the proposed concentrations when injected into rabbit eyes.
  • excipients may act as flocculating agents or suspending agents; or as surfactants or wetting agents.
  • suspension refers to a two-phase system consisting of a finely divided solid dispersed (suspended) in a liquid (the dispersing medium).
  • Suspensions possess certain advantages over other dosage forms. Some pharmaceutically active agents are insoluble in all acceptable media and must, therefore, be administered as a suspension. Due to their liquid character, suspensions represent an ideal dosage form for sub-Tenon administration. Furthermore, such agents are chemically more stable in suspensions than in solution. Over time, suspended agents tend to settle leading to a lack of uniformity of dose. This can, however, be minimized by careful formulation and shaking the suspension before administration.
  • Flocculating agents are particularly useful where suspended drug particles are desired, for example in suspension compositions.
  • suspension compositions can be provided exhibiting improved performance with respect to drug concentration, physical stability and efficacy.
  • Physical stability of suspensions are controlled by flocculating agents.
  • Flocculating agents are electrolytes that carry an electric charge opposite that of the net zeta potential of the suspended particles.
  • the addition of a flocculating agent at some critical concentration negates the surface charge on the suspended particles and allows the formation of floccules or clusters as particles that are held loosely together by weak Van der Waals forces. Since the particles are linked together loosely, they will not cake and may easily be redispersed by shaking the suspension.
  • floccules have approximately the same size particles, therefore a clear boundry is seen when the particles settle.
  • suitable flocculating agents include benzalkonium chloride, docusate sodium, sodium Iauryl sulfate, cetylpyridinium chloride, polysorbate-80, sorbitan monolaurate, carboxymethylcellulose sodium, xanthan gum, tragacanth, methylcellulose, PEG, magnesium aluminum silicate, attapulgite, bentonite, potassium dihydrogen phosphate, aluminum chloride, sodium chloride and mixtures thereof.
  • Benzalkonium chloride is a mixture of alkylbenzyldimethylammonium chlorides of the general formula:
  • R is a mixture of alkyls, including all or some of the group beginning with n-C 8 H 17 and extending through higher homologs, with n-Ci 2 H 25 , n-Ci 4 H 29 , and n-C 16 H 33 comprising the major portion.
  • the average molecular weight of benzalkonium chloride is
  • Benzalkonium chloride occurs as a white or yellowish-white amorphous powder, a thick gel, or gelatinous flakes. It is hygroscopic, soapy to the touch, and has a mild aromatic odor and very bitter taste. In ophthalmic preparations, benzalkonium chloride is one of the most widely used preservatives at concentrations of 0.01-0.02% w/v. Often it is used in combination with other preservatives or excipients to enhance its antimicrobial activity against strains of Pseudomonas.
  • Docusate sodium or sodium 1 ,4-bis(2-ethylhexyl) sulfosuccinate has an empirical formula of C 2O H 37 NaO 7 S and structural formula:
  • Docusate sodium is a white or almost white, waxlike, bitter tasting, plastic solid with a characteristic octanol-like odor. It is hygroscopic and usually available in the form of pellets, flakes, or rolls of tissue-thin material.
  • Docusate sodium and docusate salts are widely used as anionic surfactants in pharmaceutical formulations.
  • Docusate sodium is mainly used in capsule and direct-compression tablet formulations to assist in wetting and dissolution.
  • Docusate salts are also used in oral formulations as laxatives and fecal softeners.
  • Sodium lauryl sulfate is a mixture of sodium alkyl sulfates consisting chiefly of C 12 H 2S NaO 4 S and having structural formula:
  • Sodium lauryl sulfate consists of white or cream to pale yellow-colored crystals, flakes, or powder having a smooth feel, a soapy, bitter taste, and a faint odor of fatty substances.
  • Sodium lauryl sulfate is an anionic surfactant employed in a wide range of nonparenteral pharmaceutical formulations and cosmetics. It is also a detergent; emulsifying agent; skin penetrant; tablet and capsule lubricant; and a wetting agent that is effective in both alkaline and acidic conditions.
  • Surfactants or wetting agents can be either hydrophilic or hydrophobic, and act to lower the surface tension of the inventive compositions they are contained in.
  • hydrophilic and “hydrophobic” are relative terms.
  • a compound must necessarily include polar or charged hydrophilic moieties as well as non-polar hydrophobic (lipophilic) moieties (i.e., a surfactant compound must be amphiphilic).
  • An empirical parameter commonly used to characterize the relative hydrophilicity and hydrophobicity of non-ionic amphiphilic compounds is the hydrophilic-Iipophilic balance (the "HLB" value).
  • hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable.
  • hydrophobic surfactants are compounds having an HLB value less than about 10.
  • Surfactants that are useful in the inventive compositions include but are not limited to polyoxyethylenesorbitan esters (TweenTM) and block copolymers of ethylene oxide and propylene oxide (PoloxamerTM).
  • TweenTM polyoxyethylenesorbitan esters
  • PolyxamerTM block copolymers of ethylene oxide and propylene oxide
  • a variety of polyethylene sorbitan esters are commercially available and are suitable for use as surfactants in the inventive compositions. In general, these esters are hydrophilic, although several hydrophobic moieties of this class can be used, and act as surfactants.
  • polyethylene sorbitan esters useful in the inventive compositions are polyethylene sorbitan monolaurate (TweenTM 20), polyethylene sorbitan monopalmitate (TweenTM 40), polyethylene sorbitan monostearate (TweenTM 60), and polyethylene sorbitan monooleate (TweenTM 80) and the like.
  • PoloxamersTM are block copolymers of ethylene oxide and propylene oxide, and have structure: HO(C 2 H 4 ⁇ ) x (C 3 H 6 O) y (C 2 H 4 ⁇ ) x H (PLURONICTM); or HO(C 3 H 6 O) x (C 2 H 4 ⁇ ) y (C 3 H 6 O) x H (PLURONICTM R), wherein x is from about 2 to about 150, and y is from about 15 to about 70, or block copolymers as described above wherein x is about 80 and y is about 27.
  • Block copolymers of ethylene oxide and propylene oxide meeting the above descriptions are available from BASF sold under the trademark "Pluronic and Lutrol F Block Copolymers.” (For specifics of such polymers in detail, see BASF Corporation Technical Data Sheets on Pluronic polyols, copyright 1992, the disclosure of which is incorporated herein by reference).
  • PoloxamersTM useful in the inventive compositions encompass block copolymers which are water soluble, exist in cream or ointment form, and can be stored for long periods of time in anhydrous conditions, and act as surfactants and/or flocullating agents.
  • the POLOXAMERSTM described herein have a hydrophilic-lipophilic balance (HLB) value within the range of from 8 to 30, and a molecular weight within the range of 1 ,000 to 16,000 g/mole.
  • HLB hydrophilic-lipophilic balance
  • POLOXAMERTM 188 (PLURONICTM F68) is a polyethylene-polypropylene glycol copolymer having structure: HO(C 2 H 4 ⁇ ) x (C 3 H 6 O) y (C 2 H 4 ⁇ ) x H, and has average molecular weight of 8,400 g/mole.
  • PoloxamersTM for use in the inventive compositions include, but are not limited to: PluronicTM/LutrolTM F44 (PoloxamerTM 124), PluronicTM/LutrolTM F 68 (PoloxamerTM 188), PluronicTM/LutrolTM F 87 (PoloxamerTM 237), PluronicTM/LutrolTM F 108 (PoloxamerTM 338) and PluronicTM/LutrolTM F 127 (PoloxamerTM 407). Excipients may act as suspending agents in the inventive compositions.
  • Suspending agents are pharmacologically inactive substances that provide increased stability to suspensions by increasing the inventive compositions viscosity.
  • Suspending agents that are useful in the inventive compositions include but are not limited to polyethylene glycols (PEGs) such as PEG 3350, and PEG-phosphatidylethanolamine derivatives such as monomethoxypolyethyleneglycol-distearoylphosphatidyl- ethanolamine (m-PEG-DSPE); cellulose derivatives such as high, medium, and low viscosity (molecular weight) carboxymethyl celluloses (CMC) such as type 7H4, 7H3S, 7HOF, 7H, and 9H4; 7M, 7M8S, 7M2, 9M31 , 9M8, 12M31, and 12M8; 7L and 7L2, available from Hercules Inc. as AqualonTM), and methylcellulose (MC) derivatives.
  • PEGs polyethylene glycols
  • PEGs of varying molecular weights are commercially available from a number of different sources or, alternatively, they can be synthesized using standard polymerization techniques well known to those of skill in the art, and are useful as surfactants or wetting agents in the inventive compositions.
  • PEGs are ethylene glycol polymers that contain from about 20 to about 2,000,000 linked monomers.
  • PEGs containing various numbers of linked monomers are PEG 20, PEG 30, PEG 40, PEG 60, PEG 80, PEG 100, PEG 115, PEG 200, PEG 300, PEG 400, PEG 500, PEG 600, PEG 1000, PEG 1500, PEG 2000, PEG 3350, PEG 4000, PEG 4600, PEG 5000, PEG 6000, PEG 8000, PEG 11000, PEG 12000, PEG 2,000,000 and any mixtures thereof.
  • Phosphatidylethanolamines having a variety of acyl chain groups of varying chain lengths and degrees of saturation can be conjugated to polyethyleneglycol derivatives to form PEG-lipid conjugates that are useful as surfactants or wetting agents in the inventive compositions.
  • Phosphatidylethanolamines are commercially available, or are isolated or synthesized using techniques known to those skilled in the art. Phosphatidylethanolamines containing saturated or unsaturated fatty acids with carbon chain lengths in the range of C 10 to C 2 o are preferred. Phosphatidylethanolamines with mono- or di-unsaturated fatty acids and mixtures of saturated and unsaturated fatty acids can also be used. Suitable PEG-phosphatidylethanolamine derivatives include but are not limited to monomethoxypolyethyleneglycol-distearoylphosphatidyl-ethanolamine (m-PEG- DSPE).
  • m-PEG- DSPE monomethoxypolyethyleneglycol-distearoylphosphatidyl-ethanolamine
  • the inventive compositions may include one or more suspending agents.
  • Suspending agents are pharmacologically inactive substances that provide increased stability to suspensions by increasing the compositions viscosity. These agents also facilitate the redistribution of particles that have precipitated upon prolong standing.
  • a variety of cellulose derivatives are commercially available and are suitable for use as suspending agents in the present invention. For example, sodium carboxymethylcellulose (CMC) and methylcellulose (MC) are readily available and are useful as suspending agents in the inventive compositions.
  • CMC is a colorless, odorless, non-toxic, water- soluble powder and has been used in various detergents, soaps, food products, textiles, coatings, paints, cosmetics and pharmaceuticals where it acts as either a water binder, thickener, suspending agent, or emulsion stabilizer.
  • CMC is a semi-synthetic water- soluble polymer derived from cellulose. The CMC structure is based on the beta-(1->4)- D-glucopyranose polymer of cellulose. Different preparations of CMC may have different degrees of substitution, but is generally in the range of about 0.6 to about 0.9 derivatives per monomer unit.
  • High-viscosity or high-molecular weight CMC has an average molecular weight of about 700,000 g/mole and a degree of polymerization of about 3,200; medium-viscosity or medium-molecular weight CMC has an average molecular weight of about 250,000 g/mole and a degree of polymerization of about 1 ,100; and low-viscosity or low-molecular weight CMC has an average molecular weight of about 90,000 g/mole and a degree of polymerization of about 400.
  • CMC's useful in the inventive compositions include but are not limited to high viscosity CMC's such as AqualonTM type 7H4, 7H3S PH, 7HOF, 7H, and 9H4; medium viscosity CMC's such as type 7M, 7M8S, 7M2, 9M31, 9M8, 12M31, and 12M8; and low viscosity CMC's such as type 7L and 7L2, and the like.
  • high viscosity CMC's such as AqualonTM type 7H4, 7H3S PH, 7HOF, 7H, and 9H4
  • medium viscosity CMC's such as type 7M, 7M8S, 7M2, 9M31, 9M8, 12M31, and 12M8
  • low viscosity CMC's such as type 7L and 7L2, and the like.
  • AqualonTM is a CMC available from Hercules Incorporated and its technical information is described in AqualonTM Product Booklet 250-1 OH (AqualonTM Sodium Carboxymethylcellulose, Physical and Chemical Properties), and is hereby incorporated by reference is its entirety for all purposes.
  • Methylcellulose is also useful as a suspending agent in the inventive compositions.
  • MC is also a semi-synthetic water-soluble polymer derived from cellulose.
  • the MC structure is based on the beta-(1->4)-D-glucopyranose polymer of cellulose.
  • MC is a powdery substance prepared by methylation of natural cellulose and is used as a food additive, a bulk-forming laxative, an emulsifier, and as a thickener as it swells in water to form a gel.
  • Glycerin is a trihydric alcohol is a clear, water-white viscous, hygroscopic liquid at room temperatures. Glycerin has been extensively used in the pharmaceutical industry as a solvent and solubilizer in various drug vehicles for both internal and external uses and is useful as a vehicle in the inventive compositions.
  • the inventive compositions may optionally include one or more aqueous buffers, or mixtures thereof.
  • Buffers are commonly used in pharmaceutical compositions as they act to stabilize the pH of the compositions by minimizing the change in the acidity or basicity of a solution when an acid or base is added to the solution.
  • a buffer solution maintains the pH of a solution by reacting with small amounts of an added acid or base. For a buffer solution to be able to do this it must contain both an acid and a base; the acid to react with any added base and a base to react with any added acid. But these must be able to co-exist without reacting with each other. For this to be so, the acid and base must be a conjugate acid-base pair.
  • buffer solutions are a mixture of ethanoic acid and sodium ethanoate, or ammonia solution and ammonium chloride.
  • Useful buffers in the inventive compositions are commonly known as biological buffers and include but are not limited to phosphate buffers such as potassium dihydrogen phosphate (KH 2 PO 4 ), potassium hydrogen phosphate (K 2 HPO4), potassium phosphate (K 3 PO 4 ), sodium dihydrogen phosphate (Na 2 HPO 4 ), sodium hydrogen phosphate (Na 2 HPO 4 ), and sodium phosphate (Na 3 PO 4 ), and mixtures thereof.
  • phosphate buffers such as potassium dihydrogen phosphate (KH 2 PO 4 ), potassium hydrogen phosphate (K 2 HPO4), potassium phosphate (K 3 PO 4 ), sodium dihydrogen phosphate (Na 2 HPO 4 ), sodium hydrogen phosphate (Na 2 HPO 4 ), and sodium phosphate (Na 3 PO 4 ), and mixtures thereof.
  • buffers include but are not limited to citric acid and sodium citrate; citric acid and sodium hydroxide; citric acid and sodium hydrogen phosphate; boric acid-citric acid- potassium dihydrogen phosphate-diethyl-barbituric acid and sodium hydroxide; acetic acid and sodium acetate; potassium hydrogenphthalate and sodium hydroxide; cacodylic acid sodium salt-HCI; potassium dihydrogen phosphate and sodium hydrogenphosphate; sodium dihydrogen phosphate and sodium hydrogen phosphate; sodium tetraborate and boric acid; 2-amino-2-methyl-1,3-propanediol and HCI; diethanolamine and HCI; potassium chloride-boric acid and sodium hydroxide; boric acid-sodium hydroxide and potassium chloride; glycine and sodium hydroxide; sodium carbonate and sodium hydrogen carbonate; sodium hydrogen phosphate and sodium hydroxide; potassium chloride and sodium hydroxide; succinic acid, imidazole and HCI, phosphoric acid, tri
  • buffers may also be useful in the inventive compositions and are easily substituted by those of skill in the art.
  • Such buffers are readily available either commercially, or are prepared using well-known laboratory procedures by those of skill in the art.
  • 10 mM PBS phosphate buffer saline
  • inventive compositions may also include one or more tonicity adjustors. Tonicity adjustors act to increase the compositions effective osmolality, and therefore, their compatibility within a cellular environment.
  • Tonicity adjusters include but are not limited to salts, such as sodium chloride; and sugars, such as mannitol, and are present in sufficient quantities in the inventive compositions for an approximately iso-tonic preparation.
  • the tonicity and pH of the composition are adjusted to physiological conditions. For examples, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easter, Pa., 15th Edition (1975).
  • compositions and methods for sub-Tenon delivery of pharmaceutically active agents or pharmaceutically acceptable salts or solvates thereof are described in detail in the following examples.
  • compositions and methods described herein may be readily adapted to prepare a number of other compositions of the invention for sub-Tenon, intraocular, systemic or topical delivery.
  • Example 1 Bioanalytical Procedure For The Determination Of The Compound Of Formula I In Human Plasma (Sodium Heparin) Using LC- API/MS/MS
  • the compound of Formula I and an internal standard are extracted from 500 ⁇ !_ of human plasma (sodium heparin) by liquid-liquid extraction using 50:50 ethyl acetate: hexane. After evaporation to dryness and reconstitution, the extracts are analyzed by LC-API/MS/MS. Run times are approximately 2.5 minutes.
  • the Lower Limit of Quantitation (LLOQ) for the compound of Formula" I is 0.0100 ng/mL ( Figure 1). The range of reliable response is 0.0100 - 10.0 ng/mL.
  • Acceptable analytical runs should have standard curves where at least 75% of the individual standards meet method criteria. Deviations (%DEV) of the back-calculated standards must be within ⁇ 15% of the nominal concentration, except for the LLOQ, which is allowed a ⁇ 20% deviation. The calculated concentration of at least one of the duplicate lowest points in the standard curve shall meet criteria to qualify as a LLOQ. If this criterion is not met, the LLOQ may be raised to the next level. 2. The calculated concentrations of acceptable analytical QCs must be within
  • the calculated concentrations of acceptable dilution QCs must be within ⁇ 15% of the nominal concentration. At least two-thirds of the dilution QCs shall meet the given criteria for each dilution scheme. If the dilution QCs for a given dilution scheme do not meet criteria, then all of the study samples associated with that dilution scheme must be repeated.
  • SCIEX API 4000TM mass spectrometer (PE-SCIEX Concord, Ontario, Canada) Shimadzu LC-10AD HPLC pumps (2) with mixing tee (or equivalent) Shimadzu SCL-10A Controller (or equivalent) HTS-PAL or HTC-PAL Autoinjector (or equivalent)
  • the reference substance, the compound of Formula I 1 and the internal standard (the compound of Formula l-d7), are obtained from Agouron Pharmaceuticals, Inc.- A Pfizer Company. When used, acetonitrile (ACN), methanol (MeOH), ethyl acetate, hexane and
  • H2O are HPLC grade or equivalent.
  • Resconstitution Solvent 50:50 MeOH:5 mM NH4Oac. Combine 50 mL of MeOH and 50 mL of 5 mM NH4OAc.
  • Mobile Phase A 0.1% formic acid Combine 999 mL of H2O and 1 mL formic acid.
  • Mobile Phase B ACN with 0.1% formic acid Combine 999 mL of ACN and 1 mL formic acid.
  • Autoinjector Rinse 1 (50:50 ACN:H2O) with 0.3% Polyethyleneimine (PEI): Combine 500 mL of ACN, 500 mL of H2O and 3 mL PEL
  • Autoinjector Rinse 2 (10:90 MeOH:H2O) with 0.5% formic acid: Combine 100 mL of MeOH, 900 mL of H2O and 5 mL formic acid. Mix the solution well, and allow the solution to reach room temperature before use. Preparation of Standards and Quality Control Samples
  • CC and QC Stock Solutions a) Prepare a CC stock solution of the compound of Formula I in MeOH at 100 ⁇ g/mL. b) Prepare a QC stock solution of the compound of Formula I in MeOH at 100 ⁇ g/mL from an independent weighing.
  • a higher concentration e.g. 1 mL of a 1 mg/mL stock solution of the compound of Formula l-d7 to 1O mL with MeOH.
  • QCs are prepared by spiking control matrix (Human Plasma with sodium heparin) with a 10 ⁇ g/mL QC substock solution of the compound of Formula I (made by diluting 1 mL of the QC stock solution to 10 mL in MeOH) and then diluting with control matrix to the appropriate concentrations.
  • a 10 ⁇ g/mL QC substock solution of the compound of Formula I made by diluting 1 mL of the QC stock solution to 10 mL in MeOH) and then diluting with control matrix to the appropriate concentrations.
  • test solution for System Suitability A test solution containing the compound of Formula I (0.025 ng/mL) at or near the concentration of the final extract of the LLOQ and the IS (5 ng/mL) may be prepared or the low calibration curve point may be used for the test injection.
  • To make the former combine 50 ⁇ L of 5 ng/mL of the compound of Formula I (e.g., CC-0.5) and 2.5 mL of 20 ng/mL of the compound of Formula l-d7 (e.g. IS spiking solution), and dilute to a final volume of 10 mL in Reconstitution Solvent (50:50 MeOH:5 mM NH 4 OAc).
  • Reconstitution Solvent 50:50 MeOH:5 mM NH 4 OAc
  • Blank without IS samples identified as BI/BI contain control matrix and are not fortified with internal standard.
  • Blank with IS samples identified as BI/IS contain control matrix and are fortified with internal standard.
  • Solvent Blank a suitable solvent or mobile phase is used to demonstrate lack of background or carry-over from the chromatography system.
  • Sample extracts may be stored refrigerated until analysis. Chromatography
  • a 0.5 ⁇ m stainless steel precolumn filter and/or a frit may be added to prolong column life.
  • the precolumn filter may be used for several analytical sets if no significant increase in backpressure is observed
  • Suitable reagents for the autoinjector rinse(s) are Autoinjector Rinse 1 and 2. Other suitable rinse reagents may be used.
  • Mass Spectrometric Detection Detection is by tandem mass spectrometry (MS/MS).
  • the HPLC system is coupled to the mass spectrometer using a TurbolonSprayTM atmospheric pressure ionization inlet. The analysis is by positive ionization MS/MS.
  • High purity nitrogen gas from a high pressure liquid nitrogen dewar is used for the nebulizer, TurbolonSprayTM and curtain gases. Other sources of nitrogen or air may also be used.
  • Detection is in the multiple reaction monitoring mode (MRM).
  • MRM multiple reaction monitoring mode
  • the column effluent may be split post-column at an appropriate split ratio using a zero dead volume tee (Valco, Houston, TX or equivalent), otherwise all of the effluent can be directed toward the inlet.
  • a zero dead volume tee Valco, Houston, TX or equivalent
  • CE Collision Energy
  • Peak areas are integrated using Applied Biosystems/MDS SCIEX AnalystTM software.
  • a smoothing factor may be used. If used, the same smoothing factor must be used for all integrations in a given set.
  • Calibration curves are derived from peak area ratios (analyte/internal standard) using a least squares regression of the ratio versus the nominal concentration of the calibration curve standard. Deviations from the regression line are calculated by using the regression equation to back calculate the concentration at each calibration standard level. Concentrations of QC samples are also calculated from these regression curves, using the calculated peak area ratios.
  • Example 2 The Compound Of Formula I (VEGFR Inhibitor) Achieves Effective
  • the compound of Formula I may be delivered by sub-Tenon administration to the back of the eye proximate the macula in order to minimize side effects.
  • the compound of Formula I has been found to be a potent inhibitor of VEGFR2 tyrosine kinase activity, and is selective against VEGFR tyrosine kinase. This compound has also shown potent, sustained and reproducible inhibition of angiogenesis in the eye in several preclinical models including prevention of neovascularization and regression of existing vessels with reduction of leakage.
  • the compound of Formula I shows low drug solubility, ⁇ 0.8 ⁇ g/ml in PBS and about 5 ⁇ g/ml in vitreous. This compound binds tightly to proteins, for example, serum binding is ⁇ 99.9%. Such high protein binding and low solubility means that the drug forms a depot that is slowly cleared.
  • ⁇ C radioequivalents of the compound of Formula I were taken up primarily in pigmented tissues and persisted through 8 weeks postdose. Thus, drug levels in ocular tissues reach an equilibrium status and remain relatively constant for extended periods. Furthermore, the physicochemical characteristics for this compound are appropriate for sub-Tenon administration.
  • phase I/I I 1 randomized, masked, single and multiple-dose, sequential dose-escalation study of the safety and efficacy of the compound of Formula I in subjects with subfoveal choroidal neovascularization associated with age related macular degeneration was preformed.
  • This study type ran included a randomized, masked, phase I/I I single and multiple sequential dose-escalation with repeat posterior sub-Tenon dosing of the compound of Formula I for 52 weeks and additional 52 weeks follow up. This study involved two stages in which stage 2 was preformed after safety was demonstrated at 13 weeks.
  • the participants in these studies included: 144 males and females with exudative age related macular degeneration (AMD) including nonexudative (Dry) and exudative (Wet) AMD > or 55 yrs with subfoveal choroidal neovascularization in all subtypes. Their visual acuity was measured to be 73 to 24 letters (20/40 20/320), with one prior PDT allowed if within 3 months before screening., The number of groups in this study involved: four arms in 3 cohorts: 50 mg (q13 and 26 w), 150 mg (q26 w) and 600 mg (q52 w), in which the participating study centers were the Netherlands (4), U.S. (24), U.K. (6) and Australia (5), with one independent reading center at the University of Wisconsin FPRC.
  • the primary endpoints in this study were as follows: ocular and systemic safety for 13 weeks following a single sub-Tenon administration and for 104 weeks following multiple administrations.
  • the failure rate: % subjects losing fewer than 15 letters.
  • Secondary endpoints included: the response rate % subjects gaining > or 15 letters; the mean change of visual acuity from baseline; changes in fundus photographs, fluorescein angiography and OCT; pharmacokinetics of the compound of Formula I after sub-Tenon administration; and the change in health related quality of life scores.
  • the compound of Formula I shows an assay sensitivity: 10 pg/mL; plasma concentrations were measured during Stage 1 ;of 378 samples collected, 35 (9%) samples with measurable plasma concentrations; of 35 patients on active drug, 19 (54%) patients with at least 1 measurable plasma concentration; the highest measurable plasma cone: 102 pg/mL (day 3); no measurable plasma concentration after week 4.
  • Visual acuity changes from baseline at the end of 13-week follow-up period were as follows: 4 subjects gained 15 or more letters; 36 subjects had stabilization of vision (within ⁇ 14 letters from baseline); and 7 subjects lost 15 or more letters.
  • the compound of Formula I is a potent and effective small molecule inhibitor of VEGFR2.
  • the compound of Formula I exceeds target concentrations in the choroid for at least 16 weeks. Human plasma concentrations have been demonstrated to be significantly below therapeutic levels. In a phase l/ll trial to date, no significant side effects have been observed.
  • the compound of Formula I is potentially an effective drug for the treatment of neovascular age related macular degeneration including nonexudative (dry AMD) and exudative (wet AMD).
  • Example 3 Ocular and Systemic Pharmacokinetics of the compound of Formula I with Sub-Tenon Administration to Cynomolgus Monkeys
  • the compound of Formula I 1 a VEGFR tyrosine kinase inhibitor, is in clinical development with sub-Tenon administration for treatment of choroidal neovascularization associated with age-related macular degeneration.
  • the ocular and systemic distribution of the compound of Formula I was evaluated in cynomolgus monkeys following sub- Tenon administration.
  • Plasma levels of the compound of Formula I were below 0.2 ng/mL in all but one sample for all dose groups.
  • the compound of Formula I was observed up to 16 weeks in dose site tissue (conjunctiva and fatty tissue taken adjacent to the sclera at the site of administration) after a single sub-Tenon dose at all dose levels tested.
  • the compound of Formula I concentrations in choroid, the target tissue for age-related macular degeneration, were achieved within 3 days and were sustained for up to 16 weeks at 25 to 125 times the IC90 of the compound of Formula I for VEGF-R2 inhibition in a rat retina PK/PD model.
  • Retina concentrations of the compound of Formula I were generally at or below the IC90.
  • Ocular muscle also encased by Tenon's membrane, showed modest but variable levels. Concentrations of the compound of Formula I in sclera samples increased up to 8 weeks, then decreased at 12 and 16 weeks. Very low levels of the compound of Formula I were observed in the iris-ciliary body or lens and low or no levels were detected in vitreous or aqueous humor.
  • the compound of Formula I (i.e., AG-013958) is a VEGFR inhibitor which achieves effective choroidal concentrations with minimal systemic effects in cynomolgus monkeys and humans with age-related macular degeneration.
  • Sub-Tenon administration of the compound of Formula I suspension produced a depot of drug on the posterior surface of the sclera that provided sustained exposure to the choroid with little impact on peripheral tissues and no measurable systemic exposure. This data supports the preclinical safety assessment of the compound of Formula I, reported separately, and also the ongoing clinical assessment of this compound for treatment of age-related macular degeneration.
  • the physiochemical properties of the compound of Formula I include low drug solubility: ⁇ 0.8 ⁇ g/ml in PBS; about 5 ⁇ g/ml in vitreous; binds tightly to proteins; serum binding ⁇ 99.9%; High protein binding and low solubility means that the compound of Formula I forms a depot which is slowly cleared, thus allowing the drug levels in the tissue reach equilibrium and stay relatively constant for extended period. These physicochemical characteristics are appropriate for sub-Tenon administration.
  • the compound of Formula I exceeds target concentrations in the choroid for at least 16 weeks. Human plasma concentrations of the compound of Formula I have been demonstrated to be significantly below therapeutic levels. In a phase l/ll trial to date, no significant side effects have been observed.
  • the compound of Formula I is potentially an effective drug for the treatment of neovascular age-related macular degeneration 1158
  • Example 4 Assessment of a VEGF Receptor Tyrosine Kinase Inhibitor, the compound of Formula I, in Rabbits and Primates Following Ocular Administration
  • the compound of Formula I is a vascular endothelial growth factor receptor tyrosine kinase inhibitor currently in Phase l/ll clinical trails for the treatment of neovascular ocular diseases such as age-related macular degeneration.
  • the safety of the compound of Formula I was assessed in a series of nonclinical studies in rabbits and primates by sub-Tenon (ST), intravitreal (IVT) or intravenous (IV) administration at doses 1 -30-fold (in each eye) above the anticipated clinical dose.
  • a single sub-Tenon dose (intended clinical route of administration) of the compound of Formula I produced no macroscopic compound-related findings for up to 13 weeks of treatment in primates.
  • the compound of Formula I given as a single bolus IV dose at the highest IVT dose selected did not produce evidence of systemic toxicity up to five days after treatment.
  • AMD age related macular degeneration
  • wet AMD exudative
  • vascular endothelial growth factor has been implicated in angiogenesis and inhibition of VEGF pathways has demonstrated promise as pharmaceutical interventions in the treatment of choroidal neovascularization (2).
  • the compound of Formula I is a small molecule that inhibits the activity of the tyrosine-kinase (TK) domain of vascular endothelial growth factor receptor 2 (VEGF-R2).
  • TK tyrosine-kinase
  • VEGF-R2 vascular endothelial growth factor receptor 2
  • the compound of Formula I is currently in Phase l/ll clinical trials as an angiogenesis inhibitor intended for the treatment of choroidal neovascularization in subjects with age-related macular degeneration.
  • the clinical route of delivery is by sub-Tenon (ST) administration.
  • ST sub-Tenon
  • This research investigated the preclinical safety assessment of the compound of Formula I in Dutch-belted rabbits and cynomolgus monkeys by sub-Tenon and intravitreal (IVT) administration, as well as in the rabbit by intravenous bolus injection.
  • Sub-Tenon Administration in Primates Animals were anesthetized (xylazine/ketamine) and a small incision (1-2 mm) was made in the inferior temporal quadrant of the eye to expose the sclera and access the sub-Tenon space. A curved 23 gauge blunt cannula was inserted into the sub-Tenon space and advanced in a posterior direction. A 0.5 ml bolus injection of the compound of Formula I or vehicle (sucrose based formulation) was administered.
  • Vitreous opacity (4 and 8 - to -/+ -/+ to + -/+ to ++ weeks)
  • the compound of Formula I was well tolerated by sub-Tenon, IVT and intravenous administration, Electroretinography and ophthalmic exams were within normal limits throughout the duration of the study following sub-Tenon administration.
  • Formula I administered by intravenous injection did not produce systemic toxicity as determined by clinical observations and histopathology of tissues.
  • the compound of Formula I 1 a VEGFR tyrosine kinase inhibitor, is in clinical development with sub-Tenon administration for treatment of choroidal neovascularization associated with age-related macular degeneration.
  • the ocular and systemic distribution of the compound of Formula I was evaluated in cynomolgus monkeys following sub- Tenon (ST) administration.
  • Plasma levels of the compound of Formula I were below 0.2 ng/mL in all but one sample for all dose groups.
  • the compound of Formula I was observed up to 16 weeks in dose site tissue (conjunctiva and fatty tissue taken adjacent to the sclera at the site of administration) after a single sub-Tenon dose at all dose levels tested.
  • the compound of Formula I concentrations in choroid, the target tissue for age-related macular degeneration, were achieved within 3 days and were sustained for up to 16 weeks at 25 to 125 times the IC 90 of the compound of Formula I for VEGF-R2 inhibition in a rat retina PK/PD model.
  • Retina concentrations of the compound of Formula I were generally at or below the IC 90 .
  • Ocular muscle also encased by Tenon's membrane, showed modest but variable levels. Concentrations in sclera samples increased up to 8 weeks, then decreased at 12 and 16 weeks. Very low levels of the compound of Formula I were observed in the iris-ciliary body or lens and low or no levels were detected in vitreous or aqueous humor.
  • Sub-Tenon administration of the compound of Formula I suspension produced a depot of drug on the posterior surface of the sclera that provided sustained exposure to the choroid with little impact on peripheral tissues and no measurable systemic exposure.
  • This data supports the preclinical safety assessment of the compound of Formula I 1 reported separately, and also the ongoing clinical assessment of this compound for treatment of age-related macular degeneration.
  • Dose Site tissue consists of conjunctiva and fatty tissues of the sub-Tenon space collected from the region of drug deposition posterior to the macula and adjacent to the optic nerve.
  • Plasma, Aqueous and Vitreous Humor - Liquid-liquid extraction with ethyl acetate Plasma, Aqueous and Vitreous Humor - Liquid-liquid extraction with ethyl acetate.
  • the compound of Formula I concentrations in retina were lower than the target IC 90 and variable.
  • the compound of Formula I was detected at modest levels in ocular muscle and iris-ciliary body and at low levels in a few samples of lens and vitreous humor.
  • the compound of Formula I was not detected in aqueous humor or in plasma and there were no significant systemic or ocular toxicological findings.
  • the compound of Formula I was detected in the choroid at 25 to 125-fold higher than the targeted efficacious concentration (IC 90 ) as early as 3 days and maintained for up to 16 weeks.
  • the compound of Formula I concentrations in retina were much lower and more variable than choroid and dose site.
  • the compound of Formula I did not cause any ocular or systemic toxicities.
  • vehicle excipients for the compositions and methods described herein include flocculating agents such as benzalkonium chloride, docusate sodium and sodium lauryl sulfate, carboxy methylcellulose (CMC; low (90 kDa), mid (250 kDa) and high (700 kDa) molecular weight (MW), 0.25-1.0%), PolysorbateTM 80 (0.02 and
  • Nano-Edge PolyxamerTM 188 and PEG 3350 combination
  • methylcellulose MC; 0.25%
  • tonicity agents such as mannitol and salts such as NaCI and MgCI
  • buffers such as PBS buffer.
  • Poloxamer'"" 188 0.01% Poloxamer'" 188, 1OmM phosphate buffer, 0.9%NaCI; 0.25% PoloxamerTM 188, 1OmM phosphate buffer, 0.9%NaCI;
  • Poloxamer 188 (488mOsm), 50mg/mL sodium citrate; 0.1% PoloxamerTM 188 (625mOsm), 70mg/mL sodium citrate; sodium citrate buffer, pH 4.0 (1OmM, 283 mOsm); Sodium Citrate Buffer, pH 9.0 (1OmM, 287 mOsm);
  • benzalkonium chloride 4.5% mannitol; 274 mOsm, pH 7.36; 0.04% benzalkonium chloride, 4.5% mannitol; 274 mOsm, pH 7.36; 0.05% benzalkonium chloride, 4.5% mannitol; 274 mOsm, pH 7.36;
  • docusate sodium 0.9% NaCI, 300 mOsm, pH 7.2;
  • Suitable formulations have been developed for sub-Tenon administration of the compounds of Formula I, Il and III. These compounds were formulated at concentration ranges from about 0.05 to about 10mg/ml; with sodium dihydrogen phosphate buffer at physiological pH; and either sodium chloride or mannitol of sufficient quantity for an approximately iso-tonic preparation.
  • TweenTM 80 from 0.001% to 0.2% by weight
  • CMC from 0.01% to 1.0% by weight
  • PoloxamerTM 188 from 0.01% to 0.25% by weight
  • Polyethylene Glycol 3350 (PEG 3350), from 0.01% to 1.0% by weight.
  • All these formulations can be diluted to achieve drug concentration of at least 0.1 mg/ml upon dilution with a suitable vehicle.
  • the compounds of Formula Il were diluted with sodium phosphate buffer and either sodium chloride or mannitol of sufficient quantity for an approximately iso-tonic preparation:
  • the compounds of Formula III were diluted with sodium phosphate buffer and either sodium chloride or mannitol of sufficient quantity for an approximately iso-tonic preparation:
  • suspending agent solution using PBS. Filter through 0.22 or 5 ⁇ m filter into clean bottle.

Abstract

The invention provides dosage forms of compounds of Formula (I), (II) or (III), or pharmaceutically acceptable salts or solvates thereof, and pharmaceutical compositions thereof, for sub-Tenon administration to the posterior segment of the eye proximate the macula in a mammal with age-related macular degeneration. The invention further provides methods of treating age-related macular degeneration in a mammal by administering these dosage forms.

Description

DOSAGE FORMS, PHARAMCEUTICAL COMPOSITIONS AND METHODS
FOR
SUB-TENON DELIVERY Field Of The Invention
The present invention relates to drug delivery, and in particular to pharmaceutical compositions, dosage forms, and methods for the delivery of pharmaceutically active agents to the back of the eye. More particularly, the present invention relates to dosage forms of pharmaceutical compositions and methods for sub-Tenon delivery of pharmaceutically active agents to the posterior segment of the eye proximate the macula.
Background of the Invention
In recent years, significant advances have been made in optimizing the delivery of drugs to target tissues within the eye and in maintaining effective drug doses within those tissues. Most pharmacologic management of ocular disease, however, continues to use the topical application of solutions to the surface of the eye as drops. It has been estimated that typically less than 5% of a topically applied drug permeates the cornea and reaches intraocular tissues. Despite the relatively small proportion of a topically applied drug dose that ultimately reaches the anterior segment of ocular tissues, topical formulations remain effective, largely because of the very high concentrations of drugs that are administered. The delivery of therapeutic doses of drugs to the tissues in the posterior segment of the eye, however, remains a significant challenge.
Currently, the treatment of posterior segment disease is to a significant extent limited by the difficulty in delivering effective doses of drugs to target tissues in the posterior eye. Four approaches may be used to deliver drugs to the posterior segment including topical, systemic, intraocular, and periocular (including sub-Tenon, subconjunctival, and retrobulbar) delivery. Topically applied drugs may enter the eye by crossing the conjunctiva and then diffusing through the sclera, but this approach typically does not yield therapeutic drug levels in the posterior vitreous, retina, or choroids. While systemic administration can deliver drugs to the posterior of the eye, the large systemic doses necessary are often associated with significant side effects. Intravitreal injections provides the most direct approach to delivering drugs to the tissues of the posterior segment, and therapeutic tissue drug levels can be achieved, however, the inherent potential side effects of retinal detachment, hemorrhage, endophthalmitis, and cataract remain, and the often required frequent injections are not always well tolerated by the patient. Furthermore, drugs injected directly into the vitreous are rapidly eliminated. Intravitreal sustained-release devices have been used to avoid repeated injections. These devices, however, require intraocular surgery, must be replaced periodically, and have potential side effects similar to those associated with intravitreal injection. Periocular drug delivery using sub-Tenon, subconjunctival or retrobulbal injections, and placement of sustained-release devices provides alternate routes for delivering drugs to the posterior tissues of the eye. This approach to drug delivery is safer and less invasive than intravitreal injection and also offers the potential for localized, sustained-release drug delivery.
Drug delivery by this vector ideally would be transscleral and thus could take advantage of the large surface area of the sclera. The average 17-cm2 surface area of the sclera accounts for 95% of the total surface area of the globe and provides a significantly larger avenue for drug diffusion to the inside of the eye than the 1-cm2 surface area of the cornea. Also, regional differences in scleral thickness could be used to further optimize transscleral drug diffusion if sustained-release delivery devices or systems could be placed in regions where scleral permeability was greatest. The sclera, for example, is 1.0 mm thick near the optic nerve and an average of 0.53 mm thick at the corneoscleral limbus and thins to an average of 0.39 mm at the equator, where it can be as thin as 0.1 mm in a significant number of eyes. Further, an increasing body of evidence suggests that the sclera is quite permeable to a wide range of solutes and holds significant potential for posterior segment drug delivery.
. Due to the highly sensitive nature of the eye, however, delivery of drugs to the back of the eye requires vehicles that are non-irritating to the posterior tissues of the eye. Therefore, a need exists in the field of ophthalmology for improved pharmaceutical compositions and methods for their use, which are safe and effective for the delivery of pharmaceutically active substances to the posterior segment of the eye.
The present invention relates to indazole compounds, pharmaceutical compositions containing such compounds, and methods of using such compounds to mediate and/or inhibit the activity of certain protein kinases for the treatment of disease states associated with angiogenesis and/or cellular proliferation including neovascular ocular diseases such as age-related macular degeneration. More particularly, the present invention relates to dosage forms of such compounds and compositions for sub-Tenon delivery to the posterior segment of the eye proximate the macula. Indazole compounds useful in the compositions, dosage forms and methods described herein are disclosed in U.S. Patent Nos. 6,531,491; 6,534,524; and 6,869,962; U.S. Patent Application Nos. 10/737,655 and 10/796226; and U.S. Provisional Patent Application No. 60/620,394, the disclosures of each are hereby incorporated by reference in their entirety for all purposes. In particular, these patents and applications disclose compounds having Formula I1
Il or III:
Figure imgf000005_0001
and pharmaceutically acceptable salts or solvates thereof.
The compounds of Formula I, Il and III are tyrosine kinase inhibitors intended for the treatment of age-related macular degeneration. Typically, these compounds are formulated as compositions of sterile suspensions and administered to the back of the posterior segment of the eye proximate the macula via sub-Tenon injection. Currently, formulations of these compounds are being developed for Phase III studies and subsequent commercialization.
The discussion of the background of the invention is included herein to explain the context of the invention. This is not to be taken as an admission that any of the material referred to was published, known or part of the common general knowledge in the United States or in any foreign country as of the priority date of any of the claims.
Summary of the Invention It is an object of the invention to provide dosage forms of compounds of Formula I1
Il or III, or pharmaceutically acceptable salts or solvates thereof, and pharmaceutical compositions thereof, for sub-Tenon administration to the posterior segment of the eye proximate the macula in a mammal with ocular diseases, such as age-related macular degeneration. It is another object of the invention to provide methods of treating ocular diseases in a mammal by administering these dosage forms.
The therapeutically effective dose of the compounds of Formula I, Il or III may be administered to the mammal via sub-Tenon, intraocular, systemic or topical delivery. The therapeutically effective dose of the compounds of Formula I1 Il or III may be administered to one or both eyes at the same time or at different intervals. Thus, in one aspect, the invention provides dosage forms comprising a compound of Formula I, Il or III or a pharmaceutically acceptable salt or solvate thereof, wherein the compound of Formula I1 Il or III is from about 1 μg to about 1 ,500 μg. 6 001158
- A -
In another aspect, the invention provides dosage forms, wherein the dosage form further comprises one or more pharmaceutically acceptable excipients.
In another aspect, the invention provides dosage forms, wherein the compound of Formula I, Il or III is from about 50 μg to about 1 ,000 μg. In another aspect, the invention provides dosage forms, wherein the compound of Formula I, Il or III is from about 100 μg to about 600 μg.
In another aspect, the invention provides dosage forms, wherein the compound of Formula I, Il or III is about 1 μg.
In another aspect, the invention provides dosage forms, wherein the compound of Formula I, Il or III is about 50 μg.
In another aspect, the invention provides dosage forms, wherein the compound of Formula I, Il or III is about 100 μg.
In another aspect, the invention provides dosage forms, wherein the compound of Formula I, Il or III is about 150 μg. In another aspect, the invention provides dosage forms, wherein the compound of Formula I, Il or III is about 300 μg.
In another aspect, the invention provides dosage forms, wherein the compound of Formula I, Il or III is about 600 μg.
In another aspect, the invention provides dosage forms, wherein the compound of Formula I, Il or III is about 1 ,000 μg.
In another aspect, the invention provides dosage forms, wherein the compound of Formula I, Il or III is about 1,500 μg.
In another aspect, the invention provides methods for treating ocular diseases in a mammal, comprising administering to the mammal a composition comprising a therapeutically effective amount of a compound of Formula I, Il or III or a pharmaceutically acceptable salt or solvate thereof, wherein the therapeutically effective amount is about 1 μg to about 1,500 μg.
In another aspect, the invention provides methods for treating ocular diseases in a mammal, wherein the composition further comprises one or more pharmaceutically acceptable excipients.
In another aspect, the invention provides methods for treating ocular diseases in a mammal, wherein the composition is administered by sub-Tenon delivery to the eye.
In another aspect, the invention provides methods for treating ocular diseases in a mammal, wherein the ocular disease is selected from age related macular degeneration (AMD) including nonexudative (Dry AMD) and exudative (Wet AMD), choroidal neovascularization, retinopathies such as diabetic retinopathy and retinopathy of prematurity, diabetic macular edema, retinitis, uveitis, cystoid macular edema, glaucoma, and other diseases or conditions of the posterior segment of the eye. In another aspect, the invention provides methods for treating ocular diseases in a mammal, wherein the therapeutically effective amount is from about 50 μg to about 1,000 μg-
In another aspect, the invention provides methods for treating ocular diseases in a mammal, wherein the therapeutically effective amount is from about 100 μg to about 600 μg-
In another aspect, the invention provides methods for treating ocular diseases in a mammal, wherein the therapeutically effective amount is about 1 μg.
In another aspect, the invention provides methods for treating ocular diseases in a mammal, wherein the therapeutically effective amount is about 50 μg.
In another aspect, the invention provides methods for treating ocular diseases in a mammal, wherein the therapeutically effective amount is about 100 μg.
In another aspect, the invention provides methods for treating ocular diseases in a mammal, wherein the therapeutically effective amount is about 150 μg. In another aspect, the invention provides methods for treating ocular diseases in a mammal, wherein the therapeutically effective amount is about 300 μg.
In another aspect, the invention provides methods for treating ocular diseases in a. mammal, wherein the therapeutically effective amount is about 600 μg.
In another aspect, the invention provides methods for treating ocular diseases in a mammal, wherein the therapeutically effective amount is about 1 ,000 μg.
In another aspect, the invention provides methods for treating ocular diseases in a mammal, wherein the therapeutically effective amount is about 1,500 μg.
In another aspect, the invention provides methods for treating ocular diseases in a mammal, wherein the therapeutically effective amount is about 50 μg/eye to about 600 μg/eye.
In another aspect, the invention provides methods for treating ocular diseases in a mammal, wherein the therapeutically effective amount is about 150 μg/eye.
In another aspect, the invention provides methods for treating ocular diseases in a mammal, wherein the composition is administered 12 times/year. In another aspect, the invention provides methods for treating ocular diseases in a mammal, wherein the composition is administered 4 times/year.
In another aspect, the invention provides methods for treating ocular diseases in a mammal, wherein the composition is administered 3 times/year.
In another aspect, the invention provides methods for treating ocular diseases in a mammal, wherein the composition is administered 2 times/year.
In another aspect, the invention provides methods for treating ocular diseases in a mammal, wherein the composition is administered 1 time/year.
In another aspect, the invention provides methods for stabilizing visual acuity in a mammal, comprising administering the dosage forms of the invention. In another aspect, the invention provides methods for improving visual acuity in a mammal, comprising administering the dosage forms of the invention.
In another aspect, the invention provides methods for preventing ocular diseases, comprising administering the dosage forms of the invention. In another aspect, the invention provides methods for preventing ocular diseases, wherein the ocular disease is ocular neovascularization.
In another aspect, the invention provides methods for treating cancer in a mammal, comprising administering to the mammal a composition comprising a therapeutically effective amount of a compound of Formula I1 Il or III or a pharmaceutically acceptable salt or solvate thereof, wherein the compound of Formula I, Il or III is from about 1 μg to about 1 ,500 μg.
In another aspect, the invention provides methods for treating cancer, wherein the composition further comprises one or more pharmaceutically acceptable excipients.
It is another object of the invention to provide pharmaceutical compositions and methods for sub-Tenon delivery of pharmaceutically active agents to the posterior segment of the eye proximate the macula.
Thus, in one aspect, the invention provides pharmaceutical compositions, comprising a pharmaceutically active agent having Formula I1 Il or III, or a pharmaceutically acceptable salt or solvate thereof; one or more excipients; and one or more buffers, wherein the tonicity and pH of the composition are adjusted to physiological conditions; and wherein the composition is for sub-Tenon delivery to the posterior segment of the eye proximate the macula.
In another aspect, the invention provides pharmaceutical compositions, wherein one or more excipients is a flocculating agent. In another aspect, the invention provides pharmaceutical compositions, wherein the flocculating agent is about 0.001% to about 10% benzalkonium chloride.
In another aspect, the invention provides pharmaceutical compositions, wherein the flocculating agent is about 0.02% benzalkonium chloride; and the tonicity of the composition is adjusted to physiological conditions with about 4.5% mannitol. In another aspect, the invention provides pharmaceutical compositions, wherein the buffer is about a 10 mM PBS buffer.
In another aspect, the invention provides pharmaceutical compositions, comprising from about 0.01 mg/mL to about 2 mg/mL of a pharmaceutically active agent having Formula I, Il or III. In another aspect, the invention provides pharmaceutical compositions, comprising from about 0.1 mg/mL to about 1.2 mg/mL of a pharmaceutically active agent having Formula I1 Il or III; about 0.02% benzalkonium chloride; about 10 mM PBS buffer; and the tonicity of the composition is adjusted to physiological conditions with about 4.5% mannitol. In another aspect, the invention provides pharmaceutical compositions, wherein the flocculating agent is about 0.001% to about 10% docusate sodium.
In another aspect, the invention provides pharmaceutical compositions, comprising about 0.005% docusate sodium; and the tonicity of the composition is adjusted to physiological conditions with about 0.9% NaCI.
In another aspect, the invention provides pharmaceutical compositions, wherein the buffer is about a 10 mM PBS buffer.
In another aspect, the invention provides pharmaceutical compositions, comprising from about 0.01 mg/mL to about 2 mg/mL of a pharmaceutically active agent having Formula I, Il or III.
In another aspect, the invention provides pharmaceutical compositions, comprising from about 0.1 mg/mL to about 1.2 mg/mL of a pharmaceutically active agent having Formula I, Il or III; about 0.005% docusate sodium; about 10 mM PBS buffer; and the tonicity of the composition is adjusted to physiological conditions with about 0.9% NaCI.
In another aspect, the invention provides pharmaceutical compositions, wherein the flocculating agent is about 0.001% to about 10% sodium lauryl sulfate.
In another aspect, the invention provides pharmaceutical compositions, comprising about 0.01% sodium lauryl sulfate; and the tonicity of the composition is adjusted to physiological conditions with about 4% mannitol and about 0.2% MgCI.
In another aspect, the invention provides pharmaceutical compositions, wherein the buffer is about a 10 mM PBS buffer.
In another aspect, the invention provides pharmaceutical compositions, comprising from about 0.01 mg/mL to about 2 mg/mL of a pharmaceutically active agent having Formula I, Il or III.
In another aspect, the invention provides pharmaceutical compositions, comprising from about 0.1 mg/mL to about 1.2 mg/mL of a pharmaceutically active agent having Formula I, Il or III; about 0.01% sodium lauryl sulfate; about 10 mM PBS buffer; and the tonicity of the composition is adjusted to physiological conditions with about 4% mannitol and about 0.2% MgCI.
In another aspect, the invention provides pharmaceutical compositions, wherein the pharmaceutically active agent is an angiogenesis inhibitor.
In another aspect, the invention provides pharmaceutical compositions, wherein the angiogenesis inhibitor is an inhibitor of a protein kinase receptor. In another aspect, the invention provides pharmaceutical compositions, wherein the protein kinase receptor is a VEGF receptor.
In another aspect, the invention provides methods for sub-Tenon delivery of pharmaceutical compositions to the posterior of the eye proximate the macula, comprising a pharmaceutically active agent having Formula I, Il or III, or a pharmaceutically acceptable salt or solvate thereof; one or more excipients; and one or more buffers, wherein the tonicity and pH of the composition are adjusted to physiological conditions.
In another aspect, the invention provides methods for sub-Tenon delivery of pharmaceutical compositions, wherein one or more excipients is a flocculating agent.
In another aspect, the invention provides methods for sub-Tenon delivery of pharmaceutical compositions, wherein the flocculating agent is about 0.001% to about 10% benzalkonium chloride.
In another aspect, the invention provides methods for sub-Tenon delivery of pharmaceutical compositions, comprising about 0.02% benzalkonium chloride; and the tonicity of the composition is adjusted to physiological conditions with about 4.5% mannitol.
In another aspect, the invention provides methods for sub-Tenon delivery of pharmaceutical compositions, wherein the buffer is about a 10 mM PBS buffer. In another aspect, the invention provides methods for sub-Tenon delivery of pharmaceutical compositions, comprising from about 0.01 mg/mL to about 2 mg/mL of a pharmaceutically active agent having Formula I1 Il or III.
In another aspect, the invention provides methods for sub-Tenon delivery of pharmaceutical compositions, comprising from about 0.1 mg/mL to about 1.2 mg/mL of a pharmaceutically active agent having Formula I1 Il or III; about 0.02% benzalkonium chloride; about 10 mM PBS buffer; and the tonicity of the composition is adjusted to physiological conditions with about 4.5% mannitol.
In another aspect, the invention provides methods for sub-Tenon delivery of pharmaceutical compositions, wherein the flocculating agent is about 0.001% to about 10% docusate sodium.
In another aspect, the invention provides methods for sub-Tenon delivery of pharmaceutical compositions, comprising about 0.005% docusate sodium; and the tonicity of the composition is adjusted to physiological conditions with about 0.9% NaCI.
In another aspect, the invention provides methods for sub-Tenon delivery of pharmaceutical compositions, wherein the buffer is about a 10 mM PBS buffer.
In another aspect, the invention provides methods for sub-Tenon delivery of pharmaceutical compositions, comprising from about 0.01 mg/mL to about 2 mg/mL of a pharmaceutically active agent having Formula I, Il or III.
In another aspect, the invention provides methods for sub-Tenon delivery of pharmaceutical compositions, comprising from about 0.1 mg/mL to about 1.2 mg/mL of a pharmaceutically active agent having Formula I, Il or III; about 0.005% docusate sodium; about 10 mM PBS buffer; and the tonicity of the composition is adjusted to physiological conditions with about 0.9% NaCI. In another aspect, the invention provides methods for sub-Tenon delivery of pharmaceutical compositions, wherein the flocculating agent is about 0.001% to about 10% sodium lauryl sulfate.
In another aspect, the invention provides methods for sub-Tenon delivery of pharmaceutical compositions, comprising about 0.01% sodium lauryl sulfate; and the tonicity of the composition is adjusted to physiological conditions with about 4% mannitol and about 0.2% MgCI.
In another aspect, the invention provides methods for sub-Tenon delivery of pharmaceutical compositions, wherein the buffer is about a 10 mM PBS buffer. In another aspect, the invention provides methods for sub-Tenon delivery of pharmaceutical compositions, comprising from about 0.01 mg/mL to about 2 mg/mL of a pharmaceutically active agent having Formula I1 Il or III.
In another aspect, the invention provides methods for sub-Tenon delivery of pharmaceutical compositions, comprising from about 0.1 mg/mL to about 1.2 mg/mL of a pharmaceutically active agent having Formula I1 Il or III; about 0.01% sodium lauryl sulfate; about 10 mM PBS buffer; and the tonicity of the composition is adjusted to physiological conditions with about 4% mannitol and about 0.2% MgCI.
In another aspect, the invention provides methods for sub-Tenon delivery of pharmaceutical compositions, wherein the pharmaceutically active agent is an angiogenesis inhibitor.
In another aspect, the invention provides methods for sub-Tenon delivery of pharmaceutical compositions, wherein the angiogenesis inhibitor is an inhibitor of a protein kinase receptor.
In another aspect, the invention provides methods for sub-Tenon delivery of pharmaceutical compositions, wherein the protein kinase receptor is a VEGF receptor.
Definitions
As used herein, the terms "stabilization of visual acuity" or "stabilizing visual acuity", unless otherwise indicated, means that at one year or longer, there is a loss of less than 15 letters, or alternatively, a loss of less than 3 lines, of visual acuity from baseline as measured by the visual acuity charts used in the Early Treatment Diabetic Retinopathy Study (ETDRS charts). ETDRS charts are discussed in the American Journal Of Ophthalmology 94:91-96, 1982, by Ferris, F. L. et al., the disclosure of which is hereby incorporated by reference in its entirety for all purposes.
As used herein, the terms "improvement of visual acuity" or "improving visual acuity", unless otherwise indicated, means that within one year, there is a gain of 15 or more letters, or alternatively, a gain of 3 or more lines, of visual acuity from baseline as measured by the ETDRS chart.
As used herein, the terms "prevention of ocular neovascularization" or "preventing ocular neovascularization" means to stop the progression of nonexudative age related macular degeneration (dry AMD) to exudative age related macular degeneration (wet AMD), as measured by techniques well known in the art such as fluorescein angiograms and/or color fundus photographs.
As used herein, the term "treating", unless otherwise indicated, means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term "treatment", as used herein, unless otherwise indicated, refers to the act of treating as "treating" is defined immediately above.
As used herein, the phrase "pharmaceutically acceptable salt(s)", unless otherwise indicated, includes salts of acidic or basic groups, which may be present in a compound. Compounds that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edislyate, estolate, esylate, ethylsuccinate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phospate/diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodode, and valerate salts.
The subject invention also includes isotopically-labelled compounds, which are identical to those recited in Formula I, Il and III, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36CI, respectively. Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labelled compounds of the present invention, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances, lsotopically labelled compounds of Formula I, Il or III of this invention can generally be prepared by carrying out the procedures described for the non-labelled compound by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.
Description of the Drawings Fig. 1 is a schematic illustration of the eye.
Detailed Description Of The Invention The embodiments of the present invention and their advantages are best understood by referring to Figure 1 , which schematically illustrates a human eye 10. Eye 10 has a cornea 12, a lens 14, a sclera 16, a choroid 18, a retina 20, and an optic nerve 22. The anterior segment 24 of eye 10 generally includes the portions of eye 10 anterior of line 25, whereas the posterior segment 26 of eye 10 generally includes the portions of eye 10 posterior of line 25. Retina 20 is physically attached to choroid 18 in a circumferential manner proximate pars plana 28. Retina 20 has a macula 30 located slightly lateral to optic nerve 22. The macula 30 is comprised primarily of retinal cones and is the region of maximum visual acuity in retina 20. A Tenon's capsule or Tenon's membrane 34 is disposed on sclera 16. A conjunctiva 36 covers a short area of the globe of eye 10 posterior to limbus 32 (the bulbar conjunctiva) and folds up (the upper cul-de- sac) or down (the lower cul-de-sac) to cover the inner areas of upper eyelid 35 and lower eyelid 37, respectively. Conjunctiva 36 is disposed on top of Tenon's capsule 34. Sclera 16 and Tenon's capsule 34 define the exterior surface of the globe of eye 10. For treatment of age related macular degeneration (AMD) including nonexudative (dry AMD) and exudative (wet AMD), choroidal neovascularization, retinopathies, retinitis, uveitis, cystoid macular edema (CME) glaucoma, and other diseases or conditions of posterior segment 26, a specific quantity of an ophthalmically acceptable pharmaceutically active agent is directly delivered onto the outer surface of sclera 16 and below Tenon's capsule 34 to form a depot 38. In addition, in cases of age related macular degeneration (AMD) including nonexudative (dry AMD) and exudative (wet AMD) and CME a depot 38 is deposited directly onto the outer surface of sclera 16, below Tenon's capsule 34, and generally above macula 30. Periocular delivery of substances to the posterior tissues of the eye is well known by those of skill in the art. For example, U.S. Patent No. 6,413,245 describes instruments useful for sub-Tenon delivery of a drug, and is hereby incorporated by reference in its entirety for all purposes.
The present invention provides dosage forms of the compounds of Formula I1 Il and III, pharmaceutical compositions thereof, and methods for sub-Tenon delivery, in which the compounds and/or compositions are administered to the posterior-segment of the eye proximate the macula. The compositions described herein further include various excipients and buffers that are safe and non-irritating to delicate eye tissues.
Pharmaceutically active agents that are useful in the inventive compositions are useful for treating severe vision loss from age-related macular degeneration and other diseases affecting the posterior segment of the eye, such as choroidal neovascularization, diabetic retinopathy, glaucoma, and retinitis pigmentosa.
For example, the inventive compositions used to form drug depot 38 may include one or more pharmaceutically active agents, in addition to one or more non-active excipients as described herein. Examples of pharmaceutically active agents useful in the inventive compositions includes anti-infectives, including, without limitation, antibiotics, antivirals, and antifungals; antiallergenic agents and mast cell stabilizers; steroidal and nonsteroidal anti-inflammatory agents (such as nepafenac); cyclooxygenase inhibitors, including, without limitation, Cox I and Cox Il inhibitors; combinations of anti-infective and anti-inflammatory agents; decongestants; anti-glaucoma agents, including, without limitation, adrenergics, beta-adrenergic blocking agents, alpha-adrenergic agonists, parasypathomimetic agents, cholinesterase inhibitors, carbonic anhydrase inhibitors, and prostaglandins; combinations of anti-glaucoma agents; antioxidants; nutritional supplements; drugs for the treatment of cystoid macular edema including, without limitation, non-steroidal anti-inflammatory agents; drugs for the treatment of age related macular degeneration (AMD) including nonexudative (Dry) and exudative (Wet) AMD, including, without limitation, angiogenesis inhibitors, including angiogenesis inhibitors that inhibit protein kinase receptors, including protein kinase receptors that are VEGF receptors; and nutritional supplements; drugs for the treatment of herpetic infections and CMV ocular infections; drugs for the treatment of proliferative vitreoretinopathy including, without limitation, antimetabolites and fibrinolytics; wound modulating agents, including, without limitation, growth factors; antimetabolites; neuroprotective drugs, including, without limitation, eliprodil; and angiostatic steroids for the treatment of diseases or conditions of posterior segment 26, including, without limitation, age related macular degeneration (AMD) including nonexudative (Dry) and exudative (Wet) AMD, choroidal neovascularization, retinopathies, retinitis, uveitis, macular edema, and glaucoma. Such angiostatic steroids are more fully disclosed in U.S. Patent Nos. 5,679,666 and 5,770,592. A non-steroidal anti-inflammatory for the treatment of cystoid macular edema is nepafenac.
For administration to the eye, a compound of the present invention is delivered in a pharmaceutically acceptable ophthalmic vehicle such that the compound is maintained in contact with the ocular surface for a sufficient time period to allow the compound to penetrate the cornea and/or sclera and internal regions of the eye, including, for example, the anterior chamber, posterior chamber, vitreous body, aqueous humor, vitreous humor, cornea, iris/ciliary's, lens, choroid/retina and sclera. The pharmaceutically acceptable ophthalmic vehicle may be an ointment, vegetable oil, or an encapsulating material. A compound of the invention may also be injected directly into the vitreous humor or aqueous humor.
Further, a compound may be also be administered by well known, acceptable methods, such as sub-Tenon and/or subconjunctival injections. As is well known in the ophthalmic art, the macula is comprised primarily of retinal cones and is the region of maximum visual acuity in the retina. A Tenon's capsule or Tenon's membrane is disposed on the sclera. A conjunctiva covers a short area of the globe of the eyeposterior to the limbus (the bulbar conjunctiva) and folds up (the upper cul-de-sac) or down (the lower cul-de-sac) to cover the inner areas of the upper eyelid and lower eyelid, respectively. The conjunctiva is disposed on top of Tenon's capsule. The sclera and Tenon's capsule define the exterior surface of the globe of the eye. For treatment of ocular diseases such as age related macular degeneration (AMD) including nonexudative (Dry) and exudative (Wet) AMD, choroidal neovascularization, retinopathies (such as diabetic retinopathy, retinopathy of prematurity), diabetic macular edema, retinitis, uveitis, cystoid macular edema (CME), glaucoma, and other diseases or conditions of the posterior segment of the eye, it is preferable to dispose a depot of a specific quantity of an ophthalmically acceptable pharmaceutically active agent directly on the outer surface of the sclera and below Tenon's capsule. In addition, in cases of age related macular degeneration (AMD) including nonexudative (Dry) and exudative (Wet) AMD and CME it is most preferable to dispose the depot directly on the outer surface of the sclera, below Tenon's capsule, and generally above the macula.
The compounds may be formulated as a depot preparation. Such long-acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) intramuscular injection or by the above mentioned sub-Tenon or intravitreal injection. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
Within particularly preferred embodiments of the invention, the compounds may be prepared for topical administration in saline (combined with any of the preservatives and antimicrobial agents commonly used in ocular preparations), and administered in eyedrop form. The solution or suspension may be prepared in its pure form and administered several times daily. Alternatively, the present compositions, prepared as described above, may also be administered directly to the cornea.
Within preferred embodiments, the composition is prepared with a muco- adhesive polymer that binds to cornea. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion-exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt. A pharmaceutical carrier for hydrophobic compounds is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. The cosolvent system may be a VPD co-solvent system. VPD is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant polysorbate 80, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol. The VPD cosolvent system (VPD:5W) contains VPD diluted 1:1 with a 5% dextrose in water solution. This co-solvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon systemic administration. Naturally, the proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics. Furthermore, the identity of the co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of polysorbate 80; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g. polyvinyl pyrrolidone; and other sugars or polysaccharides may be substituted for dextrose. Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity. Additionally, the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials have been established and are known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed.
The pharmaceutical compositions also may comprise suitable solid- or gel-phase carriers or excipients. Examples of such carriers or excipients include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols. Some of the compounds of the invention may be provided as salts with pharmaceutically compatible counter ions. Pharmaceutically compatible salts may be formed with many acids, including hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free-base forms. The preparation of preferred compounds of the present invention is described in detail in the following examples, but the artisan will recognize that the chemical reactions described may be readily adapted to prepare a number of other compounds of the invention. For example, the synthesis of non-exemplified compounds according to the invention may be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by changing to other suitable reagents known in the art, or by making routine modifications of reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of the invention. The compounds of Formula I, Il and III are tyrosine kinase inhibitors intended for the treatment of age-related macular degeneration. Typically, these compounds are formulated as compositions of sterile suspensions and administered via sub-Tenon injection. Currently, a suspension formulation of these compounds is being developed for Phase III studies and subsequent commercialization. However, when these suspensions are filled in glass vials and stored inverted, the compound particles sediment into the annulus between the glass and stopper and are relatively difficult to resuspend. This is due in part to the tight packing of the micron-sized compound particles on these surfaces. This sedimentation results in a decreased potency of the product following resuspension by hand shaking. A drop in potency is not observed for vials stored upright. Another approach to facilitate resuspension of particles from the glass stopper annulus is to induce the particles to form loosely structured floes (aggregates) in which inter particle attraction is maximized in the secondary energy minimum desbribed by DLVO theory.
Formulation-based approaches that induce particles into a secondary energy minimum balance Van-der-Waals attractive forces with either a steric repulsive force or an electrostatic repulsive force, or a combination of the two. Generally, flocculation efficiency increases with increasing particle concentration. Controlled flocculation by steric repulsion is achieved by adsorbing large molecules (aqueous or liquid) to the particles surface. Flocculating agents can be neutral polymers such as methylcellulose or surface-active agents such as polyvinyl alcohol. With such agents, increasing molecular weight of the molecule increases the repulsion force. In contrast, flocculation controlled by electrostatic repulsion is achieved by adsorbing ionic molecules to the particles surface. Such flocculating agents are cationic surfactants such as benzalkonium chloride, docusate sodium, sodium lauryl sulfate and the like. Increasing concentration of these ionic surfactants increases the repulsive force. If adsorption of the surfactant to the particle surface is maximal, then increasing the concentration of surfactant further has no effect on the repulsive force.
Flocculated formulations are also easier to resuspend because the floes do not pack as tightly on surfaces as individual particles. For example, hand shaking these vials can break up the floes thereby rendering the formulation acceptable for injection. In these formulations, attainment of optimal conditions for the formation of loosely structured floes are facilitated by a clear mechanistic understanding of floe formataion and a comprehensive flocculation evaluation strategy. Various techniques utilizing a variety of flocculating agents have been developed to create and optimize the flocculation process. Many of the agents described have been shown to be minimally toxic at the proposed concentrations when injected into rabbit eyes.
In the compositions and methods of the invention, excipients may act as flocculating agents or suspending agents; or as surfactants or wetting agents. The term "suspension" refers to a two-phase system consisting of a finely divided solid dispersed (suspended) in a liquid (the dispersing medium). Suspensions possess certain advantages over other dosage forms. Some pharmaceutically active agents are insoluble in all acceptable media and must, therefore, be administered as a suspension. Due to their liquid character, suspensions represent an ideal dosage form for sub-Tenon administration. Furthermore, such agents are chemically more stable in suspensions than in solution. Over time, suspended agents tend to settle leading to a lack of uniformity of dose. This can, however, be minimized by careful formulation and shaking the suspension before administration.
Flocculating agents are particularly useful where suspended drug particles are desired, for example in suspension compositions. Through selection and combination of excipients, suspension compositions can be provided exhibiting improved performance with respect to drug concentration, physical stability and efficacy. Physical stability of suspensions are controlled by flocculating agents. Flocculating agents are electrolytes that carry an electric charge opposite that of the net zeta potential of the suspended particles. The addition of a flocculating agent at some critical concentration negates the surface charge on the suspended particles and allows the formation of floccules or clusters as particles that are held loosely together by weak Van der Waals forces. Since the particles are linked together loosely, they will not cake and may easily be redispersed by shaking the suspension. Generally, floccules have approximately the same size particles, therefore a clear boundry is seen when the particles settle. Non-limiting examples of suitable flocculating agents include benzalkonium chloride, docusate sodium, sodium Iauryl sulfate, cetylpyridinium chloride, polysorbate-80, sorbitan monolaurate, carboxymethylcellulose sodium, xanthan gum, tragacanth, methylcellulose, PEG, magnesium aluminum silicate, attapulgite, bentonite, potassium dihydrogen phosphate, aluminum chloride, sodium chloride and mixtures thereof.
Benzalkonium chloride is a mixture of alkylbenzyldimethylammonium chlorides of the general formula:
Figure imgf000018_0001
wherein R is a mixture of alkyls, including all or some of the group beginning with n-C8H17 and extending through higher homologs, with n-Ci2H25, n-Ci4H29, and n-C16H33 comprising the major portion. The average molecular weight of benzalkonium chloride is
360 g/mole and is known to act as an antimicrobial preservative; antiseptic; disinfectant; solubilizing agent; and as a wetting agent. Benzalkonium chloride occurs as a white or yellowish-white amorphous powder, a thick gel, or gelatinous flakes. It is hygroscopic, soapy to the touch, and has a mild aromatic odor and very bitter taste. In ophthalmic preparations, benzalkonium chloride is one of the most widely used preservatives at concentrations of 0.01-0.02% w/v. Often it is used in combination with other preservatives or excipients to enhance its antimicrobial activity against strains of Pseudomonas.
Docusate sodium or sodium 1 ,4-bis(2-ethylhexyl) sulfosuccinate has an empirical formula of C2OH37NaO7S and structural formula:
Figure imgf000019_0001
Docusate sodium is a white or almost white, waxlike, bitter tasting, plastic solid with a characteristic octanol-like odor. It is hygroscopic and usually available in the form of pellets, flakes, or rolls of tissue-thin material. Docusate sodium and docusate salts are widely used as anionic surfactants in pharmaceutical formulations. Docusate sodium is mainly used in capsule and direct-compression tablet formulations to assist in wetting and dissolution. Docusate salts are also used in oral formulations as laxatives and fecal softeners.
Sodium lauryl sulfate is a mixture of sodium alkyl sulfates consisting chiefly of C12H2SNaO4S and having structural formula:
O
H3C-(CH2)H-O-S-O- Na+ O
Sodium lauryl sulfate consists of white or cream to pale yellow-colored crystals, flakes, or powder having a smooth feel, a soapy, bitter taste, and a faint odor of fatty substances. Sodium lauryl sulfate is an anionic surfactant employed in a wide range of nonparenteral pharmaceutical formulations and cosmetics. It is also a detergent; emulsifying agent; skin penetrant; tablet and capsule lubricant; and a wetting agent that is effective in both alkaline and acidic conditions.
Surfactants or wetting agents can be either hydrophilic or hydrophobic, and act to lower the surface tension of the inventive compositions they are contained in. As is well known in the art, the terms "hydrophilic" and "hydrophobic" are relative terms. To function as a surfactant, a compound must necessarily include polar or charged hydrophilic moieties as well as non-polar hydrophobic (lipophilic) moieties (i.e., a surfactant compound must be amphiphilic). An empirical parameter commonly used to characterize the relative hydrophilicity and hydrophobicity of non-ionic amphiphilic compounds is the hydrophilic-Iipophilic balance (the "HLB" value). Surfactants with lower HLB values are more hydrophobic, and have greater solubility in oils, whereas surfactants with higher HLB values are more hydrophilic, and have greater solubility in aqueous mediums. Using HLB values as a rough guide, hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable. Similarly, hydrophobic surfactants are compounds having an HLB value less than about 10.
Surfactants that are useful in the inventive compositions include but are not limited to polyoxyethylenesorbitan esters (Tween™) and block copolymers of ethylene oxide and propylene oxide (Poloxamer™). A variety of polyethylene sorbitan esters are commercially available and are suitable for use as surfactants in the inventive compositions. In general, these esters are hydrophilic, although several hydrophobic moieties of this class can be used, and act as surfactants. Among the polyethylene sorbitan esters useful in the inventive compositions are polyethylene sorbitan monolaurate (Tween™ 20), polyethylene sorbitan monopalmitate (Tween™ 40), polyethylene sorbitan monostearate (Tween™ 60), and polyethylene sorbitan monooleate (Tween™ 80) and the like.
Poloxamers™ are block copolymers of ethylene oxide and propylene oxide, and have structure: HO(C2H4θ)x(C3H6O)y(C2H4θ)xH (PLURONIC™); or HO(C3H6O)x(C2H4θ)y(C3H6O)xH (PLURONIC™ R), wherein x is from about 2 to about 150, and y is from about 15 to about 70, or block copolymers as described above wherein x is about 80 and y is about 27. Block copolymers of ethylene oxide and propylene oxide meeting the above descriptions are available from BASF sold under the trademark "Pluronic and Lutrol F Block Copolymers." (For specifics of such polymers in detail, see BASF Corporation Technical Data Sheets on Pluronic polyols, copyright 1992, the disclosure of which is incorporated herein by reference).
Poloxamers™ useful in the inventive compositions encompass block copolymers which are water soluble, exist in cream or ointment form, and can be stored for long periods of time in anhydrous conditions, and act as surfactants and/or flocullating agents. The POLOXAMERS™ described herein have a hydrophilic-lipophilic balance (HLB) value within the range of from 8 to 30, and a molecular weight within the range of 1 ,000 to 16,000 g/mole. POLOXAMER™ 188 (PLURONIC™ F68) is a polyethylene-polypropylene glycol copolymer having structure: HO(C2H4θ)x(C3H6O)y(C2H4θ)xH, and has average molecular weight of 8,400 g/mole. Using the Poloxamers™ coding labels of BASF, suitable Poloxamers™ for use in the inventive compositions include, but are not limited to: Pluronic™/Lutrol™ F44 (Poloxamer™ 124), Pluronic™/Lutrol™ F 68 (Poloxamer™ 188), Pluronic™/Lutrol™ F 87 (Poloxamer™ 237), Pluronic™/Lutrol™ F 108 (Poloxamer™ 338) and Pluronic™/Lutrol™ F 127 (Poloxamer™ 407). Excipients may act as suspending agents in the inventive compositions. Suspending agents are pharmacologically inactive substances that provide increased stability to suspensions by increasing the inventive compositions viscosity. Suspending agents that are useful in the inventive compositions include but are not limited to polyethylene glycols (PEGs) such as PEG 3350, and PEG-phosphatidylethanolamine derivatives such as monomethoxypolyethyleneglycol-distearoylphosphatidyl- ethanolamine (m-PEG-DSPE); cellulose derivatives such as high, medium, and low viscosity (molecular weight) carboxymethyl celluloses (CMC) such as type 7H4, 7H3S, 7HOF, 7H, and 9H4; 7M, 7M8S, 7M2, 9M31 , 9M8, 12M31, and 12M8; 7L and 7L2, available from Hercules Inc. as Aqualon™), and methylcellulose (MC) derivatives.
PEGs of varying molecular weights are commercially available from a number of different sources or, alternatively, they can be synthesized using standard polymerization techniques well known to those of skill in the art, and are useful as surfactants or wetting agents in the inventive compositions. PEGs are ethylene glycol polymers that contain from about 20 to about 2,000,000 linked monomers. For example, PEGs containing various numbers of linked monomers are PEG 20, PEG 30, PEG 40, PEG 60, PEG 80, PEG 100, PEG 115, PEG 200, PEG 300, PEG 400, PEG 500, PEG 600, PEG 1000, PEG 1500, PEG 2000, PEG 3350, PEG 4000, PEG 4600, PEG 5000, PEG 6000, PEG 8000, PEG 11000, PEG 12000, PEG 2,000,000 and any mixtures thereof. Phosphatidylethanolamines having a variety of acyl chain groups of varying chain lengths and degrees of saturation can be conjugated to polyethyleneglycol derivatives to form PEG-lipid conjugates that are useful as surfactants or wetting agents in the inventive compositions. Such phosphatidylethanolamines are commercially available, or are isolated or synthesized using techniques known to those skilled in the art. Phosphatidylethanolamines containing saturated or unsaturated fatty acids with carbon chain lengths in the range of C10 to C2o are preferred. Phosphatidylethanolamines with mono- or di-unsaturated fatty acids and mixtures of saturated and unsaturated fatty acids can also be used. Suitable PEG-phosphatidylethanolamine derivatives include but are not limited to monomethoxypolyethyleneglycol-distearoylphosphatidyl-ethanolamine (m-PEG- DSPE).
The inventive compositions may include one or more suspending agents. Suspending agents are pharmacologically inactive substances that provide increased stability to suspensions by increasing the compositions viscosity. These agents also facilitate the redistribution of particles that have precipitated upon prolong standing. A variety of cellulose derivatives are commercially available and are suitable for use as suspending agents in the present invention. For example, sodium carboxymethylcellulose (CMC) and methylcellulose (MC) are readily available and are useful as suspending agents in the inventive compositions. CMC is a colorless, odorless, non-toxic, water- soluble powder and has been used in various detergents, soaps, food products, textiles, coatings, paints, cosmetics and pharmaceuticals where it acts as either a water binder, thickener, suspending agent, or emulsion stabilizer. CMC is a semi-synthetic water- soluble polymer derived from cellulose. The CMC structure is based on the beta-(1->4)- D-glucopyranose polymer of cellulose. Different preparations of CMC may have different degrees of substitution, but is generally in the range of about 0.6 to about 0.9 derivatives per monomer unit. Generally, as the molecular weight and average chain length (i.e., the degree of polymerization) of a CMC increases, there is a corresponding increase in the viscosity of these polymers. High-viscosity or high-molecular weight CMC has an average molecular weight of about 700,000 g/mole and a degree of polymerization of about 3,200; medium-viscosity or medium-molecular weight CMC has an average molecular weight of about 250,000 g/mole and a degree of polymerization of about 1 ,100; and low-viscosity or low-molecular weight CMC has an average molecular weight of about 90,000 g/mole and a degree of polymerization of about 400. Many different types of CMC's are commercially available. CMC's useful in the inventive compositions include but are not limited to high viscosity CMC's such as Aqualon™ type 7H4, 7H3S PH, 7HOF, 7H, and 9H4; medium viscosity CMC's such as type 7M, 7M8S, 7M2, 9M31, 9M8, 12M31, and 12M8; and low viscosity CMC's such as type 7L and 7L2, and the like. Aqualon™ is a CMC available from Hercules Incorporated and its technical information is described in Aqualon™ Product Booklet 250-1 OH (Aqualon™ Sodium Carboxymethylcellulose, Physical and Chemical Properties), and is hereby incorporated by reference is its entirety for all purposes.
Methylcellulose (MC) is also useful as a suspending agent in the inventive compositions. MC is also a semi-synthetic water-soluble polymer derived from cellulose. The MC structure is based on the beta-(1->4)-D-glucopyranose polymer of cellulose. MC is a powdery substance prepared by methylation of natural cellulose and is used as a food additive, a bulk-forming laxative, an emulsifier, and as a thickener as it swells in water to form a gel.
Glycerin is a trihydric alcohol is a clear, water-white viscous, hygroscopic liquid at room temperatures. Glycerin has been extensively used in the pharmaceutical industry as a solvent and solubilizer in various drug vehicles for both internal and external uses and is useful as a vehicle in the inventive compositions.
The inventive compositions may optionally include one or more aqueous buffers, or mixtures thereof. Buffers are commonly used in pharmaceutical compositions as they act to stabilize the pH of the compositions by minimizing the change in the acidity or basicity of a solution when an acid or base is added to the solution. A buffer solution maintains the pH of a solution by reacting with small amounts of an added acid or base. For a buffer solution to be able to do this it must contain both an acid and a base; the acid to react with any added base and a base to react with any added acid. But these must be able to co-exist without reacting with each other. For this to be so, the acid and base must be a conjugate acid-base pair. Examples of buffer solutions are a mixture of ethanoic acid and sodium ethanoate, or ammonia solution and ammonium chloride.
Useful buffers in the inventive compositions are commonly known as biological buffers and include but are not limited to phosphate buffers such as potassium dihydrogen phosphate (KH2PO4), potassium hydrogen phosphate (K2HPO4), potassium phosphate (K3PO4), sodium dihydrogen phosphate (Na2HPO4), sodium hydrogen phosphate (Na2HPO4), and sodium phosphate (Na3PO4), and mixtures thereof. Other useful buffers include but are not limited to citric acid and sodium citrate; citric acid and sodium hydroxide; citric acid and sodium hydrogen phosphate; boric acid-citric acid- potassium dihydrogen phosphate-diethyl-barbituric acid and sodium hydroxide; acetic acid and sodium acetate; potassium hydrogenphthalate and sodium hydroxide; cacodylic acid sodium salt-HCI; potassium dihydrogen phosphate and sodium hydrogenphosphate; sodium dihydrogen phosphate and sodium hydrogen phosphate; sodium tetraborate and boric acid; 2-amino-2-methyl-1,3-propanediol and HCI; diethanolamine and HCI; potassium chloride-boric acid and sodium hydroxide; boric acid-sodium hydroxide and potassium chloride; glycine and sodium hydroxide; sodium carbonate and sodium hydrogen carbonate; sodium hydrogen phosphate and sodium hydroxide; potassium chloride and sodium hydroxide; succinic acid, imidazole and HCI, phosphoric acid, tris(hydroxymethyl)aminomethane, glycylglycine and boric acid buffers, and mixtures thereof. Other buffers may also be useful in the inventive compositions and are easily substituted by those of skill in the art. Ideally, the buffers used in the inventive compositions are at about physiological pH (7.38), and are present in concentration ranges from about 1 rtiM to about 100 mM (1 mM = 0.001 M). Such buffers are readily available either commercially, or are prepared using well-known laboratory procedures by those of skill in the art. For example, 10 mM PBS (phosphate buffer saline) is either available commercially (Zymed Cat. No. 00-3000) or can be made by combining 0.26 g KH2PO4, 2.17 g Na2HPO4-7H20, 8.71 g NaCI, 800 ml_ H2O (distilled), and adjusting the pH to 7.4 and bring volume to 1 L with H2O (distilled) using NaOH or HCI being careful not to overshoot and back-titrate, as this may alter the salt concentration. The inventive compositions may also include one or more tonicity adjustors. Tonicity adjustors act to increase the compositions effective osmolality, and therefore, their compatibility within a cellular environment. For example, if cells are placed in a hypotonic solution (i.e., a solution having a low solute concentration and therefore a high water concentration), there will be a net movement of water into the cells, causing them to swell and burst (lyse). Conversely, if cells are placed in a hypertonic solution, they will shrink. Tonicity adjusters include but are not limited to salts, such as sodium chloride; and sugars, such as mannitol, and are present in sufficient quantities in the inventive compositions for an approximately iso-tonic preparation. In the inventive compositions, the tonicity and pH of the composition are adjusted to physiological conditions. For examples, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easter, Pa., 15th Edition (1975).
The preparation of the inventive compositions and methods for sub-Tenon delivery of pharmaceutically active agents or pharmaceutically acceptable salts or solvates thereof, are described in detail in the following examples. One of skill in the art will recognize that the compositions and methods described herein may be readily adapted to prepare a number of other compositions of the invention for sub-Tenon, intraocular, systemic or topical delivery.
Examples Example 1 : Bioanalytical Procedure For The Determination Of The Compound Of Formula I In Human Plasma (Sodium Heparin) Using LC- API/MS/MS
The compound of Formula I and an internal standard (the compound of Formula l-d7) are extracted from 500 μ!_ of human plasma (sodium heparin) by liquid-liquid extraction using 50:50 ethyl acetate: hexane. After evaporation to dryness and reconstitution, the extracts are analyzed by LC-API/MS/MS. Run times are approximately 2.5 minutes. The Lower Limit of Quantitation (LLOQ) for the compound of Formula" I is 0.0100 ng/mL (Figure 1). The range of reliable response is 0.0100 - 10.0 ng/mL.
This Bioanalytical Procedure is based on the results of a full validation study in human plasma. The associated results and narrative are in ALTA's validation reports AR139K. Acceptance Criteria
Based on the results of the validation referenced above: 1. Acceptable analytical runs should have standard curves where at least 75% of the individual standards meet method criteria. Deviations (%DEV) of the back-calculated standards must be within ±15% of the nominal concentration, except for the LLOQ, which is allowed a ±20% deviation. The calculated concentration of at least one of the duplicate lowest points in the standard curve shall meet criteria to qualify as a LLOQ. If this criterion is not met, the LLOQ may be raised to the next level. 2. The calculated concentrations of acceptable analytical QCs must be within
±15% of the nominal concentration. At least two-thirds of all analytical QCs shall meet the given criteria, with each QC level being represented.
3. The calculated concentrations of acceptable dilution QCs must be within ±15% of the nominal concentration. At least two-thirds of the dilution QCs shall meet the given criteria for each dilution scheme. If the dilution QCs for a given dilution scheme do not meet criteria, then all of the study samples associated with that dilution scheme must be repeated.
4. If the criteria for both the standard curve and analytical QCs are not met, the analytical run is rejected. Revision Notes
Revision 1 was generated to add assessment, precautions and means of protection against injector carryover effects including the addition of new rinse solvents. Analytical Procedures Equipment and Apparatus
SCIEX API 4000TM mass spectrometer, (PE-SCIEX Concord, Ontario, Canada) Shimadzu LC-10AD HPLC pumps (2) with mixing tee (or equivalent) Shimadzu SCL-10A Controller (or equivalent) HTS-PAL or HTC-PAL Autoinjector (or equivalent)
IEC Centra GP8R Centrifuge (or equivalent) TurboVap LV Evaporator
Reagents and Chemicals
The reference substance, the compound of Formula I1 and the internal standard (the compound of Formula l-d7), are obtained from Agouron Pharmaceuticals, Inc.- A Pfizer Company. When used, acetonitrile (ACN), methanol (MeOH), ethyl acetate, hexane and
H2O are HPLC grade or equivalent.
The following procedures for the preparation of reagents and solutions are provided as examples only. Other preparations may be substituted provided that the final concentrations remain the same.1 1. Make-up Reagent / Dilution Solvent: 50:50 MeOH:H2O Combine equal volumes of MeOH and H2O.
2. 1 M NH4OAc (ammonium acetate) Dissolve 77.09 g NH4OAc in 1 liter H2O.
3. 5 mM NH4OAc Combine 5 mL of 1 M NH4OAc and 995 mL of H2O.
4. 50:50 ethyl acetate:hexane Combine 500 mL of ethyl acetate and 500 mL hexane.
5. Resconstitution Solvent: 50:50 MeOH:5 mM NH4Oac. Combine 50 mL of MeOH and 50 mL of 5 mM NH4OAc.
6. Mobile Phase A: 0.1% formic acid Combine 999 mL of H2O and 1 mL formic acid. 7. Mobile Phase B: ACN with 0.1% formic acid Combine 999 mL of ACN and 1 mL formic acid.
8. Autoinjector Rinse 1: (50:50 ACN:H2O) with 0.3% Polyethyleneimine (PEI): Combine 500 mL of ACN, 500 mL of H2O and 3 mL PEL
9. Autoinjector Rinse 2: (10:90 MeOH:H2O) with 0.5% formic acid: Combine 100 mL of MeOH, 900 mL of H2O and 5 mL formic acid. Mix the solution well, and allow the solution to reach room temperature before use. Preparation of Standards and Quality Control Samples
The following procedures are provided as examples for the preparation of Calibration Curve (CC) and Quality Control (QC) solutions. Other weighings and dilutions may be substituted for the examples below provided that the calibration range is not changed and that the QC concentrations are approximately the same as given. Example calibration curve points are shown below.
1. CC and QC Stock Solutions a) Prepare a CC stock solution of the compound of Formula I in MeOH at 100 μg/mL. b) Prepare a QC stock solution of the compound of Formula I in MeOH at 100 μg/mL from an independent weighing.
2, CC Spiking Solutions Prepare CC substock and spiking solutions in Dilution Solvent (50:50
MeOH :H2O) as shown below:
Figure imgf000027_0001
3. Internal Standard Solutions a) Prepare 100 μg/mL internal standard (IS) stock solution of the compound of Formula l-d72.
5 b) Prepare the IS spiking solution in Dilution Solvent fresh on the day of analysis as shown below:
Figure imgf000027_0002
Can be prepared from a separate weighing or by diluting from a higher concentration (e.g., 1 mL of a 1 mg/mL stock solution of the compound of Formula l-d7 to 1O mL with MeOH).
10 Pooled Matrix QCs
QCs are prepared by spiking control matrix (Human Plasma with sodium heparin) with a 10 μg/mL QC substock solution of the compound of Formula I (made by diluting 1 mL of the QC stock solution to 10 mL in MeOH) and then diluting with control matrix to the appropriate concentrations. An example of QC preparation is described
15 below:
Figure imgf000027_0003
c) After fortification, thoroughly vortex mix each QC pool. d) Aliquot a suitable amount (e.g., 1.2 mi_) of each QC pool into labeled polypropylene tubes (e.g., 2 ml_). e) Store pooled QC samples frozen at -200C until use.
4. Test Solution for System Suitability A test solution containing the compound of Formula I (0.025 ng/mL) at or near the concentration of the final extract of the LLOQ and the IS (5 ng/mL) may be prepared or the low calibration curve point may be used for the test injection. To make the former, combine 50 μL of 5 ng/mL of the compound of Formula I (e.g., CC-0.5) and 2.5 mL of 20 ng/mL of the compound of Formula l-d7 (e.g. IS spiking solution), and dilute to a final volume of 10 mL in Reconstitution Solvent (50:50 MeOH:5 mM NH4OAc). Control and Blank Definitions
1. Blank without IS (BI/BO: samples identified as BI/BI contain control matrix and are not fortified with internal standard.
2. Blank with IS (BI/IS): samples identified as BI/IS contain control matrix and are fortified with internal standard.
3. Solvent Blank: a suitable solvent or mobile phase is used to demonstrate lack of background or carry-over from the chromatography system.
Special Considerations
Protect samples and extracts from light. Additional BI/BI samples should be extracted for protection of samples from injector carryover effects. Stepwise Extraction Procedure
1. Label all tubes (16 x 125- mm screw cap glass tubes or equivalent).
2. Thaw control matrix, QCs, and study samples to room temperature.
3. Mix the control matrix, QC, and study sample containers. 4. Centrifuge samples if necessary to remove particulates.
5. To the appropriate tubes: a) Pipet 500 μL of control matrix (Human Plasma with sodium heparin) to each tube labeled BI/BI (N>1), BI/IS (N>1) and calibration curve (N=2). b) Pipet 500 μL of the QC (N>2 at the low, mid, and high levels) and study samples (N=1) into their appropriately labeled tubes. If a smaller sample aliquot is taken, dilute (QS) to 500 μL with control matrix or dilute with control matrix in a separate tube and pipet a 500 μL aliquot into the extraction tube. c) If study samples are diluted, a set of QC samples (N=3) must be diluted in the same manner as the study samples. 6. Add 50 μL of each CC spiking solution to the appropriate calibration curve tube
(prepare in duplicate).
7. Add 50 μL of the IS spiking solution (20 ng/mL of the compound of Formula I- d7, made fresh on the day of analysis) to each labeled tube except for any BI/BI.
8. Add Make-up Reagent (50:50 MeOH:H2O): a) Add 100 μL of Make-up Reagent to the BI/BI sample(s). b) Add 50 μL of Make-up Reagent to the BI/IS, QC and study samples.
9. Vortex mix (~5-10 seconds).
10. Add ~8 ml_ of 50:50 ethyl acetate: hexane to each tube. 11. Cap (polypropylene or teflon) and mix on an orbital shaker for ~5 minutes at
-100 RPM.
12. Centrifuge samples at a setting of 2500 RPM for 5 minutes
13. Carefully freeze the aqueous phase using a dry ice/solvent bath or by placing the tubes in a -70oC freezer (~30 minutes). 14. Decant the supernatant into glass tubes suitable for use in the Turbo-vap.
(e.g., 16 X 100 mm glass culture tubes or equivalent).
15. Evaporate to dryness with nitrogen at 30°C.
16. Reconstitute with 200 μL of Reconstitution Solvent (50:50 MeOH:5 mM NH4OAc) and vortex briefly (~10-20 seconds). 17. Transfer to amber autoinjector vials with polypropylene inserts (or equivalent).
18. Sample extracts may be stored refrigerated until analysis. Chromatography
Separation is achieved by reversed-phased chromatography. HPLC Operating Conditions:
Column: Keystone Betasil C18, (5 μm) 100 x 2 mm (Thermo Hypersil-Keystone)
Guard: Keystone Betasil C18, (5 μm) 10 x 2 mm (Thermo Hypersil-Keystone)
Column Temp.: Ambient
Injection Vol.: 30 μL (different injection volumes may be used if chromatographic integrity is maintained)
Flow Rate: 0.4 mL/min
Mobile Phase: Isocratic, 55:45 (v/v) Mobile Phase A:Mobile Phase B
Figure imgf000029_0001
A 0.5 μm stainless steel precolumn filter and/or a frit may be added to prolong column life. The precolumn filter may be used for several analytical sets if no significant increase in backpressure is observed
Suitable reagents for the autoinjector rinse(s) are Autoinjector Rinse 1 and 2. Other suitable rinse reagents may be used. Mass Spectrometric Detection Detection is by tandem mass spectrometry (MS/MS). The HPLC system is coupled to the mass spectrometer using a TurbolonSpray™ atmospheric pressure ionization inlet. The analysis is by positive ionization MS/MS. High purity nitrogen gas from a high pressure liquid nitrogen dewar is used for the nebulizer, TurbolonSpray™ and curtain gases. Other sources of nitrogen or air may also be used.
Detection is in the multiple reaction monitoring mode (MRM). The collision gas used to produce fragment ions is high purity nitrogen.
If adequate sensitivity is achieved, the column effluent may be split post-column at an appropriate split ratio using a zero dead volume tee (Valco, Houston, TX or equivalent), otherwise all of the effluent can be directed toward the inlet.
The following reactions are monitored:
Figure imgf000030_0001
The following instrument parameters were used during the validation. Actual parameter values may be changed from day to day as the instrument is optimized for sensitivity. The actual parameter values used for an analysis set must be documented in the raw data.
Mass Spectrometer Parameters:
ISV Voltage (IS): 4400 V
Curtain Gas (CUR): 15
Turbolonspray Temp. (TEM): 7000C
Collision Pressure (CAD): N2 @ 7
Deciustering Potential (DP) 90
Collision Energy (CE) 59
GS1: 50
GS2: 75 Quantification Method
Peak areas are integrated using Applied Biosystems/MDS SCIEX Analyst™ software. A smoothing factor may be used. If used, the same smoothing factor must be used for all integrations in a given set. Calibration curves are derived from peak area ratios (analyte/internal standard) using a least squares regression of the ratio versus the nominal concentration of the calibration curve standard. Deviations from the regression line are calculated by using the regression equation to back calculate the concentration at each calibration standard level. Concentrations of QC samples are also calculated from these regression curves, using the calculated peak area ratios.
Figure imgf000030_0002
*where x is the concentration of a given calibration standard level THE COMPOUND OF FORMULA I HUMAN PLASMA PARAMETERS LOG Project: Mode: ISV Recorded by: Instrument: SX9
Figure imgf000031_0001
Example 2: The Compound Of Formula I (VEGFR Inhibitor) Achieves Effective
Choroidal Concentrations With Minimal Systemic Effects in Cynomolgus Monkeys and Humans With Age-
Related Macular Disease
The compound of Formula I may be delivered by sub-Tenon administration to the back of the eye proximate the macula in order to minimize side effects. The compound of Formula I, has been found to be a potent inhibitor of VEGFR2 tyrosine kinase activity, and is selective against VEGFR tyrosine kinase. This compound has also shown potent, sustained and reproducible inhibition of angiogenesis in the eye in several preclinical models including prevention of neovascularization and regression of existing vessels with reduction of leakage.
The compound of Formula I shows low drug solubility, ~ 0.8 μg/ml in PBS and about 5 μg/ml in vitreous. This compound binds tightly to proteins, for example, serum binding is ~99.9%. Such high protein binding and low solubility means that the drug forms a depot that is slowly cleared. For example, ^C radioequivalents of the compound of Formula I were taken up primarily in pigmented tissues and persisted through 8 weeks postdose. Thus, drug levels in ocular tissues reach an equilibrium status and remain relatively constant for extended periods. Furthermore, the physicochemical characteristics for this compound are appropriate for sub-Tenon administration.
In the clinic, a phase I/I I1 randomized, masked, single and multiple-dose, sequential dose-escalation study of the safety and efficacy of the compound of Formula I in subjects with subfoveal choroidal neovascularization associated with age related macular degeneration was preformed. This study type ran included a randomized, masked, phase I/I I single and multiple sequential dose-escalation with repeat posterior sub-Tenon dosing of the compound of Formula I for 52 weeks and additional 52 weeks follow up. This study involved two stages in which stage 2 was preformed after safety was demonstrated at 13 weeks. The participants in these studies included: 144 males and females with exudative age related macular degeneration (AMD) including nonexudative (Dry) and exudative (Wet) AMD > or = 55 yrs with subfoveal choroidal neovascularization in all subtypes. Their visual acuity was measured to be 73 to 24 letters (20/40 20/320), with one prior PDT allowed if within 3 months before screening., The number of groups in this study involved: four arms in 3 cohorts: 50 mg (q13 and 26 w), 150 mg (q26 w) and 600 mg (q52 w), in which the participating study centers were the Netherlands (4), U.S. (24), U.K. (6) and Australia (5), with one independent reading center at the University of Wisconsin FPRC.
The primary endpoints in this study were as follows: ocular and systemic safety for 13 weeks following a single sub-Tenon administration and for 104 weeks following multiple administrations. The failure rate: % subjects losing = fewer than 15 letters. Secondary endpoints included: the response rate % subjects gaining > or = 15 letters; the mean change of visual acuity from baseline; changes in fundus photographs, fluorescein angiography and OCT; pharmacokinetics of the compound of Formula I after sub-Tenon administration; and the change in health related quality of life scores.
In terms of clinical safety, the longest follow-up period was 12 months (4 injections); with Treatment-related AEs - 8/60 (13%) of subjects (all mild); no drug- related SAEs; and no deaths.
In humans, the compound of Formula I shows an assay sensitivity: 10 pg/mL; plasma concentrations were measured during Stage 1 ;of 378 samples collected, 35 (9%) samples with measurable plasma concentrations; of 35 patients on active drug, 19 (54%) patients with at least 1 measurable plasma concentration; the highest measurable plasma cone: 102 pg/mL (day 3); no measurable plasma concentration after week 4. The plasma concentrations were lower than the anticipated minimum effective tissue concentration estimated to be IC90 = 60 ng/g. In the masked efficacy study, 47 subjects completed 13-week visit in the low (50 μg), mid-dose (150 μg) & high-dose (600 μg) cohorts, in which 42 were active and 5 were placebo. Visual acuity changes from baseline at the end of 13-week follow-up period were as follows: 4 subjects gained 15 or more letters; 36 subjects had stabilization of vision (within ±14 letters from baseline); and 7 subjects lost 15 or more letters.
The compound of Formula I is a potent and effective small molecule inhibitor of VEGFR2. In preclinical species, the compound of Formula I exceeds target concentrations in the choroid for at least 16 weeks. Human plasma concentrations have been demonstrated to be significantly below therapeutic levels. In a phase l/ll trial to date, no significant side effects have been observed. Thus, the compound of Formula I is potentially an effective drug for the treatment of neovascular age related macular degeneration including nonexudative (dry AMD) and exudative (wet AMD).
Example 3: Ocular and Systemic Pharmacokinetics of the compound of Formula I with Sub-Tenon Administration to Cynomolgus Monkeys
The compound of Formula I1 a VEGFR tyrosine kinase inhibitor, is in clinical development with sub-Tenon administration for treatment of choroidal neovascularization associated with age-related macular degeneration. The ocular and systemic distribution of the compound of Formula I was evaluated in cynomolgus monkeys following sub- Tenon administration.
Single-dose pharmacokinetic and toxicokinetic studies were conducted in male and female cynomolgus monkeys. The compound of Formula I was administered by sub- Tenon injection in a sterile sucrose suspension at doses several-fold above possible clinical doses. Drug deposition was targeted posterior to the macula and adjacent to the optic nerve. Plasma was collected up to 48 hours post-dose. Ocular tissues, including choroid, retina, dose site tissue, ocular muscle, sclera, vitreous, iris-ciliary body, lens and aqueous humor were collected at various timepoints up to 16 weeks in one study. Dose site tissue, choroid, retina and vitreous concentrations of the compound of Formula I were measured at 13 weeks in a subsequent study. Plasma and tissue concentrations were evaluated by LC-MS/MS.
Plasma levels of the compound of Formula I were below 0.2 ng/mL in all but one sample for all dose groups. The compound of Formula I was observed up to 16 weeks in dose site tissue (conjunctiva and fatty tissue taken adjacent to the sclera at the site of administration) after a single sub-Tenon dose at all dose levels tested. The compound of Formula I concentrations in choroid, the target tissue for age-related macular degeneration, were achieved within 3 days and were sustained for up to 16 weeks at 25 to 125 times the IC90 of the compound of Formula I for VEGF-R2 inhibition in a rat retina PK/PD model. Retina concentrations of the compound of Formula I were generally at or below the IC90. Ocular muscle, also encased by Tenon's membrane, showed modest but variable levels. Concentrations of the compound of Formula I in sclera samples increased up to 8 weeks, then decreased at 12 and 16 weeks. Very low levels of the compound of Formula I were observed in the iris-ciliary body or lens and low or no levels were detected in vitreous or aqueous humor.
Figure imgf000034_0001
8 1 2 1 6
Tim e pos t-d os e (w e e ks )
The compound of Formula I (i.e., AG-013958) is a VEGFR inhibitor which achieves effective choroidal concentrations with minimal systemic effects in cynomolgus monkeys and humans with age-related macular degeneration. Sub-Tenon administration of the compound of Formula I suspension produced a depot of drug on the posterior surface of the sclera that provided sustained exposure to the choroid with little impact on peripheral tissues and no measurable systemic exposure. This data supports the preclinical safety assessment of the compound of Formula I, reported separately, and also the ongoing clinical assessment of this compound for treatment of age-related macular degeneration.
Figure imgf000034_0002
Figure imgf000035_0001
a Nominal dose. The actual dose delivered was ~75% of nominal. n = 3 except at 12 and 16 weeks, where n = 1.
The physiochemical properties of the compound of Formula I include low drug solubility: ~0.8 μg/ml in PBS; about 5 μg/ml in vitreous; binds tightly to proteins; serum binding ~99.9%; High protein binding and low solubility means that the compound of Formula I forms a depot which is slowly cleared, thus allowing the drug levels in the tissue reach equilibrium and stay relatively constant for extended period. These physicochemical characteristics are appropriate for sub-Tenon administration.
Figure imgf000035_0002
The compound of Formula I is a potent and effective small molecule inhibitor of
VEGFR2. In preclinical species, the compound of Formula I exceeds target concentrations in the choroid for at least 16 weeks. Human plasma concentrations of the compound of Formula I have been demonstrated to be significantly below therapeutic levels. In a phase l/ll trial to date, no significant side effects have been observed. The compound of Formula I is potentially an effective drug for the treatment of neovascular age-related macular degeneration 1158
- 34 -
Example 4: Assessment of a VEGF Receptor Tyrosine Kinase Inhibitor, the compound of Formula I, in Rabbits and Primates Following Ocular Administration
The compound of Formula I is a vascular endothelial growth factor receptor tyrosine kinase inhibitor currently in Phase l/ll clinical trails for the treatment of neovascular ocular diseases such as age-related macular degeneration. The safety of the compound of Formula I was assessed in a series of nonclinical studies in rabbits and primates by sub-Tenon (ST), intravitreal (IVT) or intravenous (IV) administration at doses 1 -30-fold (in each eye) above the anticipated clinical dose. A single sub-Tenon dose (intended clinical route of administration) of the compound of Formula I produced no macroscopic compound-related findings for up to 13 weeks of treatment in primates. Microscopic evaluation of ocular and systemic tissues revealed the presence of macrophages at the sub-Tenon dose site at 8 and 13 weeks post-treatment. This finding was consistent with a foreign body reaction to the presence of the compound of Formula I and was not associated with tissue injury or a fulminating inflammatory response. The primary finding in studies utilizing the IVT route of administration in rabbits and primates was the identification of test article grossly visible within the vitreous of both species for up to 8-weeks post injection. The presence of macrophages in the vitreous of rabbits with IVT dosing was considered a foreign body reaction. The doses selected for the IVT studies produced the compound of Formula I choroidal concentrations 2-3-fold above those tested with sub-Tenon dosing. The compound of Formula I given as a single bolus IV dose at the highest IVT dose selected did not produce evidence of systemic toxicity up to five days after treatment. Overall, the preclinical safety assessment of the compound of Formula I demonstrates that the compound is well tolerated in rabbits and primates and supports the further development of this compound for the potential treatment of age related macular degeneration (AMD) including nonexudative (dry AMD) and exudative (wet AMD).
Ocular vascular diseases, such as age-related macular degeneration are the leading causes of vision loss and blindness in the United States (1). Vascular endothelial growth factor (VEGF) has been implicated in angiogenesis and inhibition of VEGF pathways has demonstrated promise as pharmaceutical interventions in the treatment of choroidal neovascularization (2). The compound of Formula I is a small molecule that inhibits the activity of the tyrosine-kinase (TK) domain of vascular endothelial growth factor receptor 2 (VEGF-R2). The compound of Formula I is currently in Phase l/ll clinical trials as an angiogenesis inhibitor intended for the treatment of choroidal neovascularization in subjects with age-related macular degeneration. The clinical route of delivery is by sub-Tenon (ST) administration. This research investigated the preclinical safety assessment of the compound of Formula I in Dutch-belted rabbits and cynomolgus monkeys by sub-Tenon and intravitreal (IVT) administration, as well as in the rabbit by intravenous bolus injection.
Materials and Methods Animals: Male and Female Dutch Belted Rabbits (1 ,5 - 2 kg) and cynomolgus monkeys (2 - 4kg).
All animal related activities were conducted under an IACUC approved protocol in compliance with Animal Welfare Act regulations and the Guide for the Care and Use of Laboratory Animals. This research conforms to the ARVO recommendations for Use of Animals in Ophthalmic and Visual Research. Ocular Administration
Sub-Tenon Administration in Primates: Animals were anesthetized (xylazine/ketamine) and a small incision (1-2 mm) was made in the inferior temporal quadrant of the eye to expose the sclera and access the sub-Tenon space. A curved 23 gauge blunt cannula was inserted into the sub-Tenon space and advanced in a posterior direction. A 0.5 ml bolus injection of the compound of Formula I or vehicle (sucrose based formulation) was administered.
IVT Administration in Primates and Rabbits: Animals were anesthetized (xylazine/ketamine) and a 27 gauge needle was inserted approximately 3 mm posterior to the limbus in the superior/temporal quadrant. The bevel of the needle was in an anterior position and advanced to the mid vitreous. A 0.05 ml bolus injection of the compound of Formula I or vehicle (hyaluronic based formulation) was administered. Experimental Design:
Rabbit and Primate IVT Studies
Figure imgf000037_0001
-Vehicle, OD Vehicle, Vehicle, Low, Mid
-AG-013958, OU Low, Mid and High dose
(5μg, Low, 50μg, Mid; and High groups
500μg High dose) dose groups Primate Sub-Tenon Study
Figure imgf000038_0001
Notes:
•Termination endpoints: full necropsy; hematology; clinical biochemistry; histopathology
I Ophthalmic Exams; Intraocular Pressure readings I Electroretinograohy (ERG) Exams
Results:
Rabbit IVT
Dose (AG-0139S8) Vehicle Low M id High
Number of Animals M :4 F:4 M :4 F:4 M :4 F:4 M :4 F:4
NotcΛVorthy findings
Died or Euthanized Moribund O 0 0 0 0 r lb 0
Ophthalmoscopy'
Vitreous opacity (4 and 8 - to -/+ -/+ to + -/+ to ++ weeks)
Gross Pathology
Number examined'1 4/4 4/4 4/4 4/4 4/4 4/4 4/4 4/4
Eye — pale material 0/0 0/0 0/0 0/0 2/1 2/0 3/3 4/2
Histopathology
Number examined11 4/4 4/4 4/4 4/4 4/4 4/4 4/4 4/4
Macrophage accumulation 0/0 0/0 0/3 1/1 4/3 4/4 3/3 4/3 in vitreous
Mixed cell accumulation in 0/0 0/0 0/0 0/0 1/0 0/0 1/0 2/0 vitreous
On Day 56, unknown cause bOn Day 8, unknown cause
°- none; -/+ very slight; + slight; ++ moderate; +++ severe d4/4 means 4 eyes from 4- week cohort and 4 eyes from 8- week cohort
M : Males, F:Females
Monkey IVT
Dose (AG-0i3958) Vehicle Low Mid High Number of Animals M:4 F:4 M:4 F:4 M:4 F:4 M:4 F:4
Died or euthanized Moribund 0 0 0 0 0 0 0 0
Ophthalmoscopy "
Vitreous/lens opacity (4 and 8 + ++ +++
Weeks)
Gross Pathology (Number eyes 3/3 3/3 3/3 3/3 3/3 3/3 3/3 3/3 examined)'
Eye - pale material 0/0 0/0 0/1 0/0 0/1 0/0 2/1 3/1
" - none; -/+ very slight; + slight; ++ moderate; +++ severe b3/3 means n = 3 from 4 week cohort and n = 3 from 8 week cohort
M: Males, F:Females Monkev Sub-Tenon: 13 wks
Dose (AG-0139S8) Low High
Number of Animals Malcs:7 M ales:7
Noteworthy findings
Died or Sacrificed Moribund 0 0
G ross Pathology:
Presence of test material at Sub-
Tenon dose site
Day 3 3/3° 3/3
Week 4 1/3 3/3
Week 8 5/6 6/6
Week 12 1/1 1/1
Week 16 1/1 1/1
H istopathology:
Presence of m acrophages at Sub-
Tenon dose site
8- Weeks 0/3° 1/3
Severity1" - -/+
' Incidence of the observation per the number of eyes examined b — none; -/+ very slight; + slight; + + moderate; +++ severe
Monkey ST: 0.5-16 wks
Dose(AG-O13958) Vehicle Low Md
Number of Animals Ml Rl Ml F:2 Ml Fi2 Ml R2
Noteworthy findings
Died or Sacrificed Moribund 0 0 0 0
Grass Pathology:
Presence of test material at Sub-
Tenαn dose site
13-Weeks 5/ff 6/6 616
Histopathology
Presence of foamy macrophages at sub-Tenon dose site
13-Weeks l/3b 3/3 2/3
Severity0 -/+ -/+ -/+to+
"Incidence of the observation per Hie number of animals examined "incidence of the observation per thenutriber of eyes examined c-nαne; -/+ very slight; +slight; -H-moderate; -H+ severe M Males, RFemales
The compound of Formula I was well tolerated by sub-Tenon, IVT and intravenous administration, Electroretinography and ophthalmic exams were within normal limits throughout the duration of the study following sub-Tenon administration.
Systemic toxicity as determined by the endpoints captured in this research was not observed following ocular administration of the compound of Formula I. The compound of
Formula I administered by intravenous injection did not produce systemic toxicity as determined by clinical observations and histopathology of tissues.
Example 5: Ocular and Systemic Pharmacokinetics of The Compound of
Formula I with Sub-Tenon Administration to Cynomologus Monkeys
The compound of Formula I1 a VEGFR tyrosine kinase inhibitor, is in clinical development with sub-Tenon administration for treatment of choroidal neovascularization associated with age-related macular degeneration. The ocular and systemic distribution of the compound of Formula I was evaluated in cynomolgus monkeys following sub- Tenon (ST) administration.
Single-dose pharmacokinetic and toxicokinetic studies were conducted in male and female cynomolgus monkeys. The compound of Formula I was administered by sub- Tenon injection in a sterile sucrose suspension at doses several-fold above possible clinical doses. Drug deposition was targeted posterior to the macula and adjacent to the optic nerve. *Plasma was collected up to 48 hours post-dose. Ocular tissues, including choroid, retina, dose site tissue, ocular muscle, sclera, vitreous, iris-ciliary body, lens and aqueous humor were collected at various timepoints up to 16 weeks in one study. Dose site tissue, choroid, retina and vitreous concentrations of the compound of Formula I were measured at 13 weeks in a subsequent study. Plasma and tissue concentrations were evaluated by LC-MS/MS.
Plasma levels of the compound of Formula I were below 0.2 ng/mL in all but one sample for all dose groups. The compound of Formula I was observed up to 16 weeks in dose site tissue (conjunctiva and fatty tissue taken adjacent to the sclera at the site of administration) after a single sub-Tenon dose at all dose levels tested. The compound of Formula I concentrations in choroid, the target tissue for age-related macular degeneration, were achieved within 3 days and were sustained for up to 16 weeks at 25 to 125 times the IC90 of the compound of Formula I for VEGF-R2 inhibition in a rat retina PK/PD model. Retina concentrations of the compound of Formula I were generally at or below the IC90. Ocular muscle, also encased by Tenon's membrane, showed modest but variable levels. Concentrations in sclera samples increased up to 8 weeks, then decreased at 12 and 16 weeks. Very low levels of the compound of Formula I were observed in the iris-ciliary body or lens and low or no levels were detected in vitreous or aqueous humor.
Sub-Tenon administration of the compound of Formula I suspension produced a depot of drug on the posterior surface of the sclera that provided sustained exposure to the choroid with little impact on peripheral tissues and no measurable systemic exposure. This data supports the preclinical safety assessment of the compound of Formula I1 reported separately, and also the ongoing clinical assessment of this compound for treatment of age-related macular degeneration.
The following studies were conducted in cynomologus monkeys to determine the ocular and systemic distribution of the compound of Formula I. This compound was prepared in sterile sucrose suspension.
In the 16 week study male and female monkeys were lightly anaesthetized and dosed 0.5mL/eye of the compound of Formula I. Two groups were dosed via sub-Tenon injectionwith 50 or 1500 μg/eye. Blood samples were taken at 1, 2, 4, 8, 12, 24, 48, 72 hours and at 4 and 8 weeks post dose. Animals were euthanized and end points were at day 3, week 4, 8, 12 and 16. Eyes were enucleated, dissected and ocular tissues collected were dose site, choroid, retina, vitreous humor, aqueous humor, lens, sclera, iris-ciliary body and ocular muscle. Samples tested were analyzed by LC/MS/MS.
In the 13-week study three groups of male monkeys were lightly anesthetized and dosed with 50, 250 or 1500 μg/eye of the compound of Formula I. Dosing was bilateral via sub-Tenon injection near the optic nerve. Blood samples were collected at 1 , 6 and 24 hours post dose. After dissection ocular tissues collected at 13 weeks were dose site, choroid, retina and vitreous humor. Ocular tissues and plasma samples were analyzed by LC/MS/MS. Tissues Analyzed: Choroid; Dose Site*; Retina; Iris-ciliary body; Sclera; Ocular muscle; Vitreous humor; Aqueous humor; Lens; Plasma.
*Dose Site tissue consists of conjunctiva and fatty tissues of the sub-Tenon space collected from the region of drug deposition posterior to the macula and adjacent to the optic nerve. ANALYTICAL
Dose Site tissue, sclera, ocular muscle and lens - CAN (acetonitrile) with 0.1% TFA (trifluoroacetic acid).
Retina and Choroid - Protein precipitation with ACN:MeOH
Plasma, Aqueous and Vitreous Humor - Liquid-liquid extraction with ethyl acetate.
LOQ: Retina - 0.2 ng/g (concentration corrected for tissue weight) Choroid - 0.5 ng/g (concentration corrected for tissue weight) Plasma - 0.2 ng/mL Vitreous - 0.5 ng/mL
Dose Site tissue, sclera, ocular muscle and lens - 0.5 ng/mL RESULTS
Results from these studies shows that the compound of Formula I was detected in dose site tissues at both doses up to 16 weeks. Amounts of 1 μg or more were found at 13 weeks in the 50μg/eye dose group.
The compound of Formula I concentrations of at least 1 ,100 ng/g choroidal tissue, were detected by day 3 and maintained up to 16 weeks. Concentrations found in both studies were 25 to 125-fold higher than the target IC90.
The compound of Formula I concentrations in retina were lower than the target IC90 and variable. The compound of Formula I was detected at modest levels in ocular muscle and iris-ciliary body and at low levels in a few samples of lens and vitreous humor. The compound of Formula I was not detected in aqueous humor or in plasma and there were no significant systemic or ocular toxicological findings. The compound of Formula I was detected in the choroid at 25 to 125-fold higher than the targeted efficacious concentration (IC90) as early as 3 days and maintained for up to 16 weeks. The compound of Formula I concentrations in retina were much lower and more variable than choroid and dose site. The compound of Formula I did not cause any ocular or systemic toxicities.
Accumulation of the compound of Formula I in dose site tissue and choroid demonstrates slow release of the drug and suggests long intervals for dosing in the clinic. Example 6: Sub-Tenon Injection To Female Dutch Belted Rabbits
Female Dutch Belted rabbits (1.5-2 kg) were anesthetized (Ketamine/Xylazine cocktail) and both eyes were prepared for sterile sub-Tenon injection. Each eye was administered a 0.5 ml bolus injection of test excipient or formulation using a curved 23G needle. Animals were observed for 1 week post-dose for clinical signs of toxicity/irritation.
Eyes were also enucleated and fixed in Davidson's solution for histological examination.
As shown in Table I1 vehicle excipients for the compositions and methods described herein include flocculating agents such as benzalkonium chloride, docusate sodium and sodium lauryl sulfate, carboxy methylcellulose (CMC; low (90 kDa), mid (250 kDa) and high (700 kDa) molecular weight (MW), 0.25-1.0%), Polysorbate™ 80 (0.02 and
0.2%), polyethylene glycol 3350 (PEG 3350; 0.2 and 1.0%), Poloxamer™ 188 (0.01 and
0.25%), Nano-Edge (Poloxamer™ 188 and PEG 3350 combination) and methylcellulose (MC; 0.25%); tonicity agents such as mannitol and salts such as NaCI and MgCI, and buffers such as PBS buffer.
Table I
Vehicle Excipients
0.02% benzalkonium chloride, 4.5% mannitol, and 1OmM PBS buffer;
0.005% docusate sodium, 0.9% NaCI, and 1OmM PBS buffer;
0.01% sodium lauryl sulfate, 4% mannitol, 0.2% MgCI, and 10 mM PBS buffer;
0.5% Poloxamer"71 188, 0.5% m-PEG-DSPE, 2.25% glycerin, and 10 mM NaH2PO4 buffer;
0.2% PEG 3350, 3.9% mannitol, 0.01% Tween'M 80, 0.29% Na2HPO4, and 0.07% NaH2PO4 buffer (% in g/100mL);
1.0% PEG 3350, 3.9% mannitol, 0.01% Tween™ 80, 0.29% Na2HPO4, and 0.07% NaH2PO4 buffer (% in g/100mL);
0.25% High MW CMC (High Viscosity Aqualon'M CMC, 7HF PH), 0.9% NaCI, and 1OmM NaH2PO4 buffer;
0.5% High MW CMC (High Viscosity Aqualon™ CMC, 7HF PH), 0.9% NaCI, and 1OmM NaH2PO4 buffer; 0.5% Mid MW CMC (Medium Viscosity Aqualon1™ CMC, 7MF PH), 0.9% NaCI, and 1OmM NaH2PO4 buffer;
1.0% Mid MW CMC (Medium Viscosity Aqualon™ CMC, 7MF PH), 0.9% NaCI, and 1OmM NaH2PO4 buffer;
0.5% Low MW CMC (Low Viscosity Aqualon'"1 CMC, 7HF PH), 0.9% NaCI, and 1OmM NaH2PO4 buffer;
1.0% Low MW CMC (Low Viscosity Aqualon™ CMC, 7HF PH), 0.9% NaCI, and 1OmM NaH2PO4 buffer;
0.25% methylcellulose, 0.9% NaCI, and 1OmM NaH2PO4 buffer;
0.2% Tween 80, 5% mannitol, and 1OmM phosphate buffer; 0.2% Tween™ 80, 5% mannitol, and 1OmM phosphate buffer;
0.01% Poloxamer'"" 188, 1OmM phosphate buffer, 0.9%NaCI; 0.25% Poloxamer™ 188, 1OmM phosphate buffer, 0.9%NaCI;
0.1% Poloxamer 188 (488mOsm), 50mg/mL sodium citrate; 0.1% Poloxamer™ 188 (625mOsm), 70mg/mL sodium citrate; sodium citrate buffer, pH 4.0 (1OmM, 283 mOsm); Sodium Citrate Buffer, pH 9.0 (1OmM, 287 mOsm);
0.2% 1500 cP MC, 1OmM phosphate buffer, 0.9%NaCI; 0.2% 4000 cP MC, 1OmM phosphate buffer, 0.9%NaCI;
4% benzyl alcohol (EP grade), 0.2% Polysorbate I M 80, 10 mM Phosphate buffer,
359 mOsm, pH 7.75;
4% benzyl alcohol (high purity grade), 0.2% Polysorbate™ 80, 10 mM Phosphate buffer, 353 mOsm, pH 7.75;
4% benzyl alcohol (NP grade), 0.2% Polysorbate™ 80, 10 mM Phosphate buffer,
354 mOsm, pH 7.72;
0.01% benzalkonium chloride, 0.01% Tween 80, 4.5% mannitol; phosphate buffer
0.02% benzalkonium chloride, 4.5% mannitol; 274 mOsm, pH 7.36; 0.04% benzalkonium chloride, 4.5% mannitol; 274 mOsm, pH 7.36; 0.05% benzalkonium chloride, 4.5% mannitol; 274 mOsm, pH 7.36;
0.01% docusate sodium, 0.9% NaCI, 300 mOsm, pH 7.2;
0.02% sodium laurel sulfate, 0.9% NaCI, 274 mOsm, pH 7.4;
2% PoloxymerIM 182, 0.75% NaCI, 290 mOsm, pH 7.34;
Following sub-Tenon injection, mild redness around the eyelids and conjunctiva surrounding the site of needle entry was observed for most treated eyes that resolved within 2-4 days of treatment in most cases. This effect was independent of the test material administered and was considered to be associated with the sub-Tenon dosing procedure. Overall, the vehicle excipients tested were well tolerated in ocular tissue following sub-Tenon administration. Example 7: Sub-Tenon Formulations
Suitable formulations have been developed for sub-Tenon administration of the compounds of Formula I, Il and III. These compounds were formulated at concentration ranges from about 0.05 to about 10mg/ml; with sodium dihydrogen phosphate buffer at physiological pH; and either sodium chloride or mannitol of sufficient quantity for an approximately iso-tonic preparation.
1. Tween™ 80, from 0.001% to 0.2% by weight; 2. CMC, from 0.01% to 1.0% by weight;
3. Poloxamer™ 188, from 0.01% to 0.25% by weight;
4. Methylcellulose (MC), from 0.1% to 0.25% by weight; and
5. Polyethylene Glycol 3350 (PEG 3350), from 0.01% to 1.0% by weight.
All these formulations can be diluted to achieve drug concentration of at least 0.1 mg/ml upon dilution with a suitable vehicle.
The compounds of Formula Il were diluted with sodium phosphate buffer and either sodium chloride or mannitol of sufficient quantity for an approximately iso-tonic preparation:
1.2 mg/ml 0.25% CMC, 0.01 % Tween™ 80 Autoclaved 10 mg/ml filtered 0.1% MC* + 0.05% Tween™ 80 Irradiated
The compounds of Formula III were diluted with sodium phosphate buffer and either sodium chloride or mannitol of sufficient quantity for an approximately iso-tonic preparation:
1.2 mg/ml 0.01 % Tween™ 80 Autoclaved 10 mg/ml filtered 0.5% CMC+ 0.05% Tween™ 80 Autoclaved
Manufacturing Scheme For Compounds Of Formula I, Il and III:
All surfactant or suspending agent solutions can be prepared as 1-2Ox concentrate and sufficient volume added to achieve target concentration. Provided below is a manufacturing scheme for sub-Tenon compositions containing the compounds of Formula I, Il and III:
Prepare 10 mM pH 7.4 phosphate buffer/0.9% saline solution.
Prepare surfactant solution using PBS. Filter through 0.2 μm filter into clean bottle.
If required, prepare suspending agent solution using PBS. Filter through 0.22 or 5 μm filter into clean bottle.
Weigh out drug substance into suitable dispersing vessel.
Add the required volume of surfactant/suspending agent solution. Place onto magnetic stirrer until the drug is completely wetted. Transfer the suspended drug to a clean mixing vessel and then wash the dispersing vessel into this vessel using PBS.
If used, add required quantity of the suspending agent solution to the mixing vessel. Make up to 80-90% of final volume with PBS.
Mix for 15 minutes using a homogenizer.
Transfer to a measuring cylinder; wash the mixing vessel and mixer head into the bulk with PBS.
Allow to defoam and then make to volume. Transfer to clean bottle and place on a magnetic stirrer. Set mixing speed to ensure that the suspension remains homogenous during filling.
Fill 2 mL vials with 1 ml_ suspension using calibrated 1-5mL.
Stopper and cap all vials.
If required, autoclave the vials (Conditions: 1210C for 15 mins). While the invention has been described with reference to numerous specific compositions, one of ordinary skill in the art will recognize that the invention can be embodied in other specific forms without departing from the spirit of the invention. Thus, one of ordinary skill in the art would understand that the invention is not to be limited by the foregoing illustrative details, but rather is to be defined by the appended claims.

Claims

We Claim:
1. A dosage form, comprising a compound of Formula I, Il or I
Figure imgf000046_0001
or a pharmaceutically acceptable salt or solvate thereof, wherein the compound of Formula I, Il or III is from about 1 μg to about 1,500 μg.
2. The dosage form of claim 1 , wherein the dosage form further comprises one or more pharmaceutically acceptable excipients.
3. The dosage form of claim 1 , wherein the compound of Formula I, Il or III is from about 50 μg to about 1 ,000 μg.
4. The dosage form of claim 1 , wherein the compound of Formula I, Il or III is from about 100 μg to about 600 μg.
5. A method of treating ocular diseases in a mammal, comprising administering to the mammal a composition comprising a therapeutically effective amount of a compound of Formula I, Il or III:
Figure imgf000046_0002
or a pharmaceutically acceptable salt or solvate thereof, wherein the therapeutically effective amount is about 1 μg to about 1 ,500 μg.
6. The method of claim 5, wherein the composition further comprises one or more pharmaceutically acceptable excipients.
7. The method of claim 5, wherein the composition is administered by sub-
Tenon delivery to the eye.
8. The method of claim 5, wherein the ocular disease is selected from age related macular degeneration (AMD) including nonexudative (Dry AMD) and exudative (Wet AMD), choroidal neovascularization, retinopathies such as diabetic retinopathy and retinopathy of prematurity, diabetic macular edema, retinitis, uveitis, cystoid macular edema, glaucoma, and other diseases or conditions of the posterior segment of the eye.
9. The method of claim 5, wherein the therapeutically effective amount is from about 50 μg to about 1 ,000 μg.
10. The method of claim 5, wherein the therapeutically effective amount is from about 100 μg to about 600 μg.
11. The method of claim 5, wherein the composition is administered 1 to 12 times/year.
12. A method of stabilizing visual acuity in a mammal, comprising administering the dosage form of claim 1 to the mammal.
13. A method of improving visual acuity in a mammal, comprising administering the dosage form of claim 1 to the mammal.
14. A method of preventing ocular diseases, comprising administering the dosage form of claim 1 to the mammal.
15. The method of claim 14, wherein the ocular disease is ocular neovascularization.
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