WO2006043172A1

WO2006043172A1 - Pharmaceutical compositions and methods for sub-tenon delivery

Info

Publication number: WO2006043172A1
Application number: PCT/IB2005/003194
Authority: WO
Inventors: Phennapha Khamphavong; Julie Chenghie Ma; Vladislav Nodelman; Hong Qi; Shiwei Shao; Mohannad Mahmound Shawer; Yi Wu; Husam Sadoon Younis
Original assignee: Pfizer Inc.
Priority date: 2004-10-19
Filing date: 2005-10-11
Publication date: 2006-04-27

Abstract

The present invention relates to pharmaceutical compositions and methods for sub-Tenon delivery of such compositions to the posterior segment of the eye proximate the macula.

Description

PHARMACEUTICAL COMPOSITIONS AND METHODS FOR SUB-TENON DELIVERY

Field Of The Invention

The present invention relates to drug delivery, and in particular to pharmaceutical compositions and methods for the delivery of pharmaceutically active agents to the back of the eye. More particularly, the present invention relates to pharmaceutical compositions and methods for sub-Tenon delivery of pharmaceutically active agents to the posterior segment of the eye proximate the macula.

Background 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 betransscleral 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.

Summary

It is an 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.

In one embodiment, the invention provides a pharmaceutical composition 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; and wherein the composition is for sub-Tenon delivery to the posterior segment of the eye proximate the macula.

In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically active agent having Formula I, Il or III, wherein one or more excipients is a polyoxyethylenesorbitan ester.

In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically active agent having Formula I, Il or III, wherein the polyoxyethylenesorbitan ester is polyoxyethylenesorbitan monooleate.

In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically active agent having Formula I, Il or III, comprising from about 0.001% to about 10% polyoxyethylenesorbitan monooleate. In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically active agent having Formula I₁ Il or III, comprising about 0.02% to about 2.0% polyoxyethylenesorbitan monooleate; and the tonicity of the composition is adjusted to physiological conditions with about 5% mannitol.

In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically active agent having Formula I, II or III, wherein the buffer is a phosphate buffer.

In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically active agent having Formula I, Il or III, wherein the phosphate buffer is about a - A - 1 mM to about a 100 mM Na₂HPO₄ buffer, or is about a 1 mM to about a 100 mM NaH₂PO₄ buffer, or mixtures thereof.

In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically active agent having Formula I, Il or III, wherein one or more excipients is a block copolymer of ethylene oxide and propylene oxide, having structure:

HO(C₂H₄O)_x(C₃H₆O)_y(C₂H₄θ)_xH, wherein x is from about 2 to about 150, and y is from about 15 to about 70.

In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically active agent having Formula I, Il or III, wherein x is about 80, and y is about 27.

In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically active agent having Formula I, Il or III, comprising from about 0.001% to about 10% block copolymer.

In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically active agent having Formula I, Il or III, comprising from about 0.01% to about 0.25% block copolymer; and the tonicity of the composition is adjusted to physiological conditions with about 0.9% sodium chloride.

In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically active agent having Formula I, Il or III, wherein the buffer is a phosphate buffer.

In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically active agent having Formula I, Il or III, wherein the phosphate buffer is about a 1 mM to about a 100 mM Na₂HPO₄ buffer, or is about a 1 mM to about a 100 mM NaH₂PO₄ buffer, or mixtures thereof. In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically active agent having Formula I, Il or III, comprising from about 0.001% to about 10% block copolymer; from about 0.001% to about 10% m-PEG-DSPE; and from about 0.01% to about 10% glycerin.

In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically active agent having Formula I, Il or III, comprising about 0.5% block copolymer; about 0.5% m-PEG-DSPE; and about 2.25% glycerin.

In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically active agent having Formula I, Il or III, wherein the buffer is a phosphate buffer. In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically active agent having Formula I, Il or III, wherein the phosphate buffer is about a 1 mM to about a 100 mM Na₂HPO₄ buffer, or is about a 1 mM to about a 100 mM NaH₂PO₄ buffer, or mixtures thereof. In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically active agent having Formula I₁ Il or III, wherein one or more excipients is a polyethylene glycol.

In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically active agent having Formula I, Il or III, wherein the polyethylene glycol is PEG 3350.

In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically active agent having Formula I, Il or III, comprising from about 0.001% to about 10% PEG 3350. In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically active agent having Formula I, Il or III, further comprising a polyoxyethylene sorbitan ester.

In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically active agent having Formula I, Il or III, wherein the polyoxyethylene sorbitan ester is polyoxyethylene sorbitan monooleate.

In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically active agent having Formula I, Il or III, comprising from about 0.001% polyoxyethylene sorbitan monooleate to about 10% polyoxyethylene sorbitan monooleate.

In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically active agent having Formula I, Il or III, comprising from about 0.2% to about 1.0% PEG 3350; and about 0.01% polyoxyethylene sorbitan monooleate; and the tonicity of the composition is adjusted to physiological conditions with about 3.9% mannitol.

In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically active agent having Formula I, II or III, wherein the phosphate buffer is about a 1 mM to about a 100 mM Na₂HPO₄ buffer, or is about a 1 mM to about a 100 mM NaH₂PO₄ buffer, or mixtures thereof. In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically active agent having Formula I, Il or III, wherein one or more excipients is a cellulose derivative.

In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically active agent having Formula I, Il or III, wherein the cellulose derivative is high molecular weight carboxymethyl cellulose.

In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically active agent having Formula I, II or III, comprising from about 0.001% to about 10% high molecular weight carboxymethyl cellulose type. In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically active agent having Formula I, Il or III, comprising from about 0.25% to about

0.5% high molecular weight carboxymethyl cellulose; and the tonicity of the composition is adjusted to physiological conditions with about 0.9% sodium chloride. In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically active agent having Formula I, Il or III, wherein the buffer is a phosphate buffer.

In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically active agent having Formula I, Il or III, wherein the phosphate buffer is about a 1 mM to about a 100 mM Na₂HPO₄ buffer, or is about a 1 mM to about a 100 mM NaH₂PO₄ buffer, or mixtures thereof.

In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically active agent having Formula I, Il or III, wherein the cellulose derivative is middle molecular weight carboxymethyl cellulose. In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically active agent having Formula I, Il or III, comprising from about 0.001% to about

10% middle molecular weight carboxymethyl cellulose.

In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically active agent having Formula I, Il or III, comprising from about 0.5% to about 1.0% middle molecular weight carboxymethyl cellulose; and the tonicity of the composition is adjusted to physiological conditions with about 0.9% sodium chloride.

In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically active agent having Formula I, Il or III, wherein the buffer is a phosphate buffer. In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically active agent having Formula I, Il or III, wherein the phosphate buffer is about a

1 mM to about a 100 mM Na₂HPO₄ buffer, or is about a 1 mM to about a 100 mM NaH₂PO₄ buffer, or mixtures thereof.

In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically active agent having Formula I, Il or III, wherein the cellulose derivative is low molecular weight carboxymethyl cellulose.

In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically active agent having Formula I, Il or III, comprising from about 0.001% to about

10% low molecular weight carboxymethyl cellulose. In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically active agent having Formula I, Il or 111, comprising from about 0.5% to about

1.0% low molecular weight carboxymethyl cellulose; and the tonicity of the composition is adjusted to physiological conditions with about 0.9% sodium chloride. In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically active agent having Formula I, Il or III, wherein the buffer is a phosphate buffer.

In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically active agent having Formula I, Il or III, wherein the cellulose derivative is methylcellulose.

In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically active agent having Formula I, Il or III, comprising from about 0.001% to about 10% methylcellulose.

In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically active agent having Formula I, Il or III, comprising about 0.25% methylcellulose; and the tonicity of the composition is adjusted to physiological conditions with about 0.9% sodium chloride.

In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically active agent having Formula I, Il or III, wherein the phosphate buffer is about a 1 mM to about a 100 mM Na₂HPO₄ buffer, or is about a 1 mM to about a 100 mM NaH₂PO₄ buffer, or mixtures thereof. In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically active agent having Formula I, Il or III, wherein the pharmaceutically active agent is an angiogenesis inhibitor.

In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically active agent having Formula I, Il or III, wherein the angiogenesis inhibitor is an inhibitor of a protein kinase receptor.

In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically active agent having Formula I, Il or III, wherein the protein kinase receptor is a VEGF receptor.

In another embodiment, the invention provides a method for sub-Tenon delivery of a pharmaceutical composition of 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, comprising administering the pharmaceutical composition of claim 1 to the posterior of the eye proximate the macula.

In another embodiment, the invention provides a method for sub-Tenon delivery of a pharmaceutical composition of a pharmaceutically active agent having Formula I, Il or III, wherein one or more excipients is a polyoxyethylenesorbitan ester.

In another embodiment, the invention provides a method for sub-Tenon delivery of a pharmaceutical composition of a pharmaceutically active agent having Formula I, Il or III, wherein the polyoxyethylenesorbitan ester is polyoxyethylenesorbitan monooleate.

In another embodiment, the invention provides a method for sub-Tenon delivery of a pharmaceutical composition of a pharmaceutically active agent having Formula I, Il or III, comprising from about 0.001% to about 10% polyoxyethylenesorbitan monooleate. In another embodiment, the invention provides a method for sub-Tenon delivery of a pharmaceutical composition of a pharmaceutically active agent having Formula I, Il or III, comprising about 0.02% to about 2.0% polyoxyethylenesorbitan monooleate; and the tonicity of the composition is adjusted to physiological conditions with about 5% mannitol.

In another embodiment, the invention provides a method for sub-Tenon delivery of a pharmaceutical composition of a pharmaceutically active agent having Formula I, Il or III, wherein the buffer is a phosphate buffer.

In another embodiment, the invention provides a method for sub-Tenon delivery of a pharmaceutical composition of a pharmaceutically active agent having Formula I, Il or III, wherein the phosphate buffer is about a 1 mM to about a 100 mM Na₂HPO₄ buffer, or is about a 1 mM to about a 100 mM NaH₂PO₄ buffer, or mixtures thereof.

In another embodiment, the invention provides a method for sub-Tenon delivery of a pharmaceutical composition of a pharmaceutically active agent having Formula I, Il or III, wherein one or more excipients is a block copolymer of ethylene oxide and propylene oxide, having structure:

In another embodiment, the invention provides a method for sub-Tenon delivery of a pharmaceutical composition of a pharmaceutically active agent having Formula I, Il or III, wherein x is about 80, and y is about 27.

In another embodiment, the invention provides a method for sub-Tenon delivery of a pharmaceutical composition of a pharmaceutically active agent having Formula I, Il or III, comprising from about 0.001% to about 10% block copolymer. In another embodiment, the invention provides a method for sub-Tenon delivery of a pharmaceutical composition of a pharmaceutically active agent having Formula I, Il or III, comprising from about 0.01% to about 0.25% block copolymer; and the tonicity of the composition is adjusted to physiological conditions with about 0.9% sodium chloride.

In another embodiment, the invention provides a method for sub-Tenon delivery of a pharmaceutical composition of a pharmaceutically active agent having Formula I, Il or III, comprising from about 0.001% to about 10% block copolymer; from about 0.001% to about 10% m-PEG-DSPE; and from about 0.01% to about 10% glycerin. In another embodiment, the invention provides a method for sub-Tenon delivery of a pharmaceutical composition of a pharmaceutically active agent having Formula I, Il or III, comprising about 0.5% block copolymer; about 0.5% m-PEG-DSPE; and about 2.25% glycerin.

In another embodiment, the invention provides a method for sub-Tenon delivery of a pharmaceutical composition of a pharmaceutically active agent having Formula I, Il or III, wherein the phosphate buffer is about a 1 mM to about a 100 mM Na₂HPO₄ buffer, or is about a 1 mM to about a 100 mM NaH₂PO₄ buffer, or mixtures thereof. In another embodiment, the invention provides a method for sub-Tenon delivery of a pharmaceutical composition of a pharmaceutically active agent having Formula I, Il or III, wherein one or more excipients is a polyethylene glycol.

In another embodiment, the invention provides a method for sub-Tenon delivery of a pharmaceutical composition of a pharmaceutically active agent having Formula I, Il or III, wherein the polyethylene glycol is PEG 3350.

In another embodiment, the invention provides a method for sub-Tenon delivery of a pharmaceutical composition of a pharmaceutically active agent having Formula I, Il or III, comprising from about 0.001% to about 10% PEG 3350. In another embodiment, the invention provides a method for sub-Tenon delivery of a pharmaceutical composition of a pharmaceutically active agent having Formula I, Il or III, further comprising a polyoxyethylene sorbitan ester.

In another embodiment, the invention provides a method for sub-Tenon delivery of a pharmaceutical composition of a pharmaceutically active agent having Formula I, Il or III, wherein the polyoxyethylene sorbitan ester is polyoxyethylene sorbitan monooleate.

In another embodiment, the invention provides a method for sub-Tenon delivery of a pharmaceutical composition of a pharmaceutically active agent having Formula I, Il or III, comprising from about 0.001% polyoxyethylene sorbitan monooleate to about 10% polyoxyethylene sorbitan monooleate. In another embodiment, the invention provides a method for sub-Tenon delivery of a pharmaceutical composition of a pharmaceutically active agent having Formula I, Il or III, comprising from about 0.2% to about 1.0% PEG 3350; and about 0.01% polyoxyethylene sorbitan monooleate; and the tonicity of the composition is adjusted to physiological conditions with about

3.9% mannitol. In another embodiment, the invention provides a method for sub-Tenon delivery of a pharmaceutical composition of a pharmaceutically active agent having Formula I, Il or III, wherein the buffer is a phosphate buffer.

In another embodiment, the invention provides a method for sub-Tenon delivery of a pharmaceutical composition of a pharmaceutically active agent having Formula I, Il or III, wherein the phosphate buffer is about a 1 mM to about a 100 m M Na₂HPO₄ buffer, or is about a 1 mM to about a 100 mM NaH₂PO₄ buffer, or mixtures thereof.

In another embodiment, the invention provides a method for sub-Tenon delivery of a pharmaceutical composition of a pharmaceutically active agent having Formula I, Il or III, wherein one or more excipients is a cellulose derivative. In another embodiment, the invention provides a method for sub-Tenon delivery of a pharmaceutical composition of a pharmaceutically active agent having Formula I, Il or III, wherein the cellulose derivative is high molecular weight carboxymethyl cellulose. In another embodiment, the invention provides a method for sub-Tenon delivery of a pharmaceutical composition of a pharmaceutically active agent having Formula I, Il or III, comprising from about 0.001% to about 10% high molecular weight carboxymethyl cellulose type.

In another embodiment, the invention provides a method for sub-Tenon delivery of a pharmaceutical composition of a pharmaceutically active agent having Formula I, Il or III, comprising from about 0.25% to about 0.5% high molecular weight carboxymethyl cellulose; and the tonicity of the composition is adjusted to physiological conditions with about 0.9% sodium chloride.

In another embodiment, the invention provides a method for sub-Tenon delivery of a pharmaceutical composition of a pharmaceutically active agent having Formula I, Il or III, wherein the cellulose derivative is middle molecular weight carboxymethyl cellulose.

In another embodiment, the invention provides a method for sub-Tenon delivery of a pharmaceutical composition of a pharmaceutically active agent having Formula I, Il or III, comprising from about 0.001% to about 10% middle molecular weight carboxymethyl cellulose. In another embodiment, the invention provides a method for sub-Tenon delivery of a pharmaceutical composition of a pharmaceutically active agent having Formula I, Il or IN, comprising from about 0.5% to about 1.0% middle molecular weight carboxymethyl cellulose; and the tonicity of the composition is adjusted to physiological conditions with about 0.9% sodium chloride.

In another embodiment, the invention provides a method for sub-Tenon delivery of a pharmaceutical composition of a pharmaceutically active agent having Formula I, Il or III, wherein the buffer is a phosphate buffer. In another embodiment, the invention provides a method for sub-Tenon delivery of a pharmaceutical composition of a pharmaceutically active agent having Formula I, Il or III, wherein the phosphate buffer is about a 1 mM to about a 100 mM Na₂HPO₄ buffer, or is about a 1 mM to about a 100 mM NaH₂PO₄ buffer, or mixtures thereof.

In another embodiment, the invention provides a method for sub-Tenon delivery of a pharmaceutical composition of a pharmaceutically active agent having Formula I, Il or III, wherein the cellulose derivative is low molecular weight carboxymethyl cellulose.

In another embodiment, the invention provides a method for sub-Tenon delivery of a pharmaceutical composition of a pharmaceutically active agent having Formula I, Il or III, comprising from about 0.001% to about 10% low molecular weight carboxymethyl cellulose. In another embodiment, the invention provides a method for sub-Tenon delivery of a pharmaceutical composition of a pharmaceutically active agent having Formula I, Il or III, comprising from about 0.5% to about 1.0% low molecular weight carboxymethyl cellulose; and the tonicity of the composition is adjusted to physiological conditions with about 0.9% sodium chloride.

In another embodiment, the invention provides a method for sub-Tenon delivery of a pharmaceutical composition of a pharmaceutically active agent having Formula I, Il or III, wherein the cellulose derivative is methylcellulose.

In another embodiment, the invention provides a method for sub-Tenon delivery of a pharmaceutical composition of a pharmaceutically active agent having Formula I, Il or III, comprising from about 0.001% to about 10% methylcellulose.

In another embodiment, the invention provides a method for sub-Tenon delivery of a pharmaceutical composition of a pharmaceutically active agent having Formula I, Il or III, comprising about 0.25% methylcellulose; and the tonicity of the composition is adjusted to physiological conditions with about 0.9% sodium chloride.

In another embodiment, the invention provides a method for sub-Tenon delivery of a pharmaceutical composition of a pharmaceutically active agent having Formula I, Il or III, wherein the phosphate buffer is about a 1 mM to about a 100 mM Na₂HPO₄ buffer, or is about a 1 mM to about a 100 mM NaH₂PO₄ buffer, or mixtures thereof. In another embodiment, the invention provides a method for sub-Tenon delivery of a pharmaceutical composition of a pharmaceutically active agent having Formula I, Il or III, wherein the pharmaceutically active agent is an angiogenesis inhibitor.

In another embodiment, the invention provides a method for sub-Tenon delivery of a pharmaceutical composition of a pharmaceutically active agent having Formula I, Il or III, wherein the angiogenesis inhibitor is an inhibitor of a protein kinase receptor.

In another embodiment, the invention provides a method for sub-Tenon delivery of a pharmaceutical composition of a pharmaceutically active agent having Formula I, Il or III, wherein the protein kinase receptor is a VEGF receptor. Detailed Description

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 ARMD, CNV, 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 ARMD 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.

The present invention provides pharmaceutical compositions and methods for sub-Tenon delivery of pharmaceutically active agents (i.e., an ophthalmic drug or prodrug) to the posterior tissues of the eye proximate the macula. The inventive compositions described herein include various excipients, buffers and pharmaceutically active agents that are safe and non-irritating to delicate eye tissues.

Excipients may act as surfactants or wetting agents, suspending agents, or flocculating agents in the inventive compositions. 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- lipophilic 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(C₂H₄O)_x(C₃H₆O)_y(C₂H₄O)_xH (PLURONIC™); or structure:

HO(C₃H₆O)_x(C₂H₄O)_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(C₂H₄O)_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 PEΘ-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 C₂₀ 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.

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 mM to about 100 mM (1mM = 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.

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.

Pharmaceutically active agents that are useful in the inventive compositions are for treating severe vision loss from ARMD, and other diseases affecting the posterior segment of the eye, such as 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 above. 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 ARMD, 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, ARMD, CNV, 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.

Other pharmaceutically active agents useful in the inventive compositions are disclosed in U.S. Patent Nos. 6,531 ,491, 6,534,524 and U.S. Patent Application No. 20040019065 the disclosures of each are hereby incorporated by reference in their entirety. In particular, these patents disclose compounds having Formulae I, II, or III:

and pharmaceutically acceptable salts or solvates thereof.

The inventive compositions described herein are useful in methods for sub-Tenon delivery of pharmaceutical active agents and pharmaceutically acceptable salts or solvates thereof, in which the invenvtive compositions are administered to the posterior segment of the eye proximate the macula.

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 delivery. Examples

Example 1 : 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/irhtation. Eyes were also enucleated and fixed in Davidson's solution for histological examination.

As shown in Table 1 , the vehicle excipients include 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%).

Table 1

Sub-Tenon Formulations

0.027o Tween^{I M} 80; 5% Mannitol; and 1OmM NaH₂PO₄ buffer; 0.2% Tween™ 80; 5% Mannitol; and 1 OmM NaH₂PO₄ buffer.

0.01% Poloxamer¹™ 188; 0.9% NaCI; and 1OmM NaH₂PO₄ buffer; 0.25% Poloxamer™ 188; 0.9% NaCI; and 1OmM NaH₂PO₄ buffer.

0.5% Poloxamer^{1 M} 188; 0.5% m-PEG-DSPE; 2.25% glycerin; and 10 mM NaH₂PO₄ buffer.

0.2% PEG 3350; 3.9% Mannitol; 0.01% Tween^IM 80; 0.29% Na₂HPO₄ and 0.07% NaH₂PO₄ buffer (% in g/10OmL);

1.0% PEG 3350; 3.9% Mannitol; 0.01% Tween™ 80; 0.29% Na₂HPO₄ and 0.07% NaH₂PO₄ buffer (% in g/10OmL).

0.25% High MW CMC (High Viscosity Aqualon¹™ 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 Aqualon ^{I M} CMC, 7MF PH); 0.9% NaCI; and 1 OmM 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 Aqualon¹™ 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 1 OmM NaH₂PO₄ buffer.

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 2: Sub-Tenon Formulations

The compounds of Formula I, Il and III 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 Formulae 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 Formulae I, Il and III: 1. Prepare 10 mM pH 7.4 phosphate buffer/0.9% saline solution

2. Prepare surfactant solution using PBS. Filter through 0.2 μm filter into clean bottle.

3. If required, prepare suspending agent solution using PBS. Filter through 0.22 or 5 μm filter into clean bottle.

4. Weigh out drug substance into suitable dispersing vessel. 5. Add the required volume of surfactant/suspending agent solution. Place onto magnetic stirrer until the drug is completely wetted.

6. Transfer the suspended drug to a clean mixing vessel and then wash the dispersing vessel into this vessel using PBS.

7. If used, add required quantity of the suspending agent solution to the mixing vessel. 8. Make up to 80-90% of final volume with PBS.

9. Mix for 15 minutes using a homogenizer.

10. Transfer to a measuring cylinder; wash the mixing vessel and mixer head into the bulk with PBS.

11. Allow to defoam and then make to volume. 12. Transfer to clean bottle and place on a magnetic stirrer. Set mixing speed to ensure that the suspension remains homogenous during filling.

13. Fill 2 mL vials with 1 mL suspension using calibrated 1 -5mL

14. Stopper and cap all vials. 15. 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 pharmaceutical composition comprising a pharmaceutically active agent having

Formula I, Il or III:

2. The pharmaceutical composition of claim 1 , wherein one or more excipients is from about 0.02% to about 2.0% polyoxyethylenesorbitan monooleate; the buffer is from about 1 mM to about 100 mM Na₂HPO₄ buffer or is from about 1 mM to about 100 mM NaH₂PO₄ buffer, or mixtures thereof; and the tonicity of the composition is adjusted to physiological conditions with about 5% mannitol.

3. The pharmaceutical composition of claim 1 , wherein one or more excipients is from about 0.01% to about 0.5% block copolymer of ethylene oxide and propylene oxide, having structure: HO(C₂H₄O)_x(C₃H₆O)_Y(C₂H₄O)_xH, wherein x is about 80 and y is about 27; the buffer is from about 1 mM to about 100 mM Na₂HPO₄ buffer or is from about 1 mM to about 100 mM NaH₂PO₄ buffer, or mixtures thereof; and the tonicity of the composition is adjusted to physiological conditions with about 0.9% sodium chloride.

4. The pharmaceutical composition of claim 3, further comprising about 0.5% m-

PEG-DSPE and about 2.25% glycerin.

5. The pharmaceutical composition of claim 1 , wherein one or more excipients is from about 0.2% to about 1.0% PEG 3350 and from about 0.01 % to about 1.0% polyoxyethylene sorbitan monooleate; the buffer is from about 1 mM to about 100 mM Na₂HPO₄ buffer or is from about 1 mM to about 100 mM NaH₂PO₄ buffer, or mixtures thereof; and the tonicity of the composition is adjusted to physiological conditions with about 3.9% mannitol.

6. The pharmaceutical composition of claim 1 , wherein one or more excipients is from about 0.25% to about 0.5% high molecular weight carboxym ethyl cellulose; the buffer is from about 1 mM to about 100 mM Na₂HPO₄ buffer or is from about 1 mM to about 100 mM NaH₂PO₄ buffer, or mixtures thereof; and the tonicity of the composition is adjusted to physiological conditions with about 0.9% sodium chloride.

7. The pharmaceutical composition of claim 1 , wherein the cellulose derivative is from about 0.5% to about 1.0% middle molecular weight carboxymethyl cellulose; the buffer is from about 1 mM to about 100 mM Na₂HPO₄ buffer or is from about 1 mM to about 100 mM NaH₂PO₄ buffer, or mixtures thereof; and the tonicity of the composition is adjusted to physiological conditions with about 0.9% sodium chloride.

8. The pharmaceutical composition of claim 1 , wherein the cellulose derivative is from about 0.5% to about 1.0% low molecular weight carboxymethyl cellulose; the buffer is from about 1 mM to about 100 mM Na₂HPO₄ buffer or is from about 1 mM to about 100 mM NaH₂PO₄ buffer, or mixtures thereof; and the tonicity of the composition is adjusted to physiological conditions with about 0.9% sodium chloride.

9. The pharmaceutical composition of claim 1 , wherein the cellulose derivative is from about 0.25% to 1.0% methyl cellulose; the buffer is from about 1 mM to about 100 mM

Na₂HPO₄ buffer or is from about 1 mM to about 100 mM NaH₂PO₄ buffer, or mixtures thereof; and the tonicity of the composition is adjusted to physiological conditions with about 0.9% sodium chloride.

10. The pharmaceutical composition of claim 1 , wherein the pharmaceutically active agent is an angiogenesis inhibitor.

11. The pharmaceutical composition of claim 10, wherein the angiogenesis inhibitor is an inhibitor of a protein kinase receptor.

12. The pharmaceutical composition of claim 11 , wherein the protein kinase receptor is a VEGF receptor.