BRPI0721885A2 - PHARMACEUTICAL FORMULATION FOR DISTRIBUTION OF TYROSINE KINASE RECEPTOR INHIBITORS (RTKI) INHIBITORS - Google Patents

Description

Patent Descriptive Report for "PHARMACEUTICAL FORMULATION FOR DISTRIBUTION OF TYROSINE KINASE RECEPTOR INHIBITORS (RTKI) INhibitors".

Background of the Invention

This application claims priority for U.S. Interim Application Serial Number 60 / 753,749 filed December 23, 2005.

1. Field of the Invention

The present invention relates to compositions and methods useful for treating pathological conditions arising from or exacerbated by ocular angiogenesis and vascular leakage such as AMD, DR1 diabetic macular edema etc., and more specifically to compositions containing at least - an antiangiogenic agent, antiinflammatory agent or anivascular permeability agent for use in the treatment of angiogenic eye disorders.

2. Description of Related Art

Abnormal neovascularization or angiogenesis and intensified vascular permeability are the main causes of many ocular disorders including age-related macular degeneration (AMD), prematurity retinopathy (ROP), ischemic retinal vein occlusions and diabetic retinopathy (DR). AMD and DR are among the most common causes of severe and irreversible vision loss. In these and related diseases, such as retinal vein occlusion, the loss of central vision is secondary to angiogenesis, the development of new blood vessels from pre-existing vasculature, and changes in vascular permeability properties.

The angiogenic process is known by the activation of quiescent endothelial cells in pre-existing blood vessels. Normal retinal circulation is resistant to neovascular stimuli, and very little endothelial proliferation occurs in the retinal vessels. Although there seem to be many stimuli for retinal neovascularization, including tissue hypoxia, inflammatory cell infiltration and penetration barrier degradation, all increase the local concentration of cytokines (VEGF, PDGF, FGF1 TNF, IGF etc.). .), integrins and proteinases resulting in the formation of new vessels, which then disrupt the organizational structure of the neural retina or penetrate the internal limiting membranes in the vitreous. High levels of cytokine may also disrupt close endothelial cell connections, leading to increased vascular leakage and retinal edema, and disruption of the organizational structure of the neural retina. Although VEGF is considered to be the major mediator of inflammatory cell infiltration, endothelial cell proliferation and vascular leakage, other growth factors such as PDGF, FGF1 TNF, and IGF etc. are involved in these processes. Thus, growth factor inhibitors may play a significant role in inhibiting retinal damage and associated vision loss through local eye distribution or oral dosing.

There is no cure for diseases caused by ocular neovascularization and enhanced vascular permeability. Current procedures for treating AMD include laser photocoagulation and photodynamic therapy (PDT). The effects of photocoagulation on ocular neovascularization and increased vascular permeability are achieved only through thermal destruction of retinal cells. PDT usually requires slow dye infusion, followed by the application of a non-thermal laser light. Treatment usually causes abnormal vessels to temporarily stop or their leaks to decrease. PDT treatment may need to be repeated every three months up to 3 to 4 times during the first year. Potential problems associated with PDT treatment include headaches, turbidity, and decreased clarity and vision gaps, and in 1 to 4% of patients, a substantial decrease in vision with partial recovery in many patients. In addition, immediately following PDT treatment, patients should avoid direct sunlight for five (5) days to avoid sunburn. Recently, a recombinant humanized IgG monoclonal antibody fragment has been approved (ranibizumab) in the United States for treatment of patients with age-related macular degeneration. This drug is typically administered by intravitreal injection once a month.

Many compounds that may be considered potentially useful for treating ocular neovascularization and related intensified vascular permeability and other disorders are poorly soluble in water. A poorly water soluble compound is a substance that is not soluble in a therapeutically effective concentration in a physiologically acceptable aqueous vehicle. Aqueous solubility is an important parameter for the formulation development of a poorly water soluble compound. What is needed is a formulation that provides increased solubility of the compound while also providing sufficient bioavailability of the compound to maintain its therapeutic potential.

The present invention provides safe and effective formulations for ocular administration of poorly soluble compounds for the treatment of eye diseases caused by endothelial cell proliferation, vascular leakage, inflammation and angiogenesis. Summary of the Invention

The present invention overcomes these and other drawbacks of the prior art by providing compositions for treating eye disease due to angiogenesis and increased vascular permeability. Within one aspect of the present invention, erodible gel compositions are provided. Compositions of the invention include (a) an active agent, and (b) an appropriate cosolvent, such as molecular weight polyethylene glycol (i.e. PEG 1500 to PEG 8000) or high and low molecular weight PEG blends in quantitative amounts. - suitable for obtaining an erodible gel. The amount of cosolvent molecular weight plays a very important role in the efficacy of the formulation upon local distribution.

A wide variety of molecules may be used within the scope of the present invention, especially those having very low solubility. As used herein, the term "poor solubility" is used to refer to a compound having a water solubility of less than 10 micrograms / mL. The active agent for use in the compositions of the invention may be an anti-angiogenic agent, an anti-inflammatory agent or anivascular permeability agent, or any other water-insoluble active agent useful for treating eye disorders.

The erodible gel compositions of the present invention are preferably administered to the eyes of a patient suffering from a disorder characterized by neovascularization, inflammation, or vascular permeability through subsequent juxtascleral administration or intravitreal injection.

Detailed Description of Preferred Modalities

As mentioned above, the present invention provides compositions containing an active agent for use in the treatment of eye disorders caused by endothelial cell proliferation, enhanced vascular permeability, inflammation, or angiogenesis. The compositions of the invention are useful for preventing or inhibiting neovascularization and vascular leakage associated with such eye disorders. In some cases, the compositions of the invention cause regression of neovascularization. Briefly, within the context of the present invention, active agents should be understood to be any naturally occurring or synthetic molecule that acts to inhibit vascular growth, reduce vascular permeability, and / or decrease inflammation. In particular, the present invention provides erodible gel compositions comprising an active agent in a therapeutically effective amount, a suspending agent, and an appropriate amount of a cosolvent, such as high molecular weight polyethylene glycol (i.e. PEG 1500 to PEG 8000), or high and low molecular weight PEG blends, in an appropriate amount to obtain an erodible gel. Polyethylene glycols (PEG) have the general chemical formula HO-

Head (CH2OCHa) nChhOH. They are nonvolatile, water soluble or water miscible compounds and chemically inert, ranging in molecular weight from several hundred to several thousand. They are waxy liquids or solids, identified by numbers which are an approximate indication of molecular weight. PEG 400 is a liquid, while PEG 4000 is a waxy solid.

The preferred cosolvent for use in the formulations of the invention is polyethylene glycol PEG 1500 to PEG 8000. The most preferred cosolvent for use in the formulations of the present invention is PEG 1500 to PEG 3350. In some other preferred embodiments, the gel formulations of the present invention will be used. include high and low molecular weight blends of polyethylene glycols to achieve better results. For example, PEG 3350 and PEG 400 in a weight ratio of 4: 6 form a water miscible erodible gel.

The cosolvent will typically be present in the formulation of the invention in an amount from 70% to 99.999%. Preferably, the compositions for the invention will contain from 90% to 99.9% of cosolvent. More preferably, the intravitreal injection composition will contain 99% cosolvent. The composition for further juxtascleral, periocular and topical administration will most preferably contain 99% cosolvent.

Polyethylene glycol or PEG high and low molecular weight blends are identified as a key excipient for intravitreal, periocular and posterior juxtascleral edible gel formulations.

An advantage of the present invention is that the water-miscible PEG gel formulation can dissolve in water at a controlled rate, while the active agent in the formulation forms a colloidal dispersion at the site of action. This suggests that the water soluble PEG vehicle may be eliminated from the eye. At the end of use, the system does not need to be recovered. This is a significant improvement over other existing forms of active delivery agents for a patient's eyes because it allows for less invasive procedures while providing superior treatment for neovascularization, vascular permeability, or other eye disorders. Erosion can be controlled by the proportion of low and high molecular weights of PEGs. Desirable bioavailability can be achieved by controlling the erosion rate and dissolution rate of colloidal particles that are formed in situ. Any active agent that is poorly soluble in

Water may be included in the compositions of the present invention. For example, anti-angiogenic, anti-inflammatory, or anivascular permeability agents are useful in the compositions of the invention.

Preferred anti-angiogenic agents include, but are not limited to, tyrosine kinase receptor (RTKi) inhibitors, in particular those having a multi-target receptor profile such as those described in further detail herein; angiostatic cortisene; MMP inhibitors; integrin inhibitors; PDGF antagonists; antiproliferatives; HIF-1 inhibitors; fibroblast growth factor inhibitor; epidermal growth factor inhibitors; TIMP inhibitors; insulin-like growth factor inhibitors; TNF inhibitors; antisense oligonucleotides; etc. and prodrugs of any of the agents mentioned above. The preferred antiangiogenic agent for use in the present invention is a multi-targeted tyrosine kinase receptor (RTKi) inhibitor. More preferred are RTKi's with multi-target binding profiles such as N- [4- (3-amino-1H-indazol-4-yl) phenyl] -N '- (2-fluoro-5-methylphenyl) urea having the profile substantially similar to that shown in Table 1. Additional multidirectional tyrosine kinase receptor inhibitors considered for use in the compositions of the present invention are described in US Serial Application No. 2004/0235892, incorporated herein by reference. As used herein, the term "multidirectional tyrosine kinase receptor inhibitor" refers to a compound that has a receptor binding profile exhibiting selectivity for multiple receptors shown to be important in angiogenesis, such as the profile shown in the table. 1, and described in a copending application US serial number 2006/0189608, incorporated herein by reference. More preferably, the compounds for use in the formulations of the present invention will have a KDR receptor (VEGFR2), Tie-2 and PDGFR receptor binding profile. Table 1

Kinase Selectivity Profile of an RTK Inhibitor

KDR FLT1 FLT4 PDGFR CSF1R FLT3 KIT TIE2 FGFR EGFR SRC

4 3 190 66 3 14 4 170> 12,500> 50,000> 50,000 All data reported as IC50 values for kinase inhibition in cell free enzyme assays; ND denotes no data. Determined values @ 1 mM ATP.

Other agents that will be useful in the compositions and methods of the invention include anti-VEGF antibodies (i.e., bevacizumab or ranibizumab); retain VEGF; siRNA molecules, or a mixture thereof, targeting at least two of the tyrosine kinase receptors having IC 50 values of less than 200 nM in Table 1; glucocorticoids (ie dexamethasone, fluorometalone, medrisone, betamethasone, triamcinolone, triamcinolone acetonide, prednisone, prednisolone, hydrocortisone, rimexolone, and pharmaceutically acceptable salts thereof, prednicarbate, deflazacort, halometasene, thixocetone, predix -diethylaminoacetate), prednival, para-metasone, methylprednisolone, meprednisone, mazipredone, isoflupredone, halopredone acetate, halcinonide, formocortal, flprandnisolone, fluprednidine acetate, fluperolone acetate, fluocortinone, fluocortinone, flucinolone, flunisolide, flumetasone, fludrocortisone, fluclorinide, enoxolone, difluprednate, diflucortolone, diflorasone diacetate, deoxymethasone (deoxymethasone), desonide, descinolone, cortivolone, clavolone, clavolone, cortisolone, clonolone budesonide, beclomethasone, amincinide, alopregnano acetonide, alclometason α, 21-acetoxypregnenolone, tralanide, diflorasone acetate, deacilcortivazole, RU-26988, budesonide, and deacylcortivazole oxetanone); Naphthohydroquinone antibiotics (i.e., Rifamycin); and NSAIDs (i.e. nepafenac, amfenac).

The formulations described herein may be distributed topically, via intravitreal injection, and via posterior and periocular juxtascleral pathways. Preferred cosolvents for use in the compositions of the present invention include ethylene glycol, propylene glycol, N-methyl pyrrolidine, 2-pyrrolidinone, 3-pyrrolidinol, 1,4-butanediol, dimethyl glycol monomethylether, diethylene glycol monomethyl ether, solquetal, glycerol, polyethylene glycol, polypropylene glycol, etc.

The present inventors have found that certain active agents

have greater solubility in the presence of PEG than in water. For example, the compound N- [4- (3-amino-1H-indazol-4-yl) phenyl] -N '- (2-fluoro-5-methylphenyl) urea may dissolve completely and disperse. in PEG 3350 and PEG 8000 when the PEG melts at temperatures of about 60 ° C to 95 ° C and forms a wax-like pellet when cooled to room temperature. This pellet forms a colloidal type suspension when the pellet dissolves in water. In addition, using blends of high and low molecular weight PEGs, you can make erodible gel with the compound evenly dispersed therein (see examples). This provides an injection dosage form for the release of insoluble compounds through subsequent juxtascleral or intravitreal administration, which enhances the solubility of the compounds and achieves the desired bioavailability. In the formulations of the present invention, the compound forms a solid solution in the PEG matrix.

In certain preferred embodiments, the formulation of the invention will further comprise a polymer that acts as a suspending agent to enhance the physical stability of the formulation. Various polymers, such as hydroxypropyl methyl cellulose (HPMC) 1 hydroxyethyl cellulose (HEC), methyl cellulose, carboxymethylcellulose (CMC), carbopol, polyvinyl alcohol, polyvinyl pyrrolidone (PVP), xanthan, tragacanth gum, acacia gum, sodium alginate and its esters, etc. can be used for this purpose.

The specific dose level for any particular human or animal depends on a variety of factors, including active compound activity used, age, body weight, general health, time and frequency of administration, route of administration and the severity of the pathological condition. undergoing therapy.

Preferred gel formulations of the invention for administration by intravitreal injection, periocular administration, posterior juxtascleral administration, topical ocular administration may contain:

an active agent in a therapeutically effective amount;

PEG 400, PEG 3350 or PEG 8000 as a cosolvent in an amount effective to obtain an erodible gel formulation. Certain other preferred gel formulations of the invention may be

to contain:

an antiangiogenic agent in a therapeutically effective amount;

a proportion of polyethylene glycol cosolvent in an amount effective to form a gel solution.

Preferred proportions of high molecular weight PEG to low molecular weight PEG for polyethylene glycol cosolvents for use in gel formulations of the present invention are from 7: 3 to 1: 8. Most preferred portions of polyethylene glycol compounds for use in the gel formulations of the present invention are from 7 parts PEG 3350 to 3 parts PEG 400 (7: 3) to 1 part PEG 3350 to 8 parts of PEG 400 (1: 8). The most preferred ratio for polyethylene glycol cosolvents for use in the gel formulations of the present invention is approximately 4 parts PEG 3350 to approximately 6 parts PEG 400, as shown in Table 2.

table 2

The following table gives the formulation of erodible gel RTKi and PEG

level.

Code Vehicle gel 1% RTKi PEG Gel COMPONENT% weight / weight% weight / weight RTKi _ 1 polyethylene glycol 400 60 59.4 polyethylene glycol 3350 40 39.6

According to the intended route of administration (IVT or PJ), it is

It is very important that the particle size of the formulations must be small to achieve good syringability as well as comfort. Prepared formulations (for IVT or PJ) exhibit excellent syringability, even when only 2DL - 10DL of the formulation is injected into the animals' eyes.

The following examples are included to demonstrate preferred embodiments of the invention. It should be apparent to those skilled in the art that the techniques described in the following examples represent techniques discovered by the inventor to function well in the practice of the invention, and thus to be considered as constituting preferred modes for their practice. However, those skilled in the art should, in light of the present disclosure, note that many changes may be made to the specific embodiments described and still obtain the same or similar result without departing from the spirit and scope of the invention. Example 1

Procedure for making an RTKi-PEG 3350 pellet:

in a suitable bottle, weigh and add PEG 3350 powder. Place the bottle into a 75 to 80 ° C water bath, mix and let the PEG 3350 melt. Add RTKi (N- [4- (3-amino-1H-indazol-4-yl) phenyl] -N '- (2-fluoro-5-methylphenyl) urea) to the PEG fusion. Mix and let RTKi dissolve to completely melt. Place the vial containing the melted RT-Ki-PEG mixture at room temperature. A hard wax pallet is formed. She is not hygroscopic. Example 2

RTKi-PEG miscible water erodable gel procedure:

In a suitable bottle, weigh and add two different degrees of PEG. For example, add PEG 3350 powder and PEG 400 liquid in the appropriate proportion. Add powder of RTKi (N- [4- (3-amino-1H-indazol-4-yl) phenyl] -N '- (2-fluoro-5-methylphenyl) urea crude material) to the flask. Then place the vial into a 70 to 90 ° C water bath, mix and let the PEG 3350 melt and the RTKi dissolve completely. Allow the vial containing the melted RTKi-PEG mixture to cool to room temperature. An RTKi-PEG water miscible erodible gel is formed. All compositions and / or methods described and claimed

herein may be made and performed without undue experimentation in light of the present disclosure. Although the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those skilled in the art that variations may be applied to the compositions and / or methods and in steps or sequence of steps of the method. described herein without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents, which are chemically and structurally related, may be substituted for the agents described herein to achieve similar results. All such substitutions and modifications evident to those skilled in the art are considered to be within the spirit, scope and concept of the invention as defined by the appended claims.

Claims (19)

1. Ophthalmic composition for treating ocular neovascularization, said composition comprising: i) an active agent in an amount of 0.01% to 30%, and ii) a polyethylene glycol cosolvent having a molecular weight of 1500 to 8000 or blends of High and low molecular weight PEGs; wherein said cosolvent is present in an amount such that the composition forms a gel. Ophthalmic composition according to claim 1, wherein the active agent is selected from the group consisting of anti-angiogenic agents, anti-inflammatory agents, and anti-cellular permeability agents. The ophthalmic composition of claim 2, wherein the active agent is an antiangiogenic agent. The ophthalmic composition according to claim 3, wherein the antiangiogenic agent is a multidirectional tyrosine kinase receptor (RTK) inhibitor. The ophthalmic composition of claim 4, wherein the RTK inhibitor is N- [4- (3-amino-1H-indazol-4-yl) phenyl] -N '- (2-fluoro-5-methylphenyl). ) urea. The ophthalmic composition of claim 1, wherein the concentration of active agent is 1% to 15%. The ophthalmic composition of claim 3, wherein the concentration of the antiangiogenic agent is 1% to 15%. Ophthalmic composition according to claim 1, wherein the cosolvent is PEG 3350. The ophthalmic composition of claim 1, wherein the PEG cosolvent is a blend comprising PEG 400 and PEG3350, wherein the ratio of PEG 400 to PEG 3350 is such that the composition forms a water miscible erodible gel. . The ophthalmic composition of claim 9, wherein the concentration of PEG 400 in the formulation is 30% to 90%. An ophthalmic gel composition for further juxtasclaral administration, said composition comprising: i) an active agent, wherein the concentration of the active agent is from 0.01% to 30%; and ii) a polyethylene glycol cosolvent having a molecular weight of 400 to 8000 or high and low molecular weight PEG blends. The ophthalmic gel composition of claim 11, wherein the active agent is selected from the group consisting of anti-angiogenic agents, anti-inflammatory agents, and anivascular permeability agents. The ophthalmic gel composition of claim 12, wherein the active agent is an antiangiogenic agent. The ophthalmic gel composition of claim 13, wherein the antiangiogenic agent is a multireceptor directing tyrosine kinase receptor (RTK) inhibitor. The ophthalmic gel composition of claim 11, wherein the cosolvent is PEG 3350. The ophthalmic gel composition of claim 11, wherein the cosolvent is a blend of high and low molecular weight PEGs comprising PEG 400 and PEG 3350, wherein the ratio of PEG 400 to PEG 3350 is such that the composition forms a water-miscible erodible gel. The ophthalmic gel composition of claim 16, wherein the ratio of PEG to PEG 3350 is from 3: 7 to 8: 1. The ophthalmic gel composition of claim 17, wherein the ratio of PEG 400 to PEG 3350 is about 6: 4. An intravitreal injection composition for the treatment of ocular neovascularization, said composition comprising: from 0.1 to 10% of a multi-receptor receptor tyrosine kinase inhibitor; a ratio of PEG 400 to PEG 3350 such that the composition forms a water miscible erodible gel.