WO2015089559A1

WO2015089559A1 - Optimising bioavailability of intra vitreally injectable steroids

Info

Publication number: WO2015089559A1
Application number: PCT/AU2014/001141
Authority: WO
Inventors: Philip Leslie Penfold
Original assignee: Eye Co Pty Ltd
Priority date: 2013-12-17
Filing date: 2014-12-17
Publication date: 2015-06-25
Also published as: CN106232123A

Abstract

The present invention relates to pharmaceutical compositions and a method for making a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds capable of modulating an activity of a mineralocorticoid receptor and/or a glucocorticoid receptor, the method comprising formulating the composition to comprise one or more improved physicochemical properties. The receptor modulators are preferably chosen from triamcinolone acetonide, 11-desoxycortisone, fludrocortisone, deoxycorticosterone acetate, deoxycorticosterone, aldosterone, Cortisol, cortisone, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclometasone fludrocortisone or a therapeutically active analogue, derivative, homolog, pharmaceutically acceptable salt or conjugate thereof. The improved physicochemical properties include solubility, porosity, electrokinetic potential (zeta potential), flocculation and particle size.

Description

TITLE

OPTIMISING BIOAVAILABILITY OF INTRA VIT EA.LLY INJECTABLE

STEROIDS FIELD

[001] THIS INVENTION described herein relates generally to a pharmaceutical composition and method for making a pharmaceutical composition for treating an eye disease including a diabetic eye disease and an ocular tumour-. In particular, the invention is directed to a method of making such pharmaceutical compositions and to pharmaceutical compositions comprising one or more compounds capable of modulating an activity of a mifteralocorticoid receptor and/or a glucocorticoid receptor wherein the composition comprises an improved physieochemical property, although the scope of the invention is not necessarily limited thereto.

BACKGROUND

[002] Triamcinolone acetonide (TA.) is a synthetic corticosteroid indicated for various diabetic and neovasular retinal disease and inflammatory conditions which are unresponsive to topical corticosteroids. Triamcinolone acetonide has been used as a monotherapy and co-therapy for various back of eye conditions and is also indicated for visualisation during vitrectomy. Triamcinolone acetonide is widely used for treatment of diabetic retinopathy, uveitis and choroidal neovascularization associated with age-related macular degeneration.

[003] Diabetic macular edema (DME) is the leading cause of visual loss in diabetic retinopathy. Intravitreal triamcinolone acetonide has been used successfully to improve visual acuity while significantly reducing DME and also to reduce central macular thickness. Although such use is considered off-label in the US, many retina specialists advocate using intravitreal triamcinolone acetonide in primary treatment of refractory DME.

[004] A proposed mechanism of action is that TA increases the levels of tight-junction proteins and thus diminishes vessel leakage and angiostatic actions through vascular endothelial growth factor (VEGF) inhibition. Despite having great potential, intravitreal triamcinolone acetonide carries considerable risks including cataract formation and glaucoma, [005] There remains a need for alternative treatments.

SUMMARY

[006] The present invention has arisen after the inventors discovered improved, methods for making a pharmaceutical composition and improved pharmaceutical compositions for the treatment of an eye disease and/or condition or predisposition thereto.

[007] n a broad form, the invention relates to method for making a pharmaceutic a! composition and pharmaceutical compositions for the treatment of an eye disease or condition or predisposition thereto comprising one or more improved physicochemical properties.

[008] in a first aspect., the present invention is broadly directed to a method for making a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds capable of modulating an activity of a mineralocorticoid. receptor and or a glucocorticoid receptor, the method comprising formulating the composition to comprise one or more improved physicochemical properties,

[009] In a second aspect, the present invention provides a pharmaceutical compositio comprising a therapeutically effective amount of one or more compounds capable of modulating an activity of a mineralocorticoid receptor and/or a glucocorticoid receptor and at least one solvent, the composition comprising one or more improved physicochemical properties.

[010] in a third aspect, the present invention provides a pharmaceutical composition made according to the method of the first aspect ,

[Oi l ] In a fourth aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds capable of modulating an acti vity of a mineralocorticoid receptor and/or a glucocorticoid receptor for use in the treatment of an eye disease or condition or predisposition thereto wherein the composition comprises one or more improved physicochemical properties.

[012] In a fifth aspect, the present invention provides a method of treatment of art eye disease or condition or a predisposition thereto in a subject in need thereof, the method including applying to the eye a therapeutically effective amount of one or more compounds capable of modulating an activity of a mineralocorticoid receptor and/or a glucocorticoid receptor, the composition comprising one or more improved physicochemical properties to thereby treat the eye disease or condition or predisposition thereto.

[013] In a sixth aspect, the present invention provides the use of a composition comprising a therapeutically effective amount of one or more compounds capable of modulating an activity of a mineralocorticoid receptor and/or a glucocorticoid receptor, the composition comprising one or more improved physicochemical properties for the manufacture of a medicament for the therapeutic and/or prophylactic treatment of an eye disease or condition.

[014] In a seventh aspect, the present invention provides a syringe comprising the composi tion of the second aspect.

[015] In one embodiment of any one of the above aspects, the one or more improved physicochemical properties is one or more of: solubility: porosity; electrokinetic potential (zeta potential); flocculation; and particle size.

[016] In another embodiment of any one of the above aspects, the one or more compounds ma be milled to graduate and/or control particle size. The particles may be wet milled. The wet milling may comprise homogenisation. The homogenisation may comprise suspension in a wetting agent. The wetting agent may comprise a polysorbate.

[017] The particle size may comprise crystal size,

[018] In yet another embodiment of any one of the above aspects, the one or more compounds may be dissolved or redissolved in a solvent to regulate pore size. The solvent may comprise acetone.

[01 ] The porosity may comprise average pore size and/or total pore area.

[020] In one embodiment of any one of the above aspects, the one or more compounds may or may not be micronized. In a particular embodiment, the compound is not micronized.

[021] In another embodiment of any one of the above aspects, the solubility may be increased by the composition comprising a solubility partner. The solubility partner may comprise a second compound capable of modulating the activity of a mineralocorticoid receptor and/or a glucocorticoid receptor.

[022] The second compound may comprise a compound from, the same class. [023] In yet another embodiment of any one or the above aspects, the one o more improved physicochemical properties may be the result of a miscible agent. The miscible agent may comprise a solvent or solute.

[024] In one embodiment of any above aspect the solubility may be improved by adding a cyelodextrm. The cyclodextrin may comprise hydroxy-propyl β-cyclodextrin (HP-pCD).

[025] in still another embodiment of any one of the above aspects, the one or more improved physicochemical property may be the result of pH.

[026] In another embodiment of any one of the above aspects, the one or more improved physicochemical properties may be die result of fractionation.

[027] In yet another embodiment of any one of the above aspects, the one or more improved physicochemical properties may comprise one or more of improved ionic strength, improved colligative properties, improved surface chemistry and/or improved intermo!ecular forces,

[028] yet another embodiment of any one of the above aspects, the one o more improved physicochemical properties may comprise an altered dwell time and/or bioavailability.

[029] The altered dwell time of any one of the above aspects may comprise an increased or decreased dwell time. In a particular embodiment, the altered dwell time comprises an increased dwell time.

[030] in a particular embodiment of any one of the above aspects, the altered bioavailability may comprise an increased bioavailability.

[031 ] hi one embodiment of any one of the above aspects, the one or more compounds may comprise a prodrug,

[032] According to any above aspect, the one or more improved physicochemical propert may be achieved by wet sieving the compound particles to P (V, 0,9) less than 20 μΜ; freeze drying the one or more compounds alone; adding a solution of all exeipients to the one or more compounds powder; dispensing to vials and freeze drying; gamma sterilizing; and reconstituting in BSS.

[033] According to any one of the above aspects, the one or more compounds capable of modulating the activity of a mineralocorticoid receptor and or a glucocorticoid receptor may be one or more corticosteroid or a therapeutically active analogue, derivative, homoiog, pharmaceutically acceptable salt, prodrug, metabolite or conjugate thereof.

[034] According to any one of the above aspects, the one or more compounds may comprise one or more mineralocorticoids,

[035] The one or more mineralocorticoids may comprise one or more of: triamcinolone acetonide (TA); 1 i-desoxycortisone (11 -DC); fludrocortisone (FA); Deoxycorticosterone acetate (DA); Deoxycorticosterone (DS); or Aldosterone; or a therapeutically active analogue, derivative, homoiog, pharmaceutically acceptable salt or conjugate thereof.

[036] According to any one of the above aspects, the one or more compounds may comprise one or more glucocorticoids.

[037] The one or more glucocorticoids may comprise one or more of: Cortisol , cortisone, prednisone, prednisolone, methylpredmsolone, dexamethasone, betamethasone, triamcinolone, beclometasone, fludrocortisone, deoxycorticosterone, aldosterone or a therapeutically active analogue, derivative, homoiog, pharmaceutically acceptable salt or conjugate thereof.

[038] The one or more compounds may comprise one or more dual action compound/s, wherein each dual action compound is capable of modulating the activity of both a mineralocorticoid receptor and a glucocorticoid receptor.

[039] The dual action compound may comprise one or more of Cortisol; cortisone; prednisone; prednisolone; methylpredniso!one; fludrocortisone acetate; deoxycorticosterone acetate; aldosterone or a therapeutically active analogue, derivative, homoiog, pharmaceutically acceptable salt or conjugate thereof.

[040] In a particular embodiment of any of the above aspects, the one or more compound's comprises triamcinolone acetonide or a therapeutically active analogue, derivative, homoiog, pharmaceutically acceptable salt or conjugate thereof.

[041 ] in another particular embodiment of any of the above aspects, the one or more compound's comprises fludrocortisone acetate or a therapeutically active analogue, derivative, homoiog, pharmaceutically acceptable salt or conjugate thereof.

[042] m another particular embodiment of any of the above aspects, the one or more compound's comprises tiiamcinolone acetonide and fludrocortisone acetate or a therapeutically active analogue, derivative, homolog, pharmaceutically acceptable salt or conjugate of either.

[043] According to any one of the above aspects, said eye disease and/or condition may be an exudative eye disease and/or condition.

[044] According to any one of the above aspects, said eye disease and/or condition may be a back of the eye exudative eye disease and/or condition.

[045] According to any one of the above aspects, said eye disease and/or condition may be a front of the eye exudative eye disease and/or condition.

[046] According to any one of the above aspects, said eye disease and or condition may be macular degeneration including age-related macular degeneration and wet age related macular degen erati on.

[047] According to any one of the above aspects, said eye disease and/or condition may be a diabetic macular edema (DME), cystoid macular edema (CMO); maculopathy; and or an ocular tumour.

[048] The ocular tumour may comprise a retinoblastoma and/or a melanoma.

[049] Accordi tig to any one of the above aspects , said eye disease and/or condition ma be a diabetic eye disease and/or condition.

[050] Other eye disease and/conditions include (non-infectious) conjunctivitis, anterior uveitis and an ocular allergy.

[051 ] The invention according to any above aspect may further comprise one or more pharmaceutically acceptable carriers, diluents or excipients.

[052] The one or more pharmaceutically acceptable carriers, dihients or excipients may comprise one or more surfactants or wetting agent. The surfactant or wetting agent may comprise a polysorbate. The polysorbate may comprise one or more of Tween 20 and Tween 80.

[053] The one or more pharmaceutically acceptable carriers, diluents or excipients may comprise one or more of a wetting agent and a viscosity modifier . The wetti ng agent may comprise a polysorbate. The viscosity modifier may comprise carboxy methyl cellulose (CMC). The polysorbate wetting agent may comprise Tween 80 or Tween 20. In one particular embodiment, the polysorbate wetting agent comprises Tween 80. [054] The one or more pharmaceutically acceptable cafriers, diluents or excipients may comprise carboxy methyl cellulose sodium; polysorbate 80; sodium chloride; a Balanced Salt Solution; a pH adjustment composition; and/or water for injection. The BSS may comprise potassium chloride; calcium chloride (dehydrate); magnesium chloride (hexahydrate); sodium acetate (trihydrate); sodium citrate (dehydrate); hydrochloric acid and/or sodium hydro ide. The pH adjustment composi tion may comprise hydrochloric acid and/or sodium hydroxide,

[055] According to any one of the above aspects, the compositions of the invention may comprise a sustained release composition.

[056] In a particular embodiment of any one of the above aspects, the compound and compositions may be sterilized,

[057] h another particular embodiment of any one of the above aspects, the compositions of the invention are preservative free.

[058] As used herein, except where the context requires otherwise, the term "comprise" and variations of the term, such as "comprising", "compri ses" and "comprised", are not intended to exclude further additives, components, integers or steps.

BRIEF DESCRIPTION OF THE FIGURES

[059] hi order that the present invention may be readily understood and put into practical effect, reference will now be made to the accompanying illustrations, wherein like reference numerals refer to like features and wherein:

[060] Figure 1 : Solubility enhancement for MR compounds and TA in saline with addition of hydroxy propyl -cyclodextrin (data are mean ± sd, n=3). Top: FLU and TA; Bottom. 1 1-DC; DCS and DCS A.

[061 ] Figure 2 : Drug solubility in aqueous solution ofTween SO over time when stored at 37 C for 72 hr (data are mean ± sd n=3 at each time point).

[062] Figure 3 : The effect of autoclave and gamma irradiation sterilization processes on drug stability in aqueous solutions (data are mean ± sd, n=3).

[063] Figure 4: Contour plots for HPLC with absorption wavelength on the y axis and retention ti me on the X-axis, the i ntensi ty of colour indicates degree of absorbance at tha t wavelength and retention time (λτηαχ = 240 for all compounds in this study). [064] Figure 5; Stability of MR compounds and TA in dry powder form on exposure to 25kGy gamma irradiation.

[065] Figure 6; SEM images of M powders as received. All images are on similar scales, highlighting the gross differences between them,

[066] Figure 7: Reduction in Particle Size (distribution indicated by D(v,0.5) and D(v,0.9)) for 1 1 -DC, DCS and DCSA with homogemsation time.

DETAILED DESCRIPTION

[067] The invention relates to a pharmaceutical compositio and method for making a pharmaceutical composition for treating an eye disease including a diabetic eye disease and an ocular tumour.

[068] The invention is at least partly predicated on the unexpected discovery that compounds capable of modulating the activity of a mmeralocorticoid receptor and or a glucocorticoid receptor may be prepared to comprise one or more improved physicochemical properties. This improved physicochemical property may advantageously improve the required course of therapy for example, in reducing the number of intraocular injections required or increasing the period between intraocular injections and/or improve the ease of injection.

[069] hi particular, the invention is directed to a method of making such pharmaceutical compositions and to pharmaceutical compositions comprising one or more mineralocorticoids, wherein the composition comprises an improved physicochemical property, although the scope of the invention is not necessarily limited thereto.

[070] In one broad aspect, the invention arises, at least in part, from the surprising discovery that modifications to and or alterations from conventional methods of preparation may produce an improved physicochemical property. This is of significant advantage because it may lead to increased patient compliance and impro ved ocular health outcomes.

[071 ] As used herein, the term "eye condition" includes any eye condition such as, early or sub-clinical stages of an eye disease,

[072] As used herein, the term "eye disease" includes any eye disease such as, macular degeneration, macuiopathy including an age related macuiopathy (ARM), age related macular degeneration (AMD) including both the dry (geographic atrophy) and wet (choroidal neovascularization (CNV)), an exudative eye disease or condition, retinal pigment epithelium detachments (PED), forms of age related macular degeneration, a diabetic eye disease or condition including a diabetic retinopathy and diabetic macular edema (DME), corneal neovascularisation, cyelitis, Hippel-Lindel disease, retinopathy of prematurity (also known as retrolettfal fibroplasia), pterygium, histoplasmosis, iris neovascularisation, glaucoma, glaucoma-associated neovascularisation. Puncher s retinopathy, ocular hypertension, macular edema. Coats' disease, uveitis including anterior uveitis, Sicca syndrome, hereditary diseases associated with increased extra-ititracellular lipid storage/accumulation, juvenile macular degeneration, an ocular allergy and an ocular tumour. The ocular tumour may comprise a retinoblastoma and/or a melanoma,

[073] The eye disease or condition may comprise a back of eye disease or conditions including an exudative back of eye exudative disease or condition. The back of eye disease or cond ition may comprise an eye disease or condition involving the retina, macular and/or fovea in the posterior region of the eye. Examples of back of eye disease include macular oedema, such as clinical macular oedema or angiographic cystoid macular oedema arising from various aetiologies, such as diabetes, exudative macular degeneration and macula oedema arising from laser treatment of the retina, retinal ischemia and choroidal neovascularisation, a retinal disease, an inflammatory disease, uveitis associated with neoplasms, such as retinoblastoma or psuedoglionia, neovascularisation following vitrectomy, a vascular disease and neovascularisation of the optic -nerve. The retinal disease may be one or more of diabetic retinopathy, diabetic retinal oedema, retinal detachment, senile macular degeneration due to sub-retinal neovascularisation and myopic retinopathy. The vascular disease may be one or more of retinal ischemia, choroidal vascular insufficiency, choroidal thrombosis and. neovascular retinopathies resulting from carotoid artery ischemi .

[074] The eye disease or condition may also comprise a front of eye disease or condition which predominantly involves the tissue at the front of the eye, such as the cornea, iris, ciliary body and conjunctiva including an exudative front of eye disease or condition. The front of eye disease may be one or more of corneal neovascularisation, a corneal disease or opacification with an exudative or inflammatory component, diffuse lamellar keratitis, neovascularisation due to penetration of the eye or contusive ocular injury, rubosis iritis, Ftjchs' heterochromic iridocyclitis, chronic uveitis, anterior uveitis, inflammatory conditions resulting from surgeries such as LASI , LASEK, refractive surgery, IOL implantation; irreversible corneal oedema as a complication of cataract surgery, oedema as a result of insult or trauma, inflammation, infectious and non-infectious conjunctivitis, keratoconjunctivitis, iridocyclit i s, iritis, scleritis, epi scleritis, infectious ^'keratitis, superficial punctuate keratitis, keratoconus, posterior polymorphous dystrophy, Fuch's dystrophies, aphakic and pse.udoph.akic bullous keratopathy, corneal oedema, scleral disease, ocular cicatrei l pem higoid, pars anitis, Posner Schlossnian syndrome, Behcet's disease, Vogt- Koyanagi-H^'arada syndrome, hypersensitivity reactions, ocular surface disorders, conjuncti val oedema. Toxoplasmosis chorioretinitis, inflammatory pseudotumor of the orbit, eliernosis, conjunctival venous congestion, periorbiatal celkilits, acute daeroycystitis, non-specific vasculitis, sarcoidosis and cytomegalovirus infection.

[075] The compositions of the invention may have a therapeutic effect with regards to oedema, swelling and/or neovasciilarisation. in the tumor. Corticosteroids are also known to reduce inflammation and to help relieve nausea when having chemotherapy.

[076] As used herein, corticosteroid includes a therapeutically active analog, derivative, pharmaceutically acceptable salt, prodrug, metabolite or conjugate thereof.

[077] As used herein, a derivative includes a therapeutically active or pharmaceutically active fragment of a compound modulating the activity of a miiieralocoitieoid receptor or a glucocorticoid receptor.

[078] An analog may be a structur al analog or a functional analog.

[079] A homolog comprises a molecule of the same chemical type, but differing by a fixed increment of an. atom or a constant group of atoms.

An example is methyl and ethyl alcohols which are homologous.

[080] " Prevention" or "prophylaxis," as used herein, refers to prophylactic or preventative measures. Those in need of prevention or prophylaxis include those in whom the eye disease or condition is to be prevented, and in some embodiments, may be predisposed or susceptible to tire eye disease or condition e.g. ind ividuals with a family history of an eye disease or condition.

[081] Prevention or prophylaxis is successful herein if the development of an eye disease or condition is completely or partially prevented or slowed down .

1.0 [082] "Treatment" of a subject herein refers to therapeutic treatment. Those in need of treatment include those already with an eye disease or condition, as well as those in whom the progress of an eye di sease or conditio is to be prevented , Hence, the subject may have been diagnosed as having the eye disease or condition or may have an eye disease or condition or damage that is likely to progress in the absence of treatment. Alternatively, the subject may he symptom-free, but has risk factors for development of an eye disease or condition e.g., positive family history. Treatment is successful herein if the eye disease or condition is alleviated or healed, or progression of the eye disease or condition, including its signs and symptoms and/or structural damage, is halted or slowed down as compared to the condition of the subject prior to administration. Successful treatment further includes complete or partial prevention of the development of the eye disease or condition. For purposes herein, slowing down or reducing the eye disease or condition or the progression of the eye disease or condition is the same as arrest, decrease, or reversal of the eye disease or condition.

[083] The expression "effective amount" refers to an amount of an agent or medicament, either in a single dose or as part of a series, which is effective for treating or preventing an eye disease or condition or predisposition thereto. This would include an amount that is effective in achieving a reduction in one or more symptom as compared to baseline prior to administration of such amount as determined, e.g., by visual acuity or other testing. The effective amount will vary depending upon the health and physical condition of the individual to be treated, the taxonomic group of individual to be treated, the formulation of the composition, the assessment of the medical situation, and other relevant factors, it is expected that the amount will fall in a relatively broad range that can be detennined through routine trials.

[084] The terms "subject," "patient" or "individual," which are used interchangeably herein, refer to any subject, particularly a vertebrate subject and even more particularly a mammalian subject, for whom therapy or prophylaxis is desired. Suitable vertebrate animals that fall within the scope of the invention include, but are not restricted to, any member of the subphylura Chordata including humans, as well as non-human primates, rodents (e.g., mice rats, guinea pigs), lagomorphs (e.g., rabbits, hares), bovines (e.g.. cattle), ovines (e.g., sheep), eaprines (e.g., goats), porcines (e.g., pigs), equities (e.g., horses), canines (e.g., dogs), felines (e.g., cats), avians (e.g., chickens, turkeys, ducks, geese, companion birds such as canaries, budgerigars etc.), marine mammals (e.g., dolphins, whales), reptiles (snakes, frogs, lizards etc), and fish. In specific embodiments, the "subject," "patient" or "individual" is a human in need of treatment or prophylaxis of an eye disease or condition, including in subjects with a diabetic eye disease or condition or an ocular tumour, hi specific embodiments, the terms "sub ject," "patient" or "individual" refer to any single human subject, including a patient, eligible for treatment who is experiencing or has experienced one or more signs, symptoms, or other indicators of an eye disease or condition or predisposition thereto, whether, for example, newly diagnosed or previously diagnosed tod now experiencing a recurrence or relapse, or is at risk for an. eye disease or condition, no matter the cause. ntended to be included as a "subject," "patient" or "individual" are any subjects involved in clinical research trials not showing any clinical sign of disease, or subjects in volved i epidemiological studies, or subjects once used as controls. The "subject," "patient" or "individual" may have been previously treated with a medicament for an eye disease or condition, or not so treated.

[085] According to the invention, the one or more improved physicochernical properties is one or more of: solubility; porosity; eiectrokinetic potential (zeta potential); flocculation; and particle size.

[086] The one or more compounds may be dissolved or redissolved in a solvent to regulate pore size. The solvent may comprise acetone.

[087] The porosity may comprise average pore size and/or total pore area.

[088] The one or more compounds may be milled to graduate and/or control particle size.

[089] The particle size may comprise crystal size,

[090] The compound ma or may not be micronized. In a particular embodiment, the compound is not micronized.

[091 ] The particles may be wet milled. The wet milling may comprise homogenisation. The homogenisation may comprise suspension in a wetting agent. The wetting agent may comprise a poiysorbate.

[092] The solubility may be increased by the composition comprising a solubility partner. The solubility partner may comprise a second compound capable of modulating the activity of a mineralocorticoid receptor and/or a glucocorticoid receptor. The second compound

1.2 ^•may comprise a compound from the same class. I.e. when the one or more compound comprises a mineralocorticoid, the solubility partner may comprise a different mineralocorticoid.

[093] The solubility may be improved by adding a cyclodexuin. The cyclodextrin may comprise hydroxy-propyl β-c-yclodextrm (ΗΡ-βϋΒ).

[094] The improved physicochemical property may be the result of a miscible agent. The miscible agent may comprise a sol vent or a solute.

[095] The one or more Improved physicochemical properties may be the result of pH or ionic strength..

[096] The one or more improved physicochemical propertyies may be the result of fractionation. The fractionation may one or more rounds of filtration s , concentrations and separations. The filtration may comprise a Millipore filter. The concentration may comprise cenirifugation. The separation may comprise separation along a gradient.

[097] The one or more improved physicochemical properties may comprise one or more of improved ionic strength, improved colligative properties, improved surface chemistry and/or improved intermolecular forces.

[098] The one or more improved physicochemical properties may comprise an altered dwell time. The altered dwell time may comprise an increased or decreased dwell time. In a particular embodiment, tire altered dwell time comprises an increased dwell time.

[099] The one or more improved physicochemical propertyies may comprise an altered bioavailability. In a particular embodiment, the altered bioavailability may comprise an increased bioavailability.

[01.00] hi one embodiment; the one or more compounds capable of modulating the activity of a mmeralocorticoid receptor and/or a glucocorticoid receptor is one or more corticosteroids or a therapeutically active analogue, derivative, homoiog, pharmaceutically acceptable salt or conjugate thereof.

[0101] The one or more compounds may comprise one or more mineralocorticoid s. The one or more mineralocorticoids may comprise one or more of: triamcinolone acetonide (TA); 11 -desoxyeortisone (1 1-DC); fludrocortisone (FA); Deoxycorticosterone acetate (DA); Deoxycorticosterone (DS); or Aldosterone; or a therapeutically active analogue, derivative, homoiog, pharmaceutically acceptable salt or conjugate thereof. [01.O23 ¾ another embodiment, the one or more compounds may comprise one or more glucocorticoids. The one or more glucocorticoids may comprise one or more of: Cortisol., cortisone, prednisone, prednisolone, methyipredmsolone, dexamethasone, betamethasone, triamcinolone, beclometasone, fludrocortisone, deoxycorticosterone, aldosterone or a therapeutically active analogue, derivative, homolog, pharmaceutically acceptable salt or conjugate thereof.

[0103] The one or more compounds may comprise one or more dual action compounds, wherein each dual action compound is capable of modulating the activit of both a mineralocorticoid receptor and a glucocorticoid receptor. The dual action compound may comprise one or more of Cortisol; cortisone; prednisone; prednisolone; methylprednisolone; fludrocortisone acetate; deoxycorticosterone acetate; aldosterone or a therapeutically active analogue, derivative, homo!og, pharmaceutically acceptable salt or conjugate thereof.

[0104] hi a particular embodiment, the one or more compounds comprises triamcinolone acetonide or a therapeutically active analogue, derivative, homolog, pharmaceutically acceptable salt or conjugate thereof.

[0105] i another particular embodiment, the one or more compounds comprises fludrocortisone acetate or a therapeutically active analogue, derivative, homolog, pharmaceutically acceptable salt or conjugate thereof.

[0106] In another particular embodiment of any of the above aspects, the one or more compounds comprises triamcinolone acetonide and fludrocortisone acetate or a therapeutically active analogue, derivative, homolog, pharmaceutically acceptable salt or conjugate of either.

[0107] Table 1 below shows some example compounds and their measured mineralocorticoid and glucocorticoid potencies.

[0108] in one embodiment, the compositions of the invention comprise a sustained release composition. Based on the teachings herein, a skilled person is readily able to select and/or formulate a suitable sustained release composition.

[ 109] in another embodiment, the compounds and compositions ma be sterilised. From the teachings herein, a skilled person is readily able to select a suitable sterilisation method such as, heat treatment.

[01 1.0] In another embodiment, the compositions of the invention are preservati ve free. [0 i l l ] In a particular embodiment, the compositions of the invention ma be comprised in a syringe. In one embodiment, the syringe allows direct injection into an eye.

[01 12] The inventors have also provided a pharmaceutical composition comprising the therapeutic agent described herein and optionally a pharmaceutically acceptable carrier, diluent or excipient.

[01 13] In one embodiment, the one or more pharmaceutically acceptable carriers, diluents or excipients comprises a surfactant.

[01.14] As used herein, the ter "surfactant'' refers to any agent, which preferentially absorbs to an interface between two immiscible phases, such as the interface between water and an organic polyme solution, a water/air interface or organic solvent air interface. Surfactants generally possess a hydrophilic moiety and a lipophilic moiety: such that, upon absorbing to microparticles, they tend to present, moieties to the external environment that do not attract similarly coated particles, thus reducing particle agglomeration. Surfactants may also promote absorption of a therapeutic or diagnostic agent and increase bioavailability of the agent.

[01 15] The surfactant may comprise a polysorbate- such as one or more of Tween 20 and T een 80.

[0116] By "pharinaceuticaliy-acceptabie carrier, diluent or excipient" is meant a solid or liquid filler, diluent or encapsulating substance that may be safely used in systemic administration. Depending upon the particular route of administration, a variety of carriers, well known in the art ma be used. These carriers may be selected from a group including sugars, starches, cellulose and its derivatives, malt, gelatine, talc, calcium sulfate, vegetable oils, synthetic oils, po!yols, alginic acid, phosphate buffered solutions, emulsifiers, isotonic saline and salts, such as mineral acid salts including hydrochlorides, bromides and sulfates, organic acids such as acetates, propionates and malonates and pyrogen-free water.

[0117] The one or more pharmaceutically acceptable carriers, diluents or excipients may comprise one or more of a wetting agent and a. viscosity modifier. The wetting agent may comprise a polysorbate. The viscosity modifier may comprise carboxy methyl cellulose (CMC). The polysorbate wetting agent may comprise Tween 80 or Tween 20. In one particular embodiment, the polysorbate wetting agent comprises Tween 80. [01 18] A useful reference describing pharmaceutically acceptable carriers, diluents and excipients is Remington's Pharmaceutical Sciences (Mack Publishing Co. N.J. USA, 1991), which is incorporated herein by reference,

[011 ] Any safe route of administration may be employed for providing a patient with the composition of the invention. For example, oral, rectal, parenteral, sublingual, buccal, intravenous, intra-articuiar, mtra-museular, intra-derrnal, subcutaneous, inhalational, intraocular, intraperitoneal, intracerebrovenuicular and transdermal administrati n may be employed.

[0120] Dosage forms include tablets, dispersions, suspensions, injections, solutions, syrups, troches, capsules, suppositories, aerosols, transdermal patches and the like. These dosage forms may also include injecting or implanting controlled releasing devices designed specifically for this purpose or other forms of implants modified to act additionally in this fashion. Controlled release of the therapeutic agent ma be affected by coating the same, for example, with hydrophobic polymers including acrylic resins, waxes, higher aliphatic alcohols, polylactic and polyglycolic acids and certain cellulose derivatives, such as hydroxypropylmethyl cellulose, in addition, the controlled release may be affected b using other polymer matrices, liposomes and/or microspheres.

[0121] Pharmaceutical compositions of the present i nv ention suitable for oral or parenteral administration may be presented as discrete units such as capsules, sachets or tablets each containing a pre-determined amount of one or more therapeutic agents of the invention, as a powder or granules or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or a water-in-oil liquid emulsion. Such compositions may be prepared by any of the methods of pharmacy, but all methods include the step of bringing into association one or more agents as described above with the carrier which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the agents of the invention with liquid carriers or finely divided solid, carriers or both, and then, if necessary, shaping the product into the desired presentation.

[0122] The above compositions may be administered in a manner compatible with the dosage formulation, and in such amount as is pharmaceuticaily-effective. The dose administered to a patient, in the context of the present invention, should be sufficient to effect a beneficial response in a patient over an appropriate period of time. The quantity of agent(s) to be administered ma depend on the subject to be treated inclusi ve of the age, sex, weight and general healt condition thereof, factors that will depend on the judgement of the practitioner.

[0123] So that the invention ma be readily understood and put into practical effect, the following non-limiting example is provided,

EXAMPLES

Aqueous solubility and enhancement of drug solubility using cyclodextrin

[0124] We have investigated the solubility enhancement of hydroxy-propyl β-cyciodextrin (HP-fJCD) on the solubility of the MR compounds in saline, with a view to its potential use in the suspension formulations to boost the amount of drag in solution,

[0125] Figure 1 shows solubility enhancement for MR compounds and TA in sal ine with addition of hydroxy propyl β-cye!odextrm (data are mean ± sd, »=3 ). Clearly, the solubility of FLU (fludrocortisone) and TA (triamcinolone acetonide) was enhanced >30 fold over the solubility in saline and increased linearly with cyclodextrin concentration in both cases. The absolute solubility for TA is lower overall In an aqueous suspension formulation this would provide a much greater proportion of drug in solution at the time of administration, without the issues of reduced activity. The increases in concentration for DCS (deoxycorticosterone acetate) were close to a linear relationship, and was the greatest seen for all drugs, with the concentration in solution with 50mM ΗΡ-βΟ-Ο being >8 mg/mL. However, the concentrations for 11 -DC (.1 l-deoxycortisol) and DCS A (deoxycorticosterone acetate) plateau at around 2 nig/niL. While the reason for this is not clear, the difference between the two sets of compounds is that FLU and TA were micronised, whilst DCS, DCSA and 11 -DC were not, and the 48 hr mixing rime may have been insufficient to attain mil saturation of drug in saline. This is also supported by the fact that DCS was closer to saturation as it has a 4-8 fold greater solubility than 1 1 -DC and DCSA. Given longer time to equilibrate, it would be anticipated that the solubility of 1 1- DC and DCSA would exceed 6 mg/mL, while that of DCS may in fact reach greater than 20 mg mL based on the slope of the curve at low cyclodextrin concentrations.

1.7 [0126] In all cases the use of hydroxypropyl hydroxy-propyl β-cyclodextrin (ΗΡ-β€0)- cyclodextri should be considered to maximise the chance of observing a pharmacological effect with these poorl water soluble drugs.

Drug storage stability in saline

[0127] To best ensure sterility of a final dose form, it was felt that a terminal sterilizatio approac in flame sealed glass ampoules would be the preferred approach, yielding a 'Kenalog' style product., however this would necessitate the drug being in an aqueous salt environment for extended periods of time. Consequently it was felt to be important to characterise the drug stability over time in aqueous solution as an indicator of likely issues with drug content and/or degradation products in the suspensions on storage. An_. accelerated stability trial was conducted in. which saturated drug solutions were prepared in saline (as a model for BSS) and samples were stored at 60°C for up to 14 days. This was felt to reflect, likely degradation profiles over at least two-three months at ambient/refrigerated temperatures. Triplicate samples were removed from the oven at 1 , 3, 7 and 14 days and analysed for drug content to follow loss of active, and the appearance of peaks in the spectrum. (A dedicated di ode array detector is u sed with the HPLC for these studies as a powerful tool in identifying that compounds are produced that may not absorb at 240 tiro and hence would not appear as 'peaks' in the single wavelength chromatogram).

[0128] The profiles for drag concentration over time are presented in Figure 2 for each drug, it is apparent that 1 1 -DC is stable over a week, and slightly declined in the second week, but. was still at a concentration >90% of that originally in the sample. Fludrocortisone displayed marked instability, declining to only 20% of the original concentration after two weeks. The remaining drugs were essentially stable over the test period. Some variability in results was evident for DCS A and TA, which we have attributed to their very low aqueous solubilities relative to the other compounds. The instability of fludrocortisone, in particular, may exclude the use of pre-packaged aqueous suspensions as a suitable dose form, at least for fludrocortisone, due to the likely production of high levels of degradation products and other avenues need to be pursued.

1.8 Drug stability under sterilization conditions (autoclave and gamma irradiation) Drug aqueous solutions

[0129] Preferably, the study materials are sterile, at least to a large degree for preclinical studies. In the absence of a facility for complete aseptic manufacture, in order to sterilize the suspensions there are two possible approaches foreseen - autoclaving the final suspensions '.in vial', or gamma sterilization. Consequently, in order to initially test the resistance of the drag to degradation in the 'wet' environment, drug in saturated solutions were prepared as for the storage stability studies above and subjected to autoclave conditions ( 321 °C/30 min) or gamma irradiation (-25 kGy at ambient temperature).

[0130] Gamma irradiation was conducted at a firm in Melbourne (Steritech; 160 South Gippsiand Hwy, Dandenong Sth) and QC certificates provided verifying dose of gamma irradiation received. The samples were exposed to 25kGy radiation, which severely discoloured the vials, in long term this method may be very suitable when an appropriate glass container, resistant to gamma rays, is used for sample preparation,

[0131] From Figure 3 it is apparent that 1 1-DC and DSC were stable to autoclave conditions. TA was moderately stable but this was still felt to be possibly unacceptable degradation of the active under these conditions. FLU was also partly degraded to a similar or worse level as TA, while DCSA was completely degraded. Gamma irradiation had a devastating effect on drug concentration with virtually no drug remaining intact for any of the solutions except 1.1-DC where less than 20% of the initial drug content remained after sterilization.

[0132] The use of a diode array detector allows some interpretation of what is occurring in the samples based on the 3 -dimensional, absorbance versus wavelength versus retention time plots. In particular, Figure 4 below indicates that DCSA has been completely degraded to DCS under autoclave conditions, but was completely degraded under gamma irradiation, i.e. no DCS or DCSA were evident in the 3D-contour plot. The degradation of DCSA to DCS is important, as it is necessary to be certain that the pharroacoiogical response in the in vivo studies is due to DCSA and not DCS produced by drug degradation in solution. Drug powders

[0133] The poor stability of most drugs under either autoclave or gamma irradiation when in contact with aqueous diluent led to a further set of stability studies to test the effect of gamma irradiation on the dry drug powders, with a view to providing the study materials as sterile powders for reconstitutkm immediately prior to administration.

[0134] Figure 5 demonstrates the stability of the powders when subjected to gamma sterilizati on and assayed for subseq uent drug content compared to a similarly handl ed, non- irradiated control. Only DCS A appeared to demonstrate a slight reduction in drug content, however only one sample was analysed so the difference may be due to inevitable slight systematic error, but is still remarkably high when compared to the data in Figure 3. Particle size and refinement

[0135] It is recommended in the literature that particle size of ocular suspensions should be less than 50 microns and preferably less tha 25 microns to avoid irritation to ocular tissues from large crystals of drug. The triamcinolone acetonide and .fludrocortisone used in these studies were micron ised powders directly from Farmabios; however, the remaining three drugs were obtained from Sigma Alrich as commercial samples that were not micronised. Hence it was of importance to: (i) Characterize the size of the remaining three powders and to confirm that of TA and FLU before proceeding; and (ii) to refine the particle size where required to obtain appropriate sized material to progress to study material development. Particle sizing by laser light scattering

[0136] Table 2 shows the measured particle size distribution for 'as received' samples of powdered compounds, it is clear that the three non-micronised samples would need further refinement in order to make it suitable for formulation into an injectable intravitreal product.

SEM imaging of raw materials

[0137] The powders were investigated also by SEM for morphology, aggregation or other phenomena that may not be apparent in laser light scattering. The representative images shown in Figure 6 agree well with the particle sizing results in the previous section.

[0138] it is clear that all three non-micronised powders require refinement to make them suitable for formulation for back of eye applications. It became apparent that with the small quantities of the powders available, the regular- methods of bail milling or jet milling would be unlikely to yield adequate results, and very low yields of powder would likely eventuate. It was decided that wet milling with a homogenizer would be the best approach, and a homogeniser was used for the purpose (Poiytron). [0139] Samples of 11 -DC, DCS and DCSA were prepared, as suspensions with 0.4% Tween. 80 (also known as Polysorbate 80) as a wetting agent, and homogenised with a Polytron on speed 6 for varying amounts of time to determine the require processing time. As can be see in the individual plots below in Figure 7, the process was effective for all drugs. A target D(v,0.9), which indicates the size below which 90% of the particles are represented, was set at 20 micron, and in all cases this was achieved in 20 mins or less processing time, and consequently this method was used for particle refinement for the rest of the fonmuation development tasks.

Formulation Manufacture. Development and Process Optimization

[0140] The following intermediate conclusions were adopted in deciding on the final formulation, approach. 1. Autoclave and gamma sterilization are not. suitable sterilization. methods for these compounds when in aqueous form. 2. Gamma sterilization. appears to be suitable for powders when in dry form only. 3. The particle size of .1.1 -DC, DCS and DCSA needs to be refined b wet milling to be adequate for these studies.

[ 141] Thus a broad approach was adopted involving the following stages: Wet sieve drugs

Parades to D (V, 0.9) less than 20 μΜ; Freeze Dry Drug Alone; Add solution of all excipieiits to drug powder in tube; dispense to vials and freeze dry; gamm sterilize and quality control; reconstitute in BSS at time of study or use,

[0142] From Table 3, our conclusion was that all drugs apart of TA without CMC and TweenSO experienced suspendability problems therefore the recommended formulation includes CMC and Tween 80 as shown in Tables 3 and 4.

[0143] Consequently, the formulation of Table 4 was uti lized for the study materials.

Summary of hatch production results indicating applicability of method

[0144] Table 5 shows a summary of batch production results. The one failed resul t had a dose of DCS A in the vial slightly below the lower specification of 18 nig. This is likely due to slight degradation of the active during gamma sterilization, but did not give rise to unidentified peaks in the HPi.C chraraatograms.

Triesence composition

[0145] Table 6 shows the composition of Triesence as listed directly on the Product Information sheet. Accordingly, one option is to use the above process and the Triesence formulation to prepare fludrocortisone system for reconstitution. Kenalog Composition

[0146] Table 7 shows the composition of Kenalog as listed directly on the Product Information sheet. At the time of manufacture, the air in the container is replaced by nitrogen, Soitrced from http://^ckageinserts,bins om pi/pi_kenalog- 1 O.pdf.

[0147] The present invention is of significant advantage because the improved physicochemical property may improve the required course of therapy for example, i reducing the number of intraocular injections required or increasing the period betwee intraocular injections and/or improve the ease of injection.

[0148] Additionailv, the present invention is of significant advantage because the decreased nu mber of injections or increased period between o bjections may lead to increased patient compliance. This in turn will lead to improved ocular health outcomes.

[01.49] Throughout the specification the aim has been to describe the preferred embodiments of the invention without limiting the invention to an one embodiment or specific collectio of fea tures. It will therefore be appreciated by those of skill in the art. mat, in light of the instant disclosure, various modifications and changes can be made in the particular embodiments exemplified without departing from the scope of the present invention.

Table 1 : MmeralOGorticoid Receptor and Glucocorticoid Receptor activity of some eoiticosterones

Key:

i.rn. intramuscular

Table 2; Measure Particle Size Distribution

Drug D(v,0.5) microns D(v,0.9) microns

11-DC 81 233

DCS 22 80

DCSA 52 226

FLU 4 10

TA 5 11

Table 3: Suspension of compounds

Suspension with CMC!^' and T een M Susp iiswB. without CMC und INveeii

Suspension quality Drawing Expelling Suspension quality l ra»ijig-up Expelling

χϊύίό

Table 4: Formulation Utilized

Component Function Mass (ml)

Tween 80 Wetting agent 0.4 mg

CMC Viscosity modifier 12.5 mg

Drug Active 40 rng

Table 5: Suraraary of batch production results indicating applicability of method

Drug

11-DC

Test Method ID Specification Result Date tested Comments

^Dirug ^^ I ^TzoTng ϊδ.4 ± 0Ϊ5 27/Ϊ0/20Ό6 Passed!

Content per viai

Particle RGA40/2 D(G,5}=<20 3/11/2006 Passed

Size D{0.9)=<30 pH RGA40/3 6.0 - 8.0 7.0 3/11/2006 Passed

DCS

Test Method ID Specification Result Date tested Comments

Av Drug RGA40/1 20.0 ±2.0 mg 18.5± 0.7 1/11/2006 Passed

Content per vial

Particle RGA4Q/2 D(0.5)=<20 12.7 3/11/2006 Passed

Size D{0.9)=<30 30.0 pH RGA40/3 6.0 - 8.0 7.0 3/11/2006 Passed DCSA

Test Method ID Specification Result Date tested Comments

Av Drug RGA40/1 20.0 ±2.0 mg 16 ± 0.9 2/ 1/2008 Failed* Content per vial

Particle RGA4G/2 D(0.5)=<20 8.25 3/11/2008 Passed Size D£Q.9)=<3Q 28.77 pH RGA40/3 6.0 - 8.0 7.0 3/11/2008 Passed

Ftudra

Test Method tD Specification Result Date tested Comments

Av Drug RGA40/1 20.0 ± 2.0 mg 18.1 ± 0.7 25/10/2006 Passed Content per vial

Particle RGA40/2 D(0.5>=<20 3.47 3/11/2008 Passed Size D<G.9)=<30 9.16

pH RGA4G/3 6.0 - 8.0 7.0 3/1 /2006 Passed

T.A

Test Method ID Specification Result Date tested Comments

Av Drug RGA40/1 20.0 ± 2.0 mg 18.33 ± 0.7 ^' 30/10/2006 Passed Content per via!

Particle RGA40/2 D(0.5}=<20 4.43 3/ /2006 Passed Size D{G.9)=<3G 8.57 pH RGA40/3 6.0 - 8.0 7.0 3/11/2006 Passed Table 6: Composition of Trieseeenee

Table 7: Kenafog Composition

Triamcinolone acetonide 10 mg/^'mL

carboxymethylcelluiose sodium 0.75% /v; 7.5 mg mL

polysorbate 80 0.04% (not stipulated but expect w/v = 0.4 mg/^'mL sodium chloride 0.65% to isotonic

benzyl alcohol 0.9% (w/v)

hydrochloric acid and/ or sodium for pH adjustment

hydroxide

Water for injection qs

Claims

1. A method for making a pharmaceutical, composition comprising a therapeutically effective amount of one or more compounds capable of modulating an activity of a mmeralocorticoid receptor and or a glucocorticoid receptor, the method comprising formulating the composition to comprise one or more improved physicochemical properties,

2. A pharmaceutical composition comprising a therapeuti cal ly effective amount of one or more compounds capable of modulating an activity of a mineralocorticoid receptor and/or a glucocorticoid receptor and at least one solvent, the composition comprising one or more improved physicochemical properties.

3. A pharmaceutical composition made according to the method of claim 1.

4. A pharmaceutical composition comprising a therapeutically effective amount of one or more compounds capable of modulating an activity of a mineralocorticoid receptor and/or a glucocorticoid receptor for use in the treatment of an eye disease or condition or predisposition thereto wherein the composition comprises one or more improved physicochemical properties,

5. A method of treatment of an eye disease or condition or a predisposition diereto in a subject in need thereof, the method including applying to the eye a therapeutically effective amount of one or more compound capable of modulating an activity of a mineralocorticoid receptor and/or a glucocorticoid receptor, the composition comprising one or more improved physicochemical. properties to thereby treat the eye disease or condition or predisposition thereto.

6. Use of a composition comprising a therapeutically effecti ve amount of one or more compounds capable of modulating an activity of a mineralocorticoid receptor and/or a glucocorticoid receptor, the composition comprising one or more improved physicochemic al properties for the man u facture of a medicament for the therapeutic and/or prophylactic treatment of an eye disease or condition.

7. A syringe comprising the composition of claim 2.

8. The method, composit i on, use or syringe of any pre vious c 1 ai m , wherein the one or more improved physicochemical properties is/are one or more of: solubility; porosity; electrokinetic potential (zeta potential)', fiocculation; and particle size.

9, The method, comp ositi on, use or syringe o f any previous ciaim w herein the one or more compounds is milled to graduate and/or control particle size,

10. The method, composition, use or syringe of claim 9, wherein the milling comprises wet milling,

1.1. The method, composition, use or syringe of any previous claim, wherein the solubility^ is increased by the composition comprising a solubility partner.

12. The method, composition, use or syringe of claim 1 1 , wherein the solubility partner comprises cyeiodextrin.

13. The method, composition, use or syringe of any pre vious claim, wherein the one or more improved pliysicochemical property is achieved by wet sieving the compound particles to D (V, 0.9) less than 20 μΜ; freeze drying the one or more compounds alone; adding a solution of all excipients to the one or more compounds powder; dispensing to vials and freeze drying; gamma sterilizing; and reconstitute in BSS.

14. The method, composition, use or syringe of any previous claim, wherein one or more compounds capable of modulating the activity of a mineraiocorticoid receptor and/or a glucocorticoid receptor is one or more corticosteroids or a therapeutically active analogue, derivative, homolog, pharmaceutically acceptable salt, prodrug, metabolite or conjugate threreof.

15. The method, composition, use or syringe of any previous claim, wherein the one or more compounds comprises one or more mineralocorticoids.

16. The method, composition, use or syringe of claim 15, wherein the one or more mineralocorticoids comprises one or more of: triamcinolone acetonide (TA); 11 - desoxycoitisone (11 -DC); fludrocortisone (FA); Deoxycorticosterone acetate (DA); Deoxycorticosterone (DS); or Aldosterone; or a therapeutically active analogue, derivative, homolog, pharmaceutically acceptable salt or conjugate thereof.

17. The method, composition, use or syringe of any previous claim, wherein the one or more compounds comprises one or more glucocorticoids.

18. The method, composition, use or syringe of claim 17, wherein the one or more glucocorticoid comprises one or more of: Cortisol, cortisone, prednisone, prednisolone, methyl prednisolone, dexamethasone, betamethasone, triamcinolone, beclometasone,

.fludrocortisone, deoxycorticosterone, aldosterone or a therapeutically active analogue, derivative, homolog, pharmaceutically acceptable salt or conjugate thereof.

19. The method, composition, use or syringe of any previous claim, wherein the one or more compounds comprises triamcinolone acetonide or a therapeutically active analogue, derivative, homolog, pharmaceutically acceptable salt or conjugate thereof.

20. The method, composition, use or syringe of any previous claim, wherein the one or more compounds comprises fludrocortisone acetate or a therapeutically active analogue, derivative, homolog, pharmaceutically acceptable salt or conjugate thereof.

21. The method, composition, use or syringe of any previous claim, wherein the one or more compounds compiises triamcinolone acetonide and fludrocortisone acetate or a therapeutically acti ve analogue, derivative, homolog, pharmaceutically acceptable salt or conjugate of either.

22. The method, composition, use or syringe of any previous claim, wherein said eye disease and/or condition comprises an exudative eye disease and/or condition.

23. The method, composition, use or syringe of any previous claim, wherein said eye disease and/or condition comprises a back of the eye exudative eye disease and/or condition.

24. The method, composition, use or syringe of any previous claim, wherein said eye disease and/or condition is a front of the eye exudative eye disease and/or condition.

25. The method, composition, use or syringe of any previous claim, wherein said eye disease and/or condition is macular degeneration including age-related macular degeneration and wet age related macular degeneration.

26. The method, composi tion, use or syringe of any previous claim , wherein said eye disease and/or condition is a diabetic macular edema (DME), cystoid macular edema (CMO); maculopathy; and/or an ocular tumour.

27. The method, composition, use or syringe of any previous claim, wherein the ocular tumour comprises a retinoblastoma and/or a. melanoma.

28. The method, composition, use or syringe of any previous claim, wherein said eye disease and/or condition is a diabetic eye disease and/or condition.

29. The method, composition, use or syringe of any previous claim, wherein said eye disease and/condition comprises coiijimetivitis including non-infectious conjunctivitis, anterior uveitis and an ocular allergy.

30. The method, composition, use or syringe of any previous claim, further comprising one or more pharmaceutically acceptable carriers, diluents or excipients.

31. The method, composition, use or syringe of Claim 30 wherein the one or more pliannaeeutieally acceptable carriers, diluents or excipients comprise one or more wetting agent and/or a viscosity modifier.