EP2755659A2

EP2755659A2 - Pharmaceutical nanoparticle compositions

Info

Publication number: EP2755659A2
Application number: EP12762374.2A
Authority: EP
Inventors: Francesca CRAWFORD; Philip Gunning; David HERMANS; Deepak Thassu
Original assignee: Altacor Ltd
Current assignee: Altacor Ltd
Priority date: 2011-09-13
Filing date: 2012-09-13
Publication date: 2014-07-23
Also published as: WO2013038195A3; CA2845673A1; WO2013038195A2; CN103930115A

Abstract

This invention relates to the use of nanoparticles of glucocorticoid antagonists for the treatment of ocular and non-ocular conditions, compositions containing them and methods for the preparation thereof.

Description

PHARMACEUTICAL NANOPARTICLE COMPOSITIONS

FIELD OF THE INVENTION

BACKGROUND OF THE INVENTION

It has been reported that mifepristone (also known as RU38486 or RU486, a glucocorticoid antagonist) lowers the intraocular pressure (IOP) in rabbit eyes (Phillips, C, Green, K., Gore, S., Cullen, P. & Campbell, M. Lancet, 767-768 (1984)). It was suggested by the authors that if the ocular hypertensive effect of mifepristone applies in man as in rabbits, this agent (or an analogue with greater water solubility) might be valuable in the treatment of chronic open-angle glaucoma and ocular hypertension, and chronic closed angle glaucoma (after iridectomy or laser iridotomy), infantile glaucoma, and even some secondary glaucomas.

US Patent No 6090798, the disclosure of which is incorporated herein by reference in its entirety, claims a method for treating GLC 1A glaucoma which comprises administering a pharmaceutically effective amount of a glucocorticoid antagonist, preferably mifepristone. WO2007/025275, the disclosure of which is incorporated herein by reference in its entirety, claims a method for the prevention of a deleterious effect induced by a corticosteroid comprising administering a steroid antagonist in an amount sufficient to counteract the deleterious effect. WO2007/083145, the disclosure of which is incorporated herein by reference in its entirety, claims the use of a compound having glucocorticoid receptor antagonist activity and a clogP value of less than 5 for the manufacture of a medicament for the treatment of an ocular condition. This latter patent application measured intraocular pressure in rabbits after instillation of mifepristone and showed, when compared to a vehicle-treated group, that mifepristone did not induce a statistically significant decrease in IOP at 3 or 4 hours although an effect at these time points was shown by the less lipophilic substances, RU42868 and RU42698.

The significant drawback of mifepristone for use in glaucoma is its poor water solubility which limits an effective amount of material reaching the site of action. Accordingly, to date, no treatment for glaucoma using glucocorticoid antagonists has been successfully registered. It is therefore desired that a method is found to enhance the bioavailability of mifepristone (and other glucocorticoid antagonists) when applied topically to or around the eye. SUMMARY OF THE INVENTION

The present invention is directed to the use of nanoparticles of glucocorticoid antagonists, in particular mifepristone, for the treatment of ocular and non-ocular conditions, in particular ocular hypertension. The nanoparticles have the effect of improving the bioavailability of the glucocorticoid antagonists especially when administered via the ocular route.

In the first aspect of the invention, there is provided a pharmaceutical composition comprising nanoparticles of a glucocorticoid antagonist, or a physiologically acceptable salt, complex or prodrug thereof, for use as a medicament for the treatment or prophylaxis of ocular conditions in a human or non-human subject. The composition may be administered topically to or around the eye.

The pharmaceutical composition may particularly be used in the treatment or prophylaxis of ocular diseases associated with elevated intraocular pressure, especially all forms of glaucoma, e.g. primary glaucoma, including primary angle-closure glaucoma, primary open-angle glaucoma, pigmentary glaucoma, exfoliation glaucoma, developmental glaucoma, including primary congenital glaucoma, infantile glaucoma, inherited juvenile and early onset open-angle glaucoma, glaucoma associated with hereditary of familial diseases, secondary glaucoma, including inflammatory glaucoma, phacogenic glaucoma, glaucoma secondary to intraocular haemorrhage, traumatic glaucoma, neovascular glaucoma, drug-induced glaucoma, or glaucoma of miscellaneous origin i.e. toxic glaucoma. Suitably the composition is intended to reduce elevated intraocular pressure to normal levels. Normal intraocular pressure is generally defined as that between 10 mmHg and 20 mmHg.

In particular, the pharmaceutical composition may be used in the treatment or prophylaxis of steroid-induced glaucoma.

As a further aspect of the invention, there is provided a pharmaceutical composition comprising nanoparticles of a glucocorticoid antagonist, or a physiologically acceptable salt, complex or prodrug thereof for use as a medicament, for the treatment or prophylaxis of an ocular condition in which neovascularisation is involved and/or in particular, for the treatment or prophylaxis of an ocular condition selected from age-related macular degeneration, blepharitis, choroidal neovascularisation, retinal neovascularisation, corneal neovascularisation, ocular histoplasmosis syndrome, pathologic myopia, angioid streaks, idiopathic disorders, choroiditis, choroidal rupture, overlying choroid nevi, Best's disease, Stargardt's disease, Vogt-Koyanagi-Harada syndrome, toxoplasmosis, central serous chorioretinopathy, diabetic retinopathy and other proliferative retinopathy, retinopathy of prematurity, pseudoxanthoma elasticum, vein or artery occlusion, carotid obstructive disease, chronic uveitis / vitritis, mycobacterial infection, Behcet's disease, infections causing retinitis, optic pits, par planitis, chronic retinal detachment, hyperviscosity syndromes, capillary haemangioma including von Hippel-Lindau disease, post- laser complication, epidemic keratoconjunctivitis, Vitamin A deficiency, contact lens overwear, atopic keratitis, superior limbic keratitis, pterygium keratitis sicca, sjogrens, acne rosacea, phylectenulosis, Mycobacteria infections, lipid degeneration, bacterial ulcers, fungal ulcers, Herpes simplex infections, Herpes zoster infections, protozoan infections, Mooren ulcer, Terrien's marginal degeneration, mariginal keratolysis, scleritis, Steven's Johnson disease, pemphigoid radial keratotomy, and corneal graft rejection.

As a further aspect of the invention, there is provided a method for treating or preventing glaucoma and / or elevated intraocular pressure or other ocular condition in a human or non- human patient in need thereof, the method comprising administrating to the patient an effective amount of a composition comprising nanoparticles of a glucocorticoid antagonist, or a physiologically acceptable salt, complex or prodrug. The method may further comprise a prior examination of the patient which checks for symptoms of elevated intraocular pressure and / or a diagnosis of the presence of glaucoma or other ocular condition in the patient.

As a further aspect of the invention, there is provided a composition comprising nanoparticles of a glucocorticoid antagonist, or a physiologically acceptable salt, complex or prodrug for use in the manufacture of a medicament for treating or preventing glaucoma and / or elevated intraocular pressure or other ocular condition in a human or non-human patient.

According to a further aspect of the invention, there is provided a pharmaceutical composition comprising nanoparticles of a glucocorticoid antagonist, or a physiologically acceptable salt, complex or prodrug thereof for use as a medicament, e.g. for use in therapeutic and / or prophylactic treatment of non-ophthalmic conditions in a human or non-human subject.

The pharmaceutical composition may particularly be used in the treatment or prophylaxis of diseases resulting in elevated Cortisol levels.

Diseases where the use of a glucocorticoid antagonist has been proposed as a therapeutic and / or prophylactic remedy are: neuropsychiatric conditions such as psychotic major depression, bipolar depression, schizophrenia and cognitive disorders; hypertension; Cushing's syndrome; obesity; amyotrophic lateral sclerosis; endometriosis; uterine fibroids; meningiomas; and certain cancers e.g. breast cancer, ovarian cancer and androgen-independent prostate cancer. A glucocorticoid antagonist, preferably mifepristone can be used as an abortifacient (particularly in the first two months of pregnancy), and (typically in smaller doses) as an emergency contraceptive.

As a further aspect of the invention, there is provided a pharmaceutical composition comprising nanoparticles of a glucocorticoid antagonist, or a physiologically acceptable salt, complex or prodrug thereof and at least one bile acid compound. Additional pharmaceutically acceptable excipients for example at least one mucoadhesive component may optionally be present in the composition. Said additional pharmaceutically acceptable excipients may be present in the nanoparticles, in the composition but not in the nanoparticles, or in the nanoparticles and elsewhere in the composition.

The nanoparticle containing compositions of the invention have been shown to have enhanced bioavailability thus enabling a pharmacologically effective amount of the glucocorticoid antagonist to be delivered across the cornea.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to the use of nanoparticles of glucocorticoid antagonists for the treatment of ocular and non-ocular conditions, in particular ocular hypertension and methods for the preparation thereof. Mifepristone, one of a number of known glucocorticoid antagonists, has been shown to have limited effect in reducing IOP in animal models. The poor water solubility of mifepristone is a significant drawback that limits its bioavailability and hence its development as a treatment for glaucoma. There is a need to improve the bioavailability of mifepristone. Nanoparticles containing mifepristone have been prepared from DL-lactide / glycolide copolymers (W. He, S. W. Horn and M. D. Hussain, International Journal of Pharmaceutics, 334 (2007) 173-178, the disclosure of which is incorporated herein by reference in its entirety) to improve the oral bioavailability and to sustain the release of mifepristone for at least 3 days to effectively control reproduction, especially in coyotes. Whilst these nanoparticles are beneficial for long term oral dosing, it was shown by the authors that the in vitro release of mifepristone into media was only 40% for the nanoparticles after 24 h compared with 60% of uncoated mifepristone, indicating that these nanoparticles will not be suitable for topical use on the eye. To solve the problem of improving the bioavailability of mifepristone or other glucocorticoid antagonists after topical administration to the eye, we have shown that nanoparticles gave a large increase in permeability across the cornea in vitro compared to unformulated mifepristone. This increase in permeability will increase the bioavailability and hence likely to lead to a larger decrease in IOP.

The term "glucocorticoid antagonist" refers to any one of a number of steroidal and nonsteroidal compounds that have glucocorticoid antagonist activity (i.e. have activity as antagonists of the glucocorticoid receptor also known as NR3C1). Glucocorticoid antagonists are commonly water insoluble or poorly water soluble. Examples of insoluble or poorly water soluble glucocorticoid antagonists include mifepristone, tetrahydrocortisol, biclalutamide, nilretamide, tamsulosin, and testolactone. Further examples include the poorly water soluble substances 11-oxa Cortisol, 11-oxa prenisolone, Cortisol oxetanone, dexamethasone oxetanone, Cortisol mesylate, dexamethasone mesylate, Cortisol acetonide, dexamerhasone acetonide, 11- deoxycortisol, A^1,9(11)-l l-deoxycortisol, 17 -methyltestosterone and progesterone. Especially preferred is mifepristone.

The term "physiologically acceptable" means it is, within the scope of sound medical and veterinary judgement, suitable for use in contact with the cells of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. "Physiologically unacceptable" means it is not suitable for such use.

The term "salt" means the inorganic and organic acid addition salts, and base addition salts, of any compounds for use in the present invention where such salt formation is possible. These salts can be prepared in situ during the final isolation and purification of the compounds. In particular, acid addition salts can be prepared by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. See, for example S. M. Berge, et al., Pharmaceutical Salts, J. Pharm. Sci., 66: p.1-19 (1977) which is incorporated herein by reference. Base addition salts can also be prepared by separately reacting the purified compound in its acid form with a suitable organic or inorganic base and isolating the salt thus formed. Base addition salts include pharmaceutically acceptable metal and amine salts. Examples of suitable acid addition salts are those formed with acids selected from hydrochloric, sulfuric, phosphoric and nitric acids. Examples of suitable base addition salts are those formed with bases selected from sodium hydroxide, potassium hydroxide and ammonium hydroxide.

The term "prodrug" means any compound that is rapidly transformed in vivo to yield the parent compound by cleavage of one or more physiologically labile leaving group or by operation of a physiologically initiated chemical reaction, for example by hydrolysis in the gastrointestinal tract or in blood. A thorough discussion of prodrugs is provided in the following: Design of Prodrugs, H. Bundgaard, ed., Elsevier, 1985; Methods in Enzymology, K. Widder et al, Ed., Academic Press, 42, p.309-396, 1985; A Textbook of Drug Design and Development, Krogsgaard-Larsen and H. Bundgaard, ed., Chapter 5; Design and Applications of Prodrugs, p.l 13-191 , 1991 ; Advanced Drug Delivery Reviews, H. Bundgard, 8, p.1-38, 1992; Journal of Pharmaceutical Sciences, 77, p. 285, 1988; Chem. Pharm. Bull, N. Nakeya et al, 32, p. 692, 1984; Pro-drugs as Novel Delivery Systems, T. Higuchi and V. Stella, Vol. 14 of the A. C. S. Symposium Series, and Bioreversible Carriers in Drug Design, Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press, 1987, which are incorporated herein by reference.

Nanoparticles

The term "nanoparticle" refers to a particle or particles that either may be used by themselves or, preferably, in compositions comprising the nanoparticles and other compound(s) that are optimized for delivery of the nanoparticles, e.g. drug delivery. The nanoparticles of the invention have a characteristic dimension (generically, "size"), such as average diameter, of less than 10 μιη, e.g. less than 10, 5, 2, or 1 μιη. In a preferred embodiment, the nanoparticles of the invention are in a range of 0.01 μιη (10 nm) to about 5 μιη (5000 nm) of average diameter (synonymously, "average size"). In another preferred embodiment, the nanoparticles of the invention have a characteristic average diameter of less than about 1 μιη, i.e. are in the nm size range. For embodiments of the present invention specifying an average diameter of nanoparticles, this average diameter may be determined as the "average effective particle diameter", which may be measured by, e.g. light scattering methods (e.g. photon correlation spectroscopy, laser diffraction, low-angle laser light scattering (LALLS), medium-angle laser light scattering (MALLS)), rheology, or microscopy (light or electron). The preferred method is photon correlation spectroscopy such as employed with the Beckmann Coulter DelsaNano C particle size analyser. The nanoparticles of the glucocorticoid antagonist according to the invention will preferably have a diameter of 2000 nm or less and preferably have a particle distribution such that greater than 95% of the particles have a diameter of 10-2000 nm, more preferably that greater than 95% of the particles have a diameter of 10-1000 nm or less, and most preferably that greater than 95% of the particles have a diameter of 10-220 nm or less.

Nanoparticles contain at least one glucocorticoid antagonist. Suitably, nanoparticles may in addition contain at least one bile acid compound. Optionally nanoparticles contain at least one mucoadhesive component. Optionally nanoparticles contain other ingredients.

Suitably the glucocorticoid antagonist (or all of them) represents at least 80%> w/w of the nanoparticle.

Mucoadhesive component

Compositions of the invention may optionally contain a mucoadhesive component, typically a mucoadhesive polymer. Examples of suitable mucoadhesive polymers include poloxomers, e.g. poloxamer L44, Poloxamer F68, carbomers and the cellulose derivatives, e.g. hydroxypropyl methylcellulose and carboxymethyl cellulose.

The addition of the mucoadhesive component facilitates retention of the nanoparticle compositions at the eye to enhance permeability and bioavailability of the active ingredient in the nanoparticles.

The mucoadhesive component may be present in or on the nanoparticles or it may be in the vehicle alone. When the mucoadhesive component is contained in the nanoparticles, it is typically present in an amount 0.1 to 5% w/w. When the mucoadhesive component is contained in the composition but not in the nanoparticles, it is typically present in an amount of 0.1 to 25% w/w.

Bile acid compound The term "bile acid compound(s)" embraces bile acids and salts and refers to compounds including, but not limited to, a steroid acid, or salt thereof, including cholic acid, taurocholic acid, glycocholic acid, lithocholic acid, chenodeoxycholic acid, deoxycholic acid, glycodeoxycholic acid, derivatives thereof, and mixtures thereof. The term is intended to encompass any such compound recognized by a person of skill in the art as a bile-acid or a cholate derivative. The term "bile acid salt" includes mixtures of bile acid salts. Exemplary bile acid salts include the salts of dihydroxy cholic acids, such as deoxycholic acid, glycodeoxycholic acid, taurodeoxycholic acid, chenodeoxycholic acid, glycochenodeoxycholic acid, and taurocheno deoxycholic acid, and trihydroxy cholic acids, such as cholic acid, glycocholic acid, and taurocholic acid. The acid addition salts include sodium, and potassium salts. A preferred bile acid compound is a deoxycholate salt e.g. sodium deoxycholate. With regard to the amount of bile acid compound(s) present in the bulk weight of the nanoparticles, typical amounts range from 1-20% w/w, with preferably 1-10% w/w, with most preferably 1-5% w/w.

Preparation of nanoparticles The scientific literature affords numerous ways to produce nanoparticles. For example, WO2010/080754, the disclosure of which is incorporated herein by reference in its entirety, discloses methods of preparing nanoparticles of aqueous insoluble compounds. These nanoparticles are formed in the presence of one or more bile acid compounds with a narrow size distribution. Other types of stable nanoparticles include chitosan nanoparticles, human serum albumin nanoparticles, silica nanospheres, PEG'ylated core-shell nanoparticles, biodegradable PLGA (poly(D,L-lactide-co-glycolide)) particles PLA (poly lactic acid), PGA, PLG (poly(D,L- glycolide)) polymeric nanoparticles, a water-soluble porous matrix made up of polymeric materials having the water-insoluble active ingredient dispersed as nanoparticles throughout the matrix, biocompatible gliadin nanoparticles, low pH sensitive PEG stabilized plasmid-lipid nanoparticles, tocopherol derivatives stabilized nano-sized emulsion particles, PLA-PEG nanoparticles, nanoparticles composed of hydrophilic proteins coupled with apo lipoprotein E, biodegradable poly (vepsiln-caprolactone) nanoparticles, biotinylated poly( ethylene glycol) conjugated with lactobionic acid and carboxylmethyl dextran magnetic nanoparticles.

One suitable method of manufacturing nanoparticles of a glucocorticoid antagonist or a physiologically acceptable salt, complex or prodrug comprises dissolving the glucocorticoid antagonist in an organic solvent such as methanol, ethanol, acetone and subsequently adding said solution dropwise to a vigorously stirred aqueous solution of a bile acid compound (or one or more thereof). An aqueous solution of a polymer (such as a mucoadhesive polymer) may optionally be added to the solution of bile acid compound prior to addition of the glucocorticoid antagonist solution, or after the addition of the glucocorticoid antagonist solution.

Crystalline/Non-Crystalline/ Amorphous. In some embodiments, the aqueous-insoluble compound(s) component of the nanoparticles (i.e. the glucocorticoid antagonist or combination thereof) is / are substantially crystalline; in other embodiments, the compound or compounds is / are substantially non-crystalline. The term "substantially crystalline" refers to a situation where a high percentage of the aqueous-insoluble compound or compounds present in the nanoparticles exhibit long-range order in three dimensions e.g. a distance of more than a few molecules. "Substantially noncrystalline" or, synonymously, "substantially amorphous" refers to a situation where a high percentage of the compound or compounds lack long-range three-dimensional order, and includes not only material which has essentially no order, but also material which may have some small degree of order, but the order is in less than three dimensions and/or is only over short distances, e.g. a distance of a few molecules. The present invention is particularly directed to substantially noncrystalline / substantially amorphous drug compound or compounds situations, since the noncrystalline / amorphous form of a low-solubility drug provides a greater aqueous concentration of drug relative to the crystalline form of the drug in an aqueous use environment. Thus the present invention is particularly directed to aqueous-insoluble compounds(s) in nanoparticles, where the compound(s) are substantially non-crystalline, i.e. a high percentage of the aqueous- insoluble compound or compounds in the nanoparticles is/are in non-crystalline form, e.g. at least about 70%, 71%, 72%, ... 97%, 98%, 99%, etc. of the compound or compounds in the nanoparticles is/are in non-crystalline form. The degree of non-crystallinity is preferably evaluated as a percentage of the compound or compounds that are non-crystalline in the collection of nanoparticles as a whole (i.e. as a function of the bulk of nanoparticles), i.e. when at least about 70%, 71%, 72%, ... 97%, 98%, 99%, etc. by weight of the total weight of aqueous- insoluble compound or compounds in a preparation of nanoparticles are in non-crystalline form. However, in addition to being expressed as a wt%, the percentage may in some situations be measured based on individual or only small numbers of nanoparticles (i.e. non-bulk percentages). Alternatively, the degree of non-crystallinity may be expressed as a limit on the maximum amount of crystalline compound organization in a sample, e.g. no more than about 20, 19, 18, ... 3, 2, 1%), etc., of crystallinity. Amounts of crystalline compound may be measured by Polarized light microscopy, Powder X-Ray Diffraction (PXRD), Differential Scanning Calorimetry (DSC), solid-state nuclear magnetic resonance (NMR), or by any other appropriate measurement.

Polydispersity Index (PDI). The term "polydispersity index" is defined as a measure of the distribution broadness of a sample, and is typically defined as the relative variance in the correlation decay rate distribution, as is known by one skilled in the art. See BJ. Fisken, "Revisiting the method of cumulants for the analysis of dynamic light-scattering data", Applied Optics, 40(24), 4087-4091 (2001) for a discussion of cumulant diameter and polydispersity. Preferably, the polydispersity of the nanoparticles is less than 0.8, preferably less than 0.5, and more preferably less than 0.3 and most preferably less than 0.2. Pharmaceutical compositions

The term "pharmaceutical composition" in the context of this invention means a composition comprising an active agent and comprising additionally one or more pharmaceutically acceptable carriers. The composition may further contain ingredients selected from, for example, diluents, adjuvants, excipients, vehicles, preserving agents, emulsifying agents, suspending agents, antibacterial agents, antifungal agents and lubricating agents. The compositions may take the form, for example, of liquid preparations including suspensions, sprays, emulsions and solutions. Techniques and formulations generally may be found in Remington, The Science and Practice of Pharmacy, Mack Publishing Co., Easton, PA, latest edition. Compositions of the invention may be used in association with one or more further active ingredients especially one or more further pharmaceutically active ingredients suitable for administration to the eye or for treatment of ocular conditions. Exemplary further active ingredients include glucocorticoid compounds such as steroids, also prostaglandins and beta- blockers. Compositions of the invention may contain a glucorticoid antagonist (or more than one of them) optionally together with one or more further pharmaceutically active ingredients. Alternatively, further active ingredients as mentioned above may also be formulated for separate administration by the same or different route to the composition according to the invention.

Especially preferred is a combination of mifepristone with dexamethasone and a combination of mifepristone with timolol maleate.

A pharmaceutical composition according to the invention will typically comprise nanoparticles of glucocorticoid antagonists (said nanoparticles optionally containing other ingredients) together with one or more pharmaceutically acceptable carriers. There is provided a method of manufacturing a pharmaceutical composition, comprising a nanoparticle-containing composition and a physiologically acceptable carrier therefor, the method comprising bringing into admixture the said nanoparticle containing composition and the physiologically acceptable carrier therefor. The most suitable carrier is water optionally together with one or more ophthalmic adjuvant components e.g. selected from a buffer, a suspending and / or viscosity- increasing agent, a wetting and / or solubilizing agent, a preservative, a complexing agent, a tonicity modifying component (e.g. comprising about 0.05% to 1.0% w/v of sodium chloride) and combinations thereof.

Compositions of the invention may contain a mucoadhesive component, especially if not already present in the nanoparticles.

Suitably the pharmaceutical composition may be formulated as an aqueous suspension.

Suitably the composition is isotonic or slightly hypotonic with respect to natural tears, i.e. having an osmolality between 200 to 300 mOsmol/kg. Suitably the pH of the composition is between 4.5 and 8.

Examples of suspending and/or viscosity-increasing agents include carbomers and cellulose- based polymers. Preferably the polymer is a carbomer, or carboxymethylcellulose or hydroxypropyl methylcellulose, or more preferably hydroxypropyl methylcellulose (HPMC). Other polymers, e.g. hydroxyethylcellulose, ethyl cellulose, methylcellulose, sodium carboxymethylcellulose or polyvinyl alcohol may also be used. Optionally more than one viscosity increasing agent may be employed.

Examples of wetting and/or solubilizing agents include the poloxamers, polysorbates, nonoxynol-9, octoxynol-8, polyoxyl 10 oleyl ether, sodium lauryl sulfate and sorbitan esters. Examples of a complexing agent include disodium edatate, calcium disodium edatate and edetic acid.

Examples of suitable preservatives include benzalkonium chloride and the cetrimonium halides.

Example tonicity modifying components include mannitol and sodium chloride.

Other components customary for the route of administration (especially for ocular administration) may be included in compositions of the invention.

Pharmaceutical compositions or the nanoparticles may optionally be lyophilized to a dried powder and can easily be reconstituted with an aqueous medium to approximately the same nanoparticle size distribution as prior to lyophilization. After the ingredients of the pharmaceutical composition, have been brought into admixture, the composition is preferably packaged with instructions for use in the treatment or prophylaxis of glaucoma or other ocular condition or other non-ocular condition as mentioned herein in a human or non-human subject, the said instructions typically including dosage information, information concerning the appropriate administration route and protocol, and safety information relevant to the said intended use.

Therapy, routes of Administration, dosages

Therapeutic use of the compositions of the invention may be under medical or veterinary supervision or control, or may be self-administered (in the case of humans) or under the control of a person not veterinarily qualified (in the case of non-human animals).

The pharmaceutical composition according to the invention may be provided in unit dosage form, whereby typically one or more unit dosages are administered to the subject. Alternatively, the pharmaceutical composition may be provided in a form which does not comprise unit dosages, and in that case a suitable dosage is typically measured out for administration. Nanoparticle compositions according to the invention are principally intended for administration to or around the eye however the precise location will depend on the indication to be treated. Administration may, for example, be to the cornea of the eye. For treatment of glaucoma, administration to the cornea is most suitable. Alternatively administration may be to the adnexa of the eye. Suitably amounts of glucocorticoid antagonist (such as mifepristone) to be administered will depend on the indication to be treated and its severity. For example up to 600 mg per day may be suitable for treating bipolar disorder, up to 10 mg vaginal tablets may be suitable for causing a reduction of uterine fibroids size and up to 200 mg per day for androgen-independent prostate cancer. In the treatment of glaucoma, up to 50 mg per day over a period of up to 3 months may be suitable to reduce the intraocular pressure.

Percentage values mentioned herein are calculated as w/w unless otherwise stated.

Suitably a pharmaceutical composition comprising nanoparticles of a glucocorticoid antagonist demonstrates enhanced bioavailability of the glucocorticoid antagonist compared to the same active ingredient when not in the form of nanoparticles, especially when administered topically to the eye. The nanoparticles of mifepristone may demonstrate enhanced penetration of the active into biological tissue compared with a solution composition of the same active ingredient when not in the form of nanoparticles. Suitably the pharmaceutical composition may be an ophthalmic composition comprising nanoparticles of a glucocorticoid antagonist, preferably mifepristone that demonstrates enhanced penetration of the glucocorticoid antagonist across the cornea compared with a solution composition of the same active ingredient when not in the form of nanoparticles.

The pharmaceutical composition comprising nanoparticles of a glucocorticoid antagonist may effectively decrease intraocular pressure as a result of the enhanced penetration of the active across the cornea compared with a solution composition of the same active ingredient when not in the form of nanoparticles.

EXAMPLES

The invention, and some of its preferred features, is illustrated, but in no way limited by the following Examples.

Nanoparticle compositions of mifepristone described in Examples 1-5 and 8-11 below were prepared using a process similar to that described in WO 2010/080754, which is incorporated herein by reference in its entirety.

In all of these Examples, particle size and PDI were determined using photon correlation spectroscopy on a Beckman Coulter DelsaNano C particle size analyser.

Example 1

A solution of mifepristone (12.5 mg) in methanol (0.25 ml, 50 mg/ml) was added dropwise to a vigorously stirred aqueous sodium deoxycholate (DOC) solution (10 ml, 10 mg/ml) at room temperature. The resulting mifepristone nanoparticles were found to have a mean particle diameter of 175 nm diameter with a PDI of 0.168 that did not materially change during storage at 5°C for 1 hour.

Example 2

A solution of mifepristone (9 mg) in methanol (0.15 ml, 60 mg/ml) was added dropwise to either vigorously stirred water (5 ml), or vigorously stirred aqueous sodium deoxycholate (DOC) solutions (5 ml, 2, 4, 5, 6, 10 mg/ml) at room temperature. The mean particle diameter of the resulting mifepristone nanoparticles are given in the following Table:

This example shows that without using a bile acid in this process, nanoparticles of mifepristone will not be produced. The use of bile acids in the process at levels of 2 to 10 mg/ml aid in the formation of the nanoparticles. Example 3

A solution of mifepristone (125 mg) in methanol (2.5 ml, 50 mg/ml) was added dropwise to a vigorously stirred aqueous sodium deoxycholate (DOC) solution (100 ml, 10 mg/ml) at room temperature. An aqueous solution of Poloxamer (L44, 1 ml, 20 mg/ml) was added. The nanosuspension with the mifepristone concentration of 1.21 mg/ml had a mean particle diameter of 152 nm with a PDI of 0.214. The mean particle size remained similar after storage at 5°C for 22 days as shown below:

Example 4

A solution of mifepristone (525 mg) in ethanol (7.5 ml, 70 mg/ml) was added dropwise to a vigorously stirred aqueous sodium deoxycholate solution (300 ml, 10 mg/ml) at room temperature. An aqueous solution of Poloxamer (L44, 3 ml, 20 mg/ml) was added followed by an aqueous solution of Poloxamer (F68, 120 ml, 100 mg/ml) followed by a aqueous solution of sucrose (120 ml, 100 mg/ml). This intermediate nanosuspension was dispensed into lyophilization vials in 5 ml aliquots, freeze dried and sealed under vacuum. Prior to lyophilization the nanosuspension at 0.95 mg/ml had a mean particle diameter of 275 nm with a PDI of 0.200. After 1 hour at room temperature this nanosuspension had a particle diameter of 276 nm with a PDI of 0.201.

Example 5

A solution of mifepristone (162.5 mg) in ethanol (2.5 ml, 65 mg/ml) was added dropwise to a vigorously stirred aqueous sodium deoxycholate solution (100 ml, 10 mg/ml) at room temperature. An aqueous solution of Poloxamer (L44, 1 ml, 20 mg/ml) was added. The average particle size in the nanosuspension, measured as above immediately after preparation, was 154 nm with a PDI of 0.146. An aqueous solution of Poloxamer (F68, 20 ml, 100 mg/ml) was added followed by an aqueous solution of sucrose (20 ml, 100 mg/ml). The resulting solution was frozen in a super-cooled acetone bath and bulk lyophilized.

The average particle diameters, measured as above, immediately after lyophilization and reconstitution, were all less than 200 nm as shown below:

Example 6 Stability study on solid nanoparticles of mifepristone.

Vials of mifepristone nanoparticles made as per Example 4 lyophilized to afford 4.4 mg/vial were stored at 5°C until reconstituted for particle size analyses.

Following lyophilization, samples of the nanosuspension reconstituted with water for injection presented with the following mean particle diameter and PDI:

Time of Concentration Mean Particle Diameter PDI reconstitution (mg/ml) (nm)

(months)

1 1 119 0.248

1 2 196 0.213

6 1 155 0.178 6 2 204 0.249

Samples of the nanosuspension reconstituted with normal saline presented with the following mean particle diameter and PDI:

Example 7

A suspension of mifepristone nanoparticles (1600 ml) prepared as per Example 3 was lyophilized in 40 ml aliquots. The average particle size, measured as above, immediately after lyophilization and reconstitution, was as shown in the Table below:

These bulk lyophilized samples reconstituted to the similar nanoparticle size as the lyophilized and reconstituted individual dosage units.

Example 8

A solution of mifepristone (175 mg) in ethanol (2.5 ml, 70 mg/ml) was added dropwise to a vigorously stirred aqueous solution (100 ml) of a mixture of sodium deoxycholate (10 mg/ml) and Poloxamer (F68, 2 mg/ml) at room temperature. An aqueous solution of Poloxamer (F68, 20 ml, 100 mg/ml) was added followed by an aqueous solution of sucrose (40 ml, 100 mg/ml). This intermediate nanosuspension was dispensed into lyophilization vials in 5 ml aliquots, freeze dried and sealed under vacuum. The average particle size, measured as above, immediately after lyophilization and reconstitution, was

Cone, (mg/ml) Diameter PDI

(nm) 1 138 0.161

2 170 0.246

These particle sizes are consistent with those in Example 3. Example 9

A solution of mifepristone (8.75 mg) in ethanol (0.125 ml, 70 mg/ml) was added dropwise to a vigorously stirred aqueous sodium deoxycholate solution (5 ml, 5 mg/ml) at room temperature. An aqueous solution of Poloxamer (L44, 0.05 ml, 20 mg/ml) was added followed by an aqueous solution of Poloxamer (F68, 2 ml, 100 mg/ml) followed by a aqueous solution of sucrose (2 ml, 100 mg/ml).

The average particle size, was measured, immediately and 30 minutes after completing the process and is shown in the Table below.

Example 10

A solution of mifepristone (8.75 mg) in ethanol (0.125 ml, 70 mg/ml) was added dropwise to a vigorously stirred aqueous sodium deoxycholate solution (5 ml, 10 mg/ml) at room temperature. An aqueous solution of Poloxamer (L44, 0.05 ml, 20 mg/ml) was added followed by an aqueous solution of sucrose (2 ml, 100 mg/ml).

The average particle size, was measured as above, immediately and 30 minutes after completing the process.

Example 11 A solution of mifepristone (8.75 mg) in ethanol (0.125 ml, 70 mg/ml) was added dropwise to a vigorously stirred aqueous solution (5 ml) of sodium deoxycholate solution (10 mg/ml) and Poloxamer (F68, 2 mg/ml) at room temperature. An aqueous solution of Poloxamer (L44, 0.05 ml, 20 mg/ml) was added followed by an aqueous solution of Poloxamer (F68, 0.1 ml, 100 mg/ml) followed by an aqueous solution of sucrose (2 ml, 100 mg/ml).

The average particle size of the nanosuspension, measured as above, was:

Example 12

The purpose of this study was to compare the transcomeal penetration of two concentrations of mifepristone nanoparticles suspended in normal saline and two suspension compositions of mifepristone across rabbit corneas in vitro.

The mifepristone nanoparticles were prepared according to Example 6. The two suspension compositions of mifepristone tested were similar to those described in WO2007/083145 and Phillips et al (1984) {supra) (see Groups 3 and 4 below respectively).

A summary of the compositions follows:

HPpCD = Hydroxypropyl-P-cyclodextrin. HPMC = Hydroxypropylmethylcellulose.

Freshly procured rabbit corneas were mounted into modified Ussing chambers, and the dose compositions were added to the donor chamber on the epithelial side of each cornea.

Transcomeal permeation of mifepristone in each composition was monitored over 24 hours. The concentrations of mifepristone in the receiver cells were assessed in aliquots removed at specified times by using high performance liquid chromatography (HPLC) with UV detection. Flux (rate of permeation), permeability, and area under the concentration-time curve (AUC) values were calculated for each composition. Stability was assessed by analyzing pre- and postdose aliquots by HPLC.

A dose-proportional increase in flux was observed for the 2 mg/mL concentration of nanoparticles when compared to the 1 mg/mL concentration of nanoparticles. Mifepristone (2 mg/mL) (Group 3) and mifepristone nanoparticles (1 mg/mL) (Group 1) displayed similar flux and AUCo-4 values. Permeability and exposure were lowest for the 10 mg/mL mifepristone composition (Group 4), possibly due to limited solubility and lack of permeation enhancers. Exposure and flux were highest for the 2 mg/mL concentration of nanoparticles (Group 2), up to 4 hours. These data show that through at least 2 hours postdose, mifepristone exposure via transcomeal penetration in rabbit corneas is highest for the Group 2 nanoparticle composition (2 mg/mL) and lowest for the Group 4 composition of mifepristone (10 mg/mL in a vehicle of 0.3% HPMC).

Table. Rabbit transcomeal penetration assay: flux and permeability values for various mifepristone compositions

Mifepristone was considered to be stable in all donor chamber compositions and in the receiver chamber solution.

This example shows that the nanoparticles of mifepristone (i.e. Groups 1 and 2) afford an increase in permeability across the cornea compared with mifepristone formulated according to the example in WO2007/083145 (Group 3) or mifepristone formulated according to Phillips et al (1984) (Group 4). The foregoing broadly describes the present invention, without limitation. Variations and modifications as will be readily apparent to those of ordinary skill in this art are intended to be included within the scope of this application and subsequent patents.

Throughout the specification and the claims which follow, unless the context requires otherwise, the word 'comprise', and variations such as 'comprises' and 'comprising', will be understood to imply the inclusion of a stated integer, step, group of integers or group of steps but not to the exclusion of any other integer, step, group of integers or group of steps.

Claims

1. A pharmaceutical composition comprising nanoparticles of a glucocorticoid antagonist, or a physiologically acceptable salt, complex or prodrug thereof, for use as a medicament for the treatment or prophylaxis of ocular conditions in a human or non-human subject.

2. A pharmaceutical composition according to Claim 1 for topical administration to or around the eye.

3. A pharmaceutical composition according to Claim 1 or 2 for the treatment or prophylaxis of ocular conditions related to elevated intraocular pressure.

4. A pharmaceutical composition according to Claim 1 or 2 wherein the medicament is used or is to be used to reduce elevated intraocular pressure to normal levels.

5. A pharmaceutical composition according to Claim 1 or 2 wherein the medicament is used or is to be used in the treatment or prophylaxis of glaucoma, e.g. primary glaucoma, including primary angle-closure glaucoma, primary open-angle glaucoma, pigmentary glaucoma, exfoliation glaucoma, developmental glaucoma, including primary congenital glaucoma, infantile glaucoma, glaucoma associated with hereditary of familial diseases, secondary glaucoma, including inflammatory glaucoma, phacogenic glaucoma, glaucoma secondary to intraocular haemorrhage, traumatic glaucoma, neovascular glaucoma, drug- induced glaucoma, or glaucoma of miscellaneous origin i.e. toxic glaucoma.

6. A pharmaceutical composition according to any one of Claims 1 to 3 for the treatment or prophylaxis of steroid-induced glaucoma.

7. A pharmaceutical composition according to Claim 1 or 2 for the treatment or prophylaxis of an ocular condition in which neovascularisation is involved.

8. A pharmaceutical composition according to Claim 1 or 2 for the treatment or prophylaxis of a disease selected from age-related macular degeneration, blepharitis, choroidal neovascularisation, retinal neovascularisation, corneal neovascularisation, ocular histoplasmosis syndrome, pathologic myopia, angioid streaks, idiopathic disorders, choroiditis, choroidal rupture, overlying choroid nevi, Best's disease, Stargardt's disease, Vogt-Koyanagi-Harada syndrome, toxoplasmosis, central serous chorioretinopathy, diabetic retinopathy and other proliferative retinopathy, retinopathy of prematurity, pseudoxanthoma elasticum, vein or artery occlusion, carotid obstructive disease, chronic uveitis/ vitritis, mycobacterial infection, Behcet's disease, infections causing retinitis, optic pits, par planitis, chronic retinal detachment, hyperviscosity syndromes, capillary haemangioma including von Hippel-Lindau disease, post- laser complication, epidemic keratoconjunctivitis, Vitamin A deficiency, contact lens overwear, atopic keratitis, superior limbic keratitis, pterygium keratitis sicca, sjogrens, acne rosacea, phylectenulosis, Mycobacteria infections, lipid degeneration, bacterial ulcers, fungal ulcers, Herpes simplex infections, Herpes zoster infections, protozoan infections, Kaposi sarcoma, Mooren ulcer, Terrien's marginal degeneration, mariginal keratolysis, rheumatoid arthritis, Wegeners sarcoidosis, scleritis, Steven's Johnson disease, pemphigoid radial keratotomy, and corneal graft rejection.

9. A pharmaceutical composition according to any one of Claims 1 to 8 for use in association with one or more further pharmaceutically active ingredients.

10. A pharmaceutical composition according to Claim 9 for use in association with one or more glucocorticoid compounds.

11. A pharmaceutical composition according to Claim 10 wherein the glucocorticoid compound(s) is a steroid.

12. A method for treating or preventing glaucoma and / or elevated intraocular pressure in a human or non-human patient in need thereof, the method comprising administrating to the patient an effective amount of a composition comprising nanoparticles of a glucocorticoid antagonist, or a physiologically acceptable salt, complex or prodrug thereof.

13. A method according to Claim 12, further comprising a prior examination of the patient which checks for symptoms of elevated intraocular pressure and / or a diagnosis of the presence of glaucoma in the patient.

14. A pharmaceutical composition or method according to any one of Claims 1 to 13 wherein the nanoparticles comprise at least one bile acid compound.

15. A pharmaceutical composition comprising nanoparticles of a glucocorticoid antagonist, or a physiologically acceptable salt, complex or prodrug thereof and at least one bile acid compound.

16. A pharmaceutical composition or method according to any one of Claims 1 to 15 wherein the nanoparticles comprise at least one mucoadhesive component.

17. A pharmaceutical composition or method according to any one of Claims 1 to 15 wherein the composition but not the nanoparticles comprises at least one mucoadhesive component.

18. A pharmaceutical composition or method according to any one of Claims 1 to 17 wherein the nanoparticles contain at least 80% w/w of glucocorticoid antagonist.

19. A pharmaceutical composition or method according to any one of Claims 1 to 18 wherein the nanoparticles have a diameter of 2000 nm or less.

20. A pharmaceutical composition or method according to any one of Claims 1 to 19 where the glucocorticoid antagonist is mifepristone or a physiologically acceptable salt, complex or prodrug thereof.

21. A pharmaceutical composition or method according to any one of Claims 1 to 20 wherein the composition is an aqueous suspension.

22. A pharmaceutical composition or method according to any one of Claims 1 to 21 wherein the composition is formulated such that it is isotonic or slightly hypotonic with respect to natural tears and the pH of the composition is between 4.5 and 8.

23. A pharmaceutical composition or method according to any one of Claims 1 to 22 wherein the composition comprises an ophthalmic adjuvant component selected from the group consisting of: a buffer, a suspending and/or viscosity-inducing component, a complexing agent, a tonicity component and combinations thereof.

24. A pharmaceutical composition or method according to any one of Claims 1 to 20 wherein the nanoparticles have been lyophilized to a dried powder.

25. A pharmaceutical composition comprising nanoparticles of a glucocorticoid antagonist that demonstrate enhanced bioavailability of the glucocorticoid antagonist compared to the same active ingredient when not in the form of nanoparticles.

26. A pharmaceutical composition according to Claim 25 comprising nanoparticles of mifepristone that demonstrate enhanced penetration of the active ingredient into biological tissue compared with a solution composition of the same active ingredient when not in the form of nanoparticles.

27. An ophthalmic composition comprising nanoparticles of a glucocorticoid antagonist that demonstrate enhanced penetration of the glucocorticoid antagonist across the cornea compared with a solution composition of the same active ingredient when not in the form of nanoparticles.

28. An ophthalmic composition according to Claim 28 wherein the glucocorticoid antagonist is mifepristone.

29. A pharmaceutical composition comprising nanoparticles of a glucocorticoid antagonist that effectively decreases intraocular pressure as a result of the enhanced penetration of the active across the cornea compared with a solution composition of the same active ingredient when not in the form of nanoparticles.

30. A pharmaceutical composition according to Claim 29 wherein the glucocorticoid antagonist is mifepristone.

31. A pharmaceutical composition comprising nanoparticles of a glucocorticoid antagonist, or a physiologically acceptable salt, complex or prodrug thereof, for use in the therapeutic and/or prophylactic treatment of non-ophthalmic conditions in a human or non-human subject

32. A pharmaceutical composition according to Claim 31 for use in the treatment or prophylaxis of diseases resulting in elevated Cortisol levels.

33. A pharmaceutical composition according to Claim 31 for use in the treatment or prophylaxis of neuropsychiatric conditions such as psychotic major depression, bipolar depression, schizophrenia and cognitive disorders.

34. A pharmaceutical composition according to Claim 31 for use in the treatment or prophylaxis of hypertension, Cushing's syndrome, obesity, amyotrophic lateral sclerosis, endometriosis, uterine fibroids, meningiomas, breast cancer, ovarian cancer or androgen- independent prostate cancer.

35. A pharmaceutical composition according to Claim 31 for use as an abortifacient or as an emergency contraceptive.