EP2755659A2 - Compositions de nanoparticules pharmaceutiques - Google Patents

Compositions de nanoparticules pharmaceutiques

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Publication number
EP2755659A2
EP2755659A2 EP12762374.2A EP12762374A EP2755659A2 EP 2755659 A2 EP2755659 A2 EP 2755659A2 EP 12762374 A EP12762374 A EP 12762374A EP 2755659 A2 EP2755659 A2 EP 2755659A2
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EP
European Patent Office
Prior art keywords
pharmaceutical composition
nanoparticles
glaucoma
mifepristone
composition according
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP12762374.2A
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German (de)
English (en)
Inventor
Francesca CRAWFORD
Philip Gunning
David HERMANS
Deepak Thassu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Altacor Ltd
Original Assignee
Altacor Ltd
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Filing date
Publication date
Application filed by Altacor Ltd filed Critical Altacor Ltd
Publication of EP2755659A2 publication Critical patent/EP2755659A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/5123—Organic compounds, e.g. fats, sugars
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/04—Drugs for genital or sexual disorders; Contraceptives for inducing labour or abortion; Uterotonics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • 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.
  • mifepristone also known as RU38486 or RU486, a glucocorticoid antagonist
  • IOP intraocular pressure
  • 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.
  • 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 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.
  • 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.
  • the composition is intended to reduce elevated intraocular
  • the pharmaceutical composition may be used in the treatment or prophylaxis of steroid-induced glaucoma.
  • 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
  • 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 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.
  • 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.
  • 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.
  • glucocorticoid antagonists 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.
  • 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.
  • 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.
  • 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.
  • Nanoparticles containing mifepristone have been prepared from DL-lactide / glycolide copolymers (W. He, S.
  • 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.
  • 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.
  • mifepristone is especially preferred.
  • 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.
  • 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.
  • 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.
  • suitable acid addition salts are those formed with acids selected from hydrochloric, sulfuric, phosphoric and nitric acids.
  • suitable base addition salts are those formed with bases selected from sodium hydroxide, potassium hydroxide and ammonium hydroxide.
  • 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.
  • prodrugs 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.
  • 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 ⁇ , e.g. less than 10, 5, 2, or 1 ⁇ .
  • size such as average diameter, of less than 10 ⁇ , e.g. less than 10, 5, 2, or 1 ⁇ .
  • the nanoparticles of the invention are in a range of 0.01 ⁇ (10 nm) to about 5 ⁇ (5000 nm) of average diameter (synonymously, "average size").
  • the nanoparticles of the invention have a characteristic average diameter of less than about 1 ⁇ , i.e. are in the nm size range.
  • 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.
  • nanoparticles may in addition contain at least one bile acid compound.
  • nanoparticles contain at least one mucoadhesive component.
  • nanoparticles contain other ingredients.
  • the glucocorticoid antagonist (or all of them) represents at least 80%> w/w of the nanoparticle.
  • compositions of the invention may optionally contain a mucoadhesive component, typically a mucoadhesive polymer.
  • a mucoadhesive component typically a mucoadhesive polymer.
  • 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(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.
  • typical amounts range from 1-20% w/w, with preferably 1-10% w/w, with most preferably 1-5% w/w.
  • WO2010/080754 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.
  • 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
  • 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.
  • the aqueous-insoluble compound(s) component of the nanoparticles i.e. the glucocorticoid antagonist or combination thereof
  • the compound or compounds is / are substantially non-crystalline.
  • 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.
  • 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.
  • aqueous- insoluble compound or compounds in a preparation of nanoparticles are in non-crystalline form.
  • the percentage may in some situations be measured based on individual or only small numbers of nanoparticles (i.e. non-bulk percentages).
  • 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 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • mifepristone with dexamethasone 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.
  • 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.
  • a buffer 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.
  • a suspending and / or viscosity- increasing agent 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.
  • a tonicity modifying component e.g. comprising about 0.05% to 1.0% w/v of sodium chloride
  • compositions of the invention may contain a mucoadhesive component, especially if not already present in the nanoparticles.
  • the pharmaceutical composition may be formulated as an aqueous suspension.
  • the composition is isotonic or slightly hypotonic with respect to natural tears, i.e. having an osmolality between 200 to 300 mOsmol/kg.
  • the pH of the composition is between 4.5 and 8.
  • suspending and/or viscosity-increasing agents include carbomers and cellulose- based polymers.
  • the polymer is a carbomer, or carboxymethylcellulose or hydroxypropyl methylcellulose, or more preferably hydroxypropyl methylcellulose (HPMC).
  • HPMC hydroxypropyl methylcellulose
  • Other polymers e.g. hydroxyethylcellulose, ethyl cellulose, methylcellulose, sodium carboxymethylcellulose or polyvinyl alcohol may also be used.
  • more than one viscosity increasing agent may be employed.
  • wetting and/or solubilizing agents include the poloxamers, polysorbates, nonoxynol-9, octoxynol-8, polyoxyl 10 oleyl ether, sodium lauryl sulfate and sorbitan esters.
  • a complexing agent include disodium edatate, calcium disodium edatate and edetic acid.
  • Suitable preservatives include benzalkonium chloride and the cetrimonium halides.
  • Example tonicity modifying components include mannitol and sodium chloride.
  • compositions of the invention may be included in compositions of the invention.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • up to 50 mg per day over a period of up to 3 months may be suitable to reduce the intraocular pressure.
  • 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.
  • 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.
  • 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.
  • 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.
  • particle size and PDI were determined using photon correlation spectroscopy on a Beckman Coulter DelsaNano C particle size analyser.
  • 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.
  • DOC sodium deoxycholate
  • 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.
  • 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:
  • This intermediate nanosuspension was dispensed into lyophilization vials in 5 ml aliquots, freeze dried and sealed under vacuum.
  • 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.
  • 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.
  • 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:
  • 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.
  • 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 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).
  • HPpCD Hydroxypropyl-P-cyclodextrin.
  • HPMC Hydroxypropylmethylcellulose.
  • Transcomeal permeation of mifepristone in each composition was monitored over 24 hours.
  • 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.
  • Mifepristone was considered to be stable in all donor chamber compositions and in the receiver chamber solution.

Abstract

La présente invention concerne l'utilisation de nanoparticules d'antagonistes glucocorticoïdes pour le traitement de pathologies oculaires et non-oculaires, ainsi que des compositions les contenant et leurs procédés de préparation.
EP12762374.2A 2011-09-13 2012-09-13 Compositions de nanoparticules pharmaceutiques Withdrawn EP2755659A2 (fr)

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