NZ624920B2 - PHARMACEUTICAL COMPOSITIONS AND METHODS OF USE OF 4-PREGENEN-11ß-17-21-TRIOL-3,20-DIONE DERIVATIVES - Google Patents
PHARMACEUTICAL COMPOSITIONS AND METHODS OF USE OF 4-PREGENEN-11ß-17-21-TRIOL-3,20-DIONE DERIVATIVES Download PDFInfo
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- NZ624920B2 NZ624920B2 NZ624920A NZ62492012A NZ624920B2 NZ 624920 B2 NZ624920 B2 NZ 624920B2 NZ 624920 A NZ624920 A NZ 624920A NZ 62492012 A NZ62492012 A NZ 62492012A NZ 624920 B2 NZ624920 B2 NZ 624920B2
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- New Zealand
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- tetradecahydro
- cyclopenta
- glycoloylhydroxy
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- C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
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- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
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- C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
- C07J5/0053—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa not substituted in position 16
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- C07—ORGANIC CHEMISTRY
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- C07J7/008—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms substituted in position 21
Abstract
Provided are ophthalmic compositions of 4-pregenen-11-17-21-triol-3,20-dione derivatives, for example (8S,9S,10R,11S,13S,14S,17R)-17-glycoloyl-11-hydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-ylphenylacetate, and their use in the manufacture of a medicament for the treatment of ocular conditions associated with the glucocorticoid receptors (GR) and/or the mineralocorticoid receptors (MR). In a preferred embodiment the ocular condition is ocular rosacea, dry eye, blepharitis or meibomian gland dysfunction. acture of a medicament for the treatment of ocular conditions associated with the glucocorticoid receptors (GR) and/or the mineralocorticoid receptors (MR). In a preferred embodiment the ocular condition is ocular rosacea, dry eye, blepharitis or meibomian gland dysfunction.
Description
CEUTICAL COMPOSITIONS AND METHODS OF USE OF 4-PREGENEN-11β21-TRIOL-3,20-DIONE DERIVATIVES By Inventors: Jeffery L. Edelman and Alissar Nehme RELATED APPLICATION This application claims the benefit of U.S. Provisional Application Serial No. 61/558,775, filed er 11, 2011, the disclosure of which is hereby incorporated in its ty herein by reference.
FIELD OF THE INVENTION The present invention relates to pharmaceutical compositions comprising 4-pregenen- 11β21-triol-3,20-dione derivatives, and their use as pharmaceuticals as modulators of the glucocorticoid receptors (GR) and/or the mineralocorticoid receptors (MR). The invention relates specifically to the use of these compounds and their pharmaceutical compositions to treat ocular conditions associated with the glucocorticoid receptors (GR) and/or the mineralocorticoid receptors (MR).
OUND OF THE INVENTION Glucocorticoid (GC) agonists represent a class of anti-inflammatory compounds that are useful in treating multiple ocular conditions including elevated intraocular pressure, glaucoma, uveitis, retinal vein occlusions, r degeneration, diabetic retinopathy, various forms of macular edema, post-surgical inflammation, inflammatory conditions of the palpebral and bulbar conjunctiva, cornea, and anterior segment of the globe, such as ic conjunctivitis, ocular rosacea, dry eye, blepharitis, retinal detachment, meibomian gland dysfunction (MGD), superficial punctate keratitis, herpes zoster keratitis, iritis, cyclitis, selected infective conjunctivitis, l injury from chemical, radiation, or l burns, ation of foreign , allergy, or combinations thereof.
A potential use limiting and sight-threatening side-effect of traditional GC agonist therapies (e.g. fluocinolone acetonide) is ocular hypertension that is likely generated by an increased resistance of aqueous humor flow through the trabecular meshwork. The mechanism of GC agonist-induced outflow resistance and subsequent ocular hypertension is not well understood.
As such, GC modulation through agonist or antagonist activity of GC receptors that does not result in increased intraocular pressure or other side effects is needed in the art and is described herein. It is an object of the present ion to go someway s meeting this need and/or to provide the public with a useful choice.
SUMMARY OF THE INVENTION It has now been discovered the use of a group of 4-pregenen-11β21-triol-3,20-dione derivatives as potent and selective glucocorticoid receptors (GR) and/or the mineralocorticoid receptors (MR). As such, the compounds described herein are useful in treating a wide variety of disorders ated with modulation of the orticoid receptors (GR) receptor or the locorticoid receptors (MR). The term "modulator" as used herein, includes but is not limited to: receptor t, antagonist, inverse agonist, inverse antagonist, partial agonist, partial antagonist.
In a first aspect, the invention provides a use, in the manufacture of a medicament for treating an ocular ion associated with glucocorticoid and or mineralocorticoid or modulation in a patient in need thereof, of at least one compound selected from: ,10R,11S,13S,14S,17R)glycoloylhydroxy-10,13-dimethyloxo- 2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrenyl phenylacetate; (8S,9S,10R,11S,13S,14S,17R)glycoloylhydroxy-10,13-dimethyloxo- 2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrenyl propionate; (8S,9S,10R,11S,13S,14S,17R)glycoloylhydroxy-10,13-dimethyloxo- 2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrenyl ate; (8S,9S,10R,11S,13S,14S,17R)-17 -Glycoloylhydroxy-10,13-dimethyloxo- 2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrenyl hexanoate; (8S,9S,10R,11S,13S,14S,17R)glycoloylhydroxy-10,13-dimethyloxo- 2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrenyl benzoate; (8S,9S,10R,11S,13S,14S,17R)glycoloylhydroxy-10,13-dimethyloxo- 2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrenyl heptanoate; (8S,9S,10R,11S,13S,14S,17R)glycoloylhydroxy-10,13-dimethyloxo- 7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrenyl 2-methylpropanoate; and (8S,9S,10R,11S,13S,14S,17R)glycoloylhydroxy-10,13-dimethyloxo- 2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrenyl cyclopentanecarboxylate.
In a second aspect, the invention provides a composition suitable for treating an ocular condition ated with glucocorticoid and or mineralocorticoid receptor modulation sing at least one compound selected from the group consisting of: (8S,9S,10R,11S,13S,14S,17R)glycoloylhydroxy-10,13-dimethyloxo- 2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrenyl phenylacetate; (8S,9S,10R,11S,13S,14S,17R)glycoloylhydroxy-10,13-dimethyloxo- 2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrenyl propionate; (8S,9S,10R,11S,13S,14S,17R)glycoloylhydroxy-10,13-dimethyloxo- 2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrenyl octanoate; (8S,9S,10R,11S,13S,14S,17R)Glycoloylhydroxy-10,13-dimethyloxo- 2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrenyl ate; (8S,9S,10R,11S,13S,14S,17R)glycoloylhydroxy-10,13-dimethyloxo- 2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrenyl benzoate; (8S,9S,10R,11S,13S,14S,17R)glycoloylhydroxy-10,13-dimethyloxo- 2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrenyl heptanoate; (8S,9S,10R,11S,13S,14S,17R)glycoloylhydroxy-10,13-dimethyloxo- 2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrenyl ylpropanoate; and (8S,9S,10R,11S,13S,14S,17R)glycoloylhydroxy-10,13-dimethyloxo- 2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrenyl cyclopentanecarboxylate; wherein the composition is formulated to be topically ophthalmically able.
In a third aspect, the ion provides a use, in the manufacture of a medicament for treating an ocular condition associated with glucocorticoid and or mineralocorticoid or modulation in a patient in need thereof, of: (8S,9S,10R,11S,13S,14S,17R)glycoloylhydroxy-10,13-dimethyloxo- 2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrenyl butyrate; wherein the ocular condition is selected from elevated intraocular pressure, glaucoma, uveitis, retinal vein occlusions, macular degeneration, diabetic retinopathy, various forms of macular edema, post-surgical inflammation, matory conditions of the palpebral and bulbar conjunctiva, cornea, and or segment of the globe, such as allergic conjunctivitis, ocular rosacea, dry eye, retinal detachment, meibomian gland dysfunction, superficial punctate keratitis, herpes zoster keratitis, , cyclitis, selected infective conjunctivitis, corneal injury from chemical, radiation, or thermal burns, penetration of foreign bodies, allergy, and combinations thereof.
In a fourth aspect, the ion provides a composition suitable for treating an ocular condition associated with glucocorticoid and or mineralocorticoid receptor tion comprising: (8S,9S,10R,11S,13S,14S,17R)glycoloylhydroxy-10,13-dimethyloxo- 7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrenyl butyrate; n the composition is formulated to be lly ophthalmically acceptable; and wherein the composition further comprises one or more vehicles selected from the group consisting of polyvinyl alcohol, povidone, hydroxypropyl methyl ose, poloxamers, carboxymethyl ose, hydroxyethyl cellulose and purified water.
Also described are pharmaceutical compositions comprising enen-11β21- triol-3,20-dione derivatives useful in ng one or more ocular conditions. Methods of treating one or more ocular conditions are also disclosed. Ocular conditions treated using compounds and/or formulations described herein include, but are not limited to, elevated intraocular pressure, glaucoma, uveitis, retinal vein occlusions, macular degeneration, diabetic retinopathy, various forms of macular edema, post-surgical inflammation, inflammatory conditions of the palpebral and bulbar conjunctiva, cornea, and anterior segment of the globe, such as allergic conjunctivitis, ocular a, dry eye, blepharitis, retinal detachment, meibomian gland dysfunction (MGD), superficial te keratitis, herpes zoster keratitis, iritis, cyclitis, selected infective conjunctivitis, corneal injury from chemical, radiation, or thermal burns, penetration of foreign , y, or combinations thereof.
Also described is a method of treating a disorder associated with modulation of the glucocorticoid receptors (GR) and/or the mineralocorticoid receptors (MR), which comprises administering a therapeutically effective amount of a composition comprising a 4-pregenen-11β21-triol-3,20-dione derivative. The compounds described herein are thus of use in medicine, for example in the treatment of humans with diseases and conditions that are alleviated by glucocorticoid or mineralocorticoid receptors modulation.
Also described is a pharmaceutical composition of a 4-pregenen-11β21-triol-3,20- dione derivative selected from the group of compounds from Table 1: Table 1 Compound IUPAC name Structure 1 (8S,9S,10R,11S,13S,14S,17R)- 17-glycoloylhydroxy-10,13- dimethyloxo- 2,3,6,7,8,9,10,11,12,13,14,15,16, 17-tetradecahydro-1H- cyclopenta[a]phenanthrenyl phenylacetate 2 (8S,9S,10R,11S,13S,14S,17R)- 17-glycoloylhydroxy-10,13- dimethyloxo- 2,3,6,7,8,9,10,11,12,13,14,15,16, 17-tetradecahydro-1H- enta[a]phenanthrenyl butyrate 3 (8S,9S,10R,11S,13S,14S,17R)- 17-glycoloylhydroxy-10,13- dimethyloxo- 2,3,6,7,8,9,10,11,12,13,14,15,16, 17-tetradecahydro-1H- cyclopenta[a]phenanthrenyl nate 4 (8S,9S,10R,11S,13S,14S,17R)- OH 17-glycoloylhydroxy-10,13- O yloxo- HO O 2,3,6,7,8,9,10,11,12,13,14,15,16, H 17-tetradecahydro-1H- O cyclopenta[a]phenanthrenyl H H octanoate (8S,9S,10R,11S,13S,14S,17R)Glycoloylhydroxy-10,13- dimethyloxo- 2,3,6,7,8,9,10,11,12,13,14,15,16, 17-tetradecahydro-1H- cyclopenta[a]phenanthrenyl 6 (8S,9S,10R,11S,13S,14S,17R)- 17-glycoloylhydroxy-10,13- dimethyloxo- 2,3,6,7,8,9,10,11,12,13,14,15,16, 17-tetradecahydro-1H- cyclopenta[a]phenanthrenyl benzoate 7 ,10R,11S,13S,14S,17R)- OH 17-glycoloylhydroxy-10,13- dimethyloxo- 2,3,6,7,8,9,10,11,12,13,14,15,16, O 17-tetradecahydro-1H- O cyclopenta[a]phenanthrenyl H H heptanoate O 8 (8S,9S,10R,11S,13S,14S,17R)- OH 17-glycoloylhydroxy-10,13- dimethyloxo- O 2,3,6,7,8,9,10,11,12,13,14,15,16, HO O radecahydro-1H- cyclopenta[a]phenanthrenyl 2- O methylpropanoate H H 9 (8S,9S,10R,11S,13S,14S,17R)- 17-glycoloylhydroxy-10,13- dimethyloxo- 2,3,6,7,8,9,10,11,12,13,14,15,16, 17-tetradecahydro-1H- cyclopenta[a]phenanthrenyl cyclopentanecarboxylate The term ising" as used in this specification and claims means "consisting at least in part of". When interpreting statements in this specification, and claims which include the term ising", it is to be understood that other features that are additional to the features prefaced by this term in each statement or claim may also be present. Related terms such as "comprise" and "comprised" are to be interpreted in similar manner.
The term "pharmaceutically acceptable salts" refers to salts or complexes that retain the d biological activity of the above identified compounds and exhibit minimal or no undesired toxicological effects. The "pharmaceutically acceptable salts" according to the invention include therapeutically active, non-toxic base or acid salt forms, which the nds of Table 1 are able to form.
The acid addition salt form of a compound described herein that occurs in its free form as a base can be obtained by treating the free base with an appropriate acid such as an inorganic acid, such as for example, hydrochloric acid, romic acid, sulfuric acid, phosphoric acid, nitric acid and the like; or an organic acid such as for example, acetic, hydroxyacetic, propanoic, lactic, pyruvic, malonic, fumaric acid, maleic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, citric, sulfonic, ethanesulfonic, esulfonic, formic and the like (Handbook of Pharmaceutical Salts, P.Heinrich Stahal& Camille G. Wermuth (Eds), Verlag Helvetica Chemica Acta- Zürich, 2002, 329-345).
The base addition salt form of a compound bed herein that occurs in its acid form can be obtained by treating the acid with an appropriate base such as an inorganic base, for example, sodium hydroxide, magnesium hydroxide, potassium hydroxide, m hydroxide, ammonia and the like; or an c base such as for example, LArginine , ethanolamine, betaine, benzathine, morpholine and the like. (Handbook of Pharmaceutical Salts, P.Heinrich & Camille G. Wermuth (Eds), Verlag Helvetica Chemica Acta- Zürich, 2002, 329-345).
Compounds described herein and their salts can be in the form of a solvate, which is included within the scope of the present sure. Such solvates include for example hydrates, alcoholates and the like.
The nds described herein are useful in treating a variety of ocular conditions including, but not limited to elevated intraocular pressure, glaucoma, uveitis, retinal vein occlusions, macular degeneration, diabetic retinopathy, various forms of macular edema, post-surgical inflammation, inflammatory conditions of the palpebral and bulbar conjunctiva, , and anterior segment of the globe, such as allergic ctivitis, ocular rosacea, dry eye, blepharitis, retinal detachment, meibomian gland dysfunction (MGD), superficial punctate keratitis, herpes zoster keratitis, iritis, cyclitis, selected ive conjunctivitis, corneal injury from chemical, radiation, or thermal burns, penetration of foreign bodies, allergy, or combinations thereof.
Also described are s for treating disorders associated with modulation of the glucocorticoid receptors (GR) and/or the mineralocorticoid receptors (MR). Such methods can be performed, for example, by administering to a subject in need thereof a therapeutically effective amount of at least one nd of Table 1, or any combination thereof, or pharmaceutically acceptable salts thereof.
In another embodiment, there are bed pharmaceutical compositions including at least one compound of Table 1 in a pharmaceutically acceptable carrier.
The compounds described herein may be administered at pharmaceutically effective dosages. Such dosages are normally the minimum dose necessary to achieve the desired therapeutic . Generally, such doses will be in the range of about 1 mg/day to about 1000 mg/day; more ably in the range of about 10 mg/day to about 500 mg/day. In another example embodiment, the compound or compounds may be present in a composition or formulation in a range of about 0.5 mg/kg/day to about 100 mg/kg/day or about 1 mg/kg/day to about 100 day. However, the actual amount of the nd to be administered in any given case will be ined by a physician taking into account the nt circumstances, such as the age and weight of the patient, the patient’s general physical condition, the severity of ocular condition, and the route of stration. In some instances, dosing is ted on a case-by-case basis.
In another example embodiment, bed are pharmaceutical compositions including at least one compound in a pharmaceutically acceptable carrier. Pharmaceutical compositions can be used in the form of a solid, a on, an emulsion, a dispersion, a micelle, a liposome, and the like, wherein the resulting composition contains one or more compounds described herein, as an active ingredient, in ure with an organic or inorganic carrier or excipient suitable for enteral or parenteral applications. One or more compounds may be combined, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The carriers which can be used include glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea, medium chain length triglycerides, ns, and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form. In addition ary, stabilizing, thickening and coloring agents and perfumes may be used. Compounds described herein are included in pharmaceutical compositions in an amount sufficient to produce the desired effect upon the process or disease condition.
In another embodiment, the compounds described herein can be administered orally in any able form, such as a tablet, liquid, capsule, powder and the like. However, other routes may be desirable or necessary, particularly if the patient suffers from . Such other routes may include, without exception, transdermal, parenteral, subcutaneous, asal, intrathecal, intramuscular, intravenous, and ectal modes of delivery. Additionally, formulations may be designed to delay release of the active compound over a given period of time, or to carefully control the amount of drug released at a given time during the course of therapy.
Pharmaceutical compositions in a form suitable for oral use, for example, are administered as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
Compositions intended for oral use may be prepared ing to any method known to the art for the manufacture of ceutical compositions and such compositions may n one or more agents selected from the group consisting of a sweetening agent such as sucrose, lactose, or saccharin, flavoring agents such as peppermint, oil of wintergreen or cherry, coloring agents and ving agents in order to provide pharmaceutically t and palatable preparations. Tablets containing compounds described herein in admixture with non-toxic pharmaceutically acceptable excipients may also be manufactured by known methods.
The pharmaceutical compositions may be in the form of a sterile injectable suspension.
This sion may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents. The e able preparation may also be a sterile injectable solution or suspension in a non-toxic parenterallyacceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including tic mono- or diglycerides, fatty acids (including oleic acid), naturally occurring vegetable oils like sesame oil, coconut oil, peanut oil, cottonseed oil, etc., or synthetic fatty vehicles like ethyl oleate or the like.
Buffers, preservatives, antioxidants, and the like can be incorporated as required.
Compounds described herein may also be administered in the form of suppositories for rectal administration of the drug. These compositions may be prepared by mixing the invention compounds with a suitable non-irritating ent, such as cocoa butter, synthetic glyceride esters of polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or ve in the rectal cavity to release the drug.
The actual amount of the compound to be administered in any given case will be determined by a physician taking into account the relevant circumstances, such as the ty of the condition, the age and weight of the patient, the patient’s general al ion, the cause of the condition, and the route of administration.
Described herein are compounds capable of ting glucocorticoid receptors (GR) and/or mineralocorticoid receptors (MR). The compounds described can have r GR activation and/or g y compared to a compound such as cortisol. As such, the compounds can ently treat ocular indications. The nds can further be metabolized by esterase enzymes within the eye to form the natural agonist cortisol, y reducing the risk of ocular hypertension. The cortisol remaining within the eye and body is further metabolized to inactive compounds via naturally occurring dehydroxylases and other enzymes making this a safe therapeutic approach.
In patients, the naturally occurring endogenous GC agonist cortisol (hydrocortisone) has a minimal effect on intraocular pressure when applied locally via eye drops compared to synthetic GCs such as dexamethasone, prednisolone, and metholone (Cantrill et aI., 1975). Further support of the overall superior safety of cortisol as a therapeutic is the fact that various topical hydrocortisone formulations are currently sold over the counter directly to consumers.
Without wishing the bound to any particular theory, it was surprisingly discovered that the presently described compounds can have more glucocorticoid receptor modulation than cortisol because of the modification to the 17-position of the cortisol molecule.
As used herein, the term "therapeutically ive amount" means the amount of the pharmaceutical composition that will elicit the biological or medical response of a subject in need thereof that is being sought by the researcher, veterinarian, medical doctor or other clinician. In some embodiments, the subject in need thereof is a mammal. In some embodiments, the mammal is human.
The excipients used may be, for example, (1) inert diluents such as calcium carbonate, e, calcium phosphate or sodium phosphate; (2) granulating and disintegrating agents such as corn starch, potato starch or alginic acid; (3) binding agents such as gum tragacanth, corn starch, gelatin or acacia, and (4) lubricating agents such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the intestinal tract and thereby provide a sustained action over a longer period. For e, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
In some cases, formulations for oral use may be in the form of hard n capsules wherein the compounds are mixed with an inert solid diluent, for example, calcium ate, calcium phosphate or kaolin. They may also be in the form of soft gelatin capsules wherein the compounds are mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil.
The compounds bed herein can also be administered as an ophthalmically acceptable formulation or composition. A liquid which is ophthalmically acceptable is formulated such that it can be stered topically to the eye. The comfort should be maximized as much as possible, although sometimes formulation considerations (e.g. stability) may necessitate less than optimal comfort. In the case that t cannot be maximized, the liquid should be formulated such that the liquid is tolerable to the patient for topical ophthalmic use. Additionally, an ophthalmically able liquid should either be packaged for single use, or contain a preservative to prevent contamination over multiple uses.
For ophthalmic application, solutions or medicaments are often ed using a physiological saline solution as a major e. Ophthalmic solutions should preferably be ined at a comfortable pH with an appropriate buffer system. The formulations may also contain conventional, pharmaceutically acceptable preservatives, stabilizers and surfactants.
Preservatives that may be used in ophthalmic compositions described herein include, but are not limited to, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate and phenylmercuric nitrate. A useful surfactant is, for example, Tween 80.
Likewise, s useful vehicles may be used in the lmic preparations described herein. These es include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose and purified water.
Tonicity adjustors may be added as needed or convenient. They include, but are not limited to, salts, particularly sodium de, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable ty adjustor.
Various buffers and means for adjusting pH may be used so long as the resulting preparation is ophthalmically acceptable. Accordingly, buffers include acetate buffers, citrate buffers, ate buffers and borate buffers. Acids or bases may be used to adjust the pH of these formulations as needed.
In one example embodiment, an ophthalmic ition as described herein may have ingredients used in the following amounts listed in Table 2.
Table 2 Ingredient Amount (% w/v) active ingredient about 0.001-5 preservative 0-0.10 vehicle 0-40 tonicity adjustor 1-10 buffer 0.01-10 pH adjustor q.s. pH 4.5-7.5 antioxidant as needed surfactant as needed purified water as needed to make 100% In other embodiments, the ophthalmically acceptable liquid can be formulated for intraocular injection. The compounds described herein can be formulated as a liquid, gel, paste, cream, oil. Further, the compounds can be formulated into sustained release or controlled release cular implants comprising biodegradable rs such as polylactic acid, poly glycolic acid, combinations thereof and the like.
Some exemplary itions can include a combination of two or more compounds as described herein. Different ratios of compounds can be formulated depending on a particular ocular condition or set of conditions being treated.
Since individual subjects may present a wide variation in severity of symptoms and each composition has its unique eutic characteristics, the e mode of stration and dosage employed for each subject is left to the discretion of the practitioner.
ED DESCRIPTION It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention claimed. As used herein, the use of the singular includes the plural unless ically stated otherwise.
The following examples are for illustrative purposes only and are not ed, nor should they be construed as limiting the invention in any manner. Those d in the art will appreciate that variations and modifications of the following examples can be made without exceeding the spirit or scope of the invention.
As will be evident to those skilled in the art, individual isomeric forms can be obtained by separation of mixtures thereof in tional manner. For example, in the case of diasteroisomeric isomers, chromatographic separation may be employed.
Example 1 orticoid Receptor Transactivation Potencies for Cortisol and 17-ester Derivatives Glucocorticoid receptor (GR) activation potency was assessed using a HeLa cell line containing the MMTV-bla reporter (MMTV-bla HeLa CELLSENSOR®, Invitrogen Corp., Carlsbad, CA). This cell line was stably transfected with an expression construct containing β-lactamase cDNA under l of the MMTV response element previously identified as a glucocorticoid receptor response element.
Results from one experiment med in duplicate for 9 compounds and the l compound, dexamethasone, are summarized in Table 3. All assays were performed as -point dose responses using a half log-fold dilution series starting with a maximum compound concentration of 100 nM. The compounds were incubated for 5 hours. The activation of endogenous GR leads to expression of the reporter β-Iactamase which is ed by the conversion of a FRET substrate in a ratiometric assay format. This functional assay allows for measurement of receptor agonism by compounds and can be used to determine compound y and selectivity. Assay reproducibility was determined by ating Z' values for untreated versus maximum stimulation. The Z' value was greater than 0.6, ting good reproducibility of the assay format.
Several compounds showed ependent stimulation of the GR signaling pathway (Table 3). Compounds of Table 1 showed about 30-fold greater potency compared to the parent molecule cortisol.
Table 3: Glucocorticoid receptor potency. Shown are the EC50 (nM) and Z' values for the control compound, dexamethasone, and compounds tested in agonist mode.
Compound EC50 % Activation Z’ (nM) GR at 100 nM Dexamethasone 1.05 Control 0.87 Compound 1.35 88 0.87 nd EC50 % Activation Z’ (nM) GR at 100 nM 1.41 85 0.87 OH 1.97 86 0.87 HO O H H 3.25 65 0.87 6.04 47 0.87 nd EC50 % Activation Z’ (nM) GR at 100 nM 6.31 85 0.87 OH 7.07 84 0.87 HO O H H 41.6 43 0.87 cortisol >100 15 0.87 Compound EC50 % Activation Z’ (nM) GR at 100 nM >100 5 0.87 Example 2 Mineralocorticoid Receptor Transactivation Potencies for Cortisol and 17-ester Derivatives Mineralocorticoid receptor (MR) activation potency was ed using a HEK 293T cell line containing the UAS-bla reporter (UAS-bla HEK 293T NSOR®). This cell line was stably cotransfected with an expression uct containing β-Iactamase cDNA under control of the GAL4 Upstream Activator ce (UAS) and another expression construct encoding for the fusion protein GAL4(DBD)-MR(LBD). Results for one experiment performed in duplicate for 9 compounds and the l compound, aldosterone, in agonist mode are summarized in Table 4. All assays were performed as -point dose responses using a half log-fold dilution series starting with a maximum compound concentration of 100 nM. The compounds were incubated for 16 hours. The activation of the fusion n GAL4(DBD)-MR(LBD) leads to expression of the reporter β-lactamase which is detected by the sion of a FRET substrate in a ratiometric assay format. This functional assay allows for measurement of receptor agonism by compounds and can be used to determine compound potency and selectivity. Assay reproducibility was determined by calculating Z' values for untreated versus maximum stimulation. The Z' value was r than 0.6, indicating good reproducibility of the assay format. Several compounds showed dose-dependent ation of the MR signaling pathway (Table 4).
Table 4. Mineralocorticoid receptor potency. Shown are the EC50 (nM) and Z' values for the control nd, aldosterone, and all 10 compounds tested in agonist mode.
Table 4 Compound EC50 % Activation Z’ (nM) GR at 100 nM 0.47 Control 0.77 Compound Aldosterone 2.85 81 0.77 2.90 75 0.77 cortisol nd EC50 % Activation Z’ (nM) GR at 100 nM OH 2.94 77 0.77 HO O H H 3.17 76 0.77 .27 72 0.77 .68 64 0.77 nd EC50 % Activation Z’ (nM) GR at 100 nM 7.46 62 0.77 9.29 56 0.77 OH 15.6 62 0.77 HO O H H >100 27 0.77 Example 3 ng Elevated Intraocular Pressure A 58 year old male visits his ophthalmologist for a e check-up. The ian discovers that the patient exhibits an elevated intraocular re and is at high risk for future complications. The patient is instructed to apply a topical liquid formulation containing one of the compounds in Table 1 once daily to each eye.
The patient returns for a follow-up visit three months later. Upon measuring intraocular pressure, it is noted that the patient now exhibits a reduced intraocular pressure.
Example 4 Treating Ocular Irritation A 38 year old male visits his ophthalmologist complaining of irritation in his right eye.
The physician discovers that the patient’s right eye is inflamed and red. The patient is instructed to apply a topical liquid formulation containing one of the compounds in Table 1 twice daily to the right eye.
The patient returns for a follow-up visit a week later. Upon inspection of the right eye, it is noted that the t’s eye is no longer red and the patient indicates that the irritation is gone.
Unless otherwise indicated, all s expressing quantities of ingredients, properties such as lar weight, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about." ingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be ed by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.
Notwithstanding that the cal ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing ements.
The terms "a," "an," "the" and similar nts used in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the , unless otherwise ted herein or clearly contradicted by t. Recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods bed herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed t essential to the practice of the invention. ngs of alternative elements or ments of the invention disclosed herein are not to be ued as limitations. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion , the specification is deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims. n embodiments of this invention are described herein, including the best mode known to the inventors for ng out the invention. Of course, variations on these described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventor expects d artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced ise than specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by able law. Moreover, any combination of the abovedescribed elements in all possible ions thereof is encompassed by the invention unless ise indicated herein or otherwise clearly contradicted by context.
It is also to be understood that the embodiments of the invention disclosed herein are illustrative of the principles of the present invention. Other modifications that may be employed are within the scope of the invention. Thus, by way of example, but not of limitation, alternative configurations of the present invention may be utilized in accordance with the teachings herein. Accordingly, the present invention is not limited to that ely as shown and described.
In this ication where reference has been made to patent specifications, other external documents, or other sources of information, this is generally for the purpose of providing a context for discussing the features of the invention. Unless specifically stated otherwise, reference to such external documents is not to be construed as an admission that such documents, or such sources of information, in any jurisdiction, are prior art, or form part of the common l knowledge in the art.
In the description in this specification reference may be made to subject matter that is not within the scope of the claims of the current application. That subject matter should be y identifiable by a person skilled in the art and may assist in putting into practice the invention as defined in the claims of this application.
Claims (61)
1. A use, in the manufacture of a medicament for treating an ocular condition ated with glucocorticoid and or mineralocorticoid or modulation in a patient in need thereof, of at least one compound selected from: 8S,9S,10R,11S,13S,14S,17R)glycoloylhydroxy-10,13-dimethyloxo- 2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrenyl acetate; (8S,9S,10R,11S,13S,14S,17R)glycoloylhydroxy-10,13-dimethyloxo- 2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrenyl propionate; (8S,9S,10R,11S,13S,14S,17R)glycoloylhydroxy-10,13-dimethyloxo- 2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrenyl octanoate; (8S,9S,10R,11S,13S,14S,17R)-17 -Glycoloylhydroxy-10,13-dimethyloxo- 2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrenyl hexanoate; ,10R,11S,13S,14S,17R)glycoloylhydroxy-10,13-dimethyloxo- 2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrenyl benzoate; (8S,9S,10R,11S,13S,14S,17R)glycoloylhydroxy-10,13-dimethyloxo- 2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrenyl heptanoate; (8S,9S,10R,11S,13S,14S,17R)glycoloylhydroxy-10,13-dimethyloxo- 2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrenyl 2-methylpropanoate; and (8S,9S,10R,11S,13S,14S,17R)glycoloylhydroxy-10,13-dimethyloxo- 2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrenyl cyclopentanecarboxylate; wherein the ocular condition is selected from elevated cular pressure, glaucoma, uveitis, retinal vein occlusions, macular degeneration, diabetic retinopathy, various forms of macular edema, post-surgical inflammation, matory conditions of the palpebral and bulbar conjunctiva, cornea, and anterior segment of the globe, such as allergic conjunctivitis, ocular rosacea, dry eye, blepharitis, retinal detachment, meibomian gland dysfunction, superficial punctate keratitis, herpes zoster keratitis, iritis, cyclitis, selected infective conjunctivitis, corneal injury from chemical, radiation, or thermal burns, penetration of foreign bodies, allergy, and combinations thereof.
2. The use according to claim 1 n the ocular condition is selected from, ocular a, dry eye, blepharitis, meibomian and gland dysfunction.
3. The use according to claim 1 wherein the compound is: (8S,9S,10R,11S,13S,14S,17R)glycoloylhydroxy-10,13-dimethyloxo- 2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrenyl
4. The use ing to claim 1 wherein the compound is: (8S,9S,10R,11S,13S,14S,17R)-17 -Glycoloylhydroxy-10,13-dimethyloxo- 2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrenyl hexanoate .
5. The use according to claim 1 wherein the compound is: (8S,9S,10R,11S,13S,14S,17R)glycoloylhydroxy-10,13-dimethyloxo- 2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrenyl octanoate.
6. The use according to claim 1 wherein the compound is: (8S,9S,10R,11S,13S,14S,17R)glycoloylhydroxy-10,13-dimethyloxo- 2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrenyl phenylacetate.
7. The use according to claim 1 wherein the compound is: (8S,9S,10R,11S,13S,14S,17R)glycoloylhydroxy-10,13-dimethyloxo- 7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrenyl propionate.
8. The use according to claim 1 wherein the compound is: (8S,9S,10R,11S,13S,14S,17R)glycoloylhydroxy-10,13-dimethyloxo- 2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrenyl heptanoate.
9. The use according to claim 1 wherein the compound is: (8S,9S,10R,11S,13S,14S,17R)glycoloylhydroxy-10,13-dimethyloxo- 2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrenyl 2-methylpropanoate.
10. The use according to claim 1 wherein the compound is: (8S,9S,10R,11S,13S,14S,17R)glycoloylhydroxy-10,13-dimethyloxo- 2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrenyl cyclopentanecarboxylate.
11. A composition suitable for treating an ocular condition associated with glucocorticoid and or mineralocorticoid receptor modulation sing at least one compound selected from the group consisting of: ,10R,11S,13S,14S,17R)glycoloylhydroxy-10,13-dimethyloxo- 2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrenyl phenylacetate; (8S,9S,10R,11S,13S,14S,17R)glycoloylhydroxy-10,13-dimethyloxo- 7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrenyl propionate; (8S,9S,10R,11S,13S,14S,17R)glycoloylhydroxy-10,13-dimethyloxo- 2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrenyl octanoate; (8S,9S,10R,11S,13S,14S,17R)Glycoloylhydroxy-10,13-dimethyloxo- 2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrenyl hexanoate; (8S,9S,10R,11S,13S,14S,17R)glycoloylhydroxy-10,13-dimethyloxo- 2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrenyl benzoate; (8S,9S,10R,11S,13S,14S,17R)glycoloylhydroxy-10,13-dimethyloxo- 2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrenyl heptanoate; (8S,9S,10R,11S,13S,14S,17R)glycoloylhydroxy-10,13-dimethyloxo- 2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrenyl 2-methylpropanoate; and (8S,9S,10R,11S,13S,14S,17R)glycoloylhydroxy-10,13-dimethyloxo- 2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrenyl cyclopentanecarboxylate; wherein the composition is formulated to be topically ophthalmically acceptable.
12. The composition according to claim 11 wherein the ocular condition is selected from elevated intraocular pressure, ma, uveitis, retinal vein occlusions, macular degeneration, diabetic retinopathy, various forms of macular edema, post-surgical inflammation, inflammatory conditions of the palpebral and bulbar conjunctiva, , and anterior segment of the globe, such as allergic ctivitis, ocular rosacea, dry eye, blepharitis, retinal detachment, meibomian gland dysfunction, superficial te keratitis, herpes zoster tis, iritis, cyclitis, selected ive conjunctivitis, corneal injury from chemical, radiation, or thermal burns, ation of foreign bodies, allergy, and combinations thereof.
13. The composition according to claim 12 wherein the ocular condition is ed from, ocular rosacea, dry eye, blepharitis, meibomian and gland ction.
14. The composition according to claim 11 wherein the nd is: (8S,9S,10R,11S,13S,14S,17R)glycoloylhydroxy-10,13-dimethyloxo- 2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrenyl benzoate.
15. The composition according to claim 11 wherein the compound is: (8S,9S,10R,11S,13S,14S,17R)Glycoloylhydroxy-10,13-dimethyloxo- 2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrenyl ate.
16. The composition according to claim 11 wherein the compound is: (8S,9S,10R,11S,13S,14S,17R)glycoloylhydroxy-10,13-dimethyloxo- 2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrenyl octanoate.
17. The composition according to claim 11 wherein the compound is: (8S,9S,10R,11S,13S,14S,17R)glycoloylhydroxy-10,13-dimethyloxo- 2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrenyl phenylacetate.
18. The composition ing to claim 11 wherein the compound is: (8S,9S,10R,11S,13S,14S,17R)glycoloylhydroxy-10,13-dimethyloxo- 2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrenyl propionate.
19. The composition according to claim 11 wherein the compound is: (8S,9S,10R,11S,13S,14S,17R)glycoloylhydroxy-10,13-dimethyloxo- 2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrenyl heptanoate.
20. The composition according to claim 11 wherein the compound is (8S,9S,10R,11S,13S,14S,17R)glycoloylhydroxy-10,13-dimethyloxo- 2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrenyl 2-methylpropanoate.
21. The composition according to claim 11 wherein the compound is (8S,9S,10R,11S,13S,14S,17R)glycoloylhydroxy-10,13-dimethyloxo- 2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrenyl cyclopentanecarboxylate.
22. The composition according to any one of claims 11-21, wherein the composition further comprises one or more es selected from the group consisting of polyvinyl alcohol, ne, hydroxypropyl methyl ose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose and purified water.
23. The composition according to any one of claims 11-22, n the composition further comprises one or more tonicity adjusters selected from the group consisting of sodium chloride, ium de, ol, and glycerin.
24. The composition according to any one of claims 11-23, wherein the composition further comprises one or more buffers ed from the group consisting of acetate buffers, citrate buffers, phosphate buffers, and borate buffers.
25. The composition according to any one of claims 11-24, wherein the ition further comprises one or more preservatives selected from the group consisting of benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, and phenylmercuric nitrate.
26. The composition according to any one of claims 11-25, wherein the composition has a pH from about 4.5 to about 7.5.
27. The composition according to claim 11, wherein the composition further comprises one or more vehicles selected from the group ting of polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, and purified water; one or more tonicity adjusters selected from the group consisting of sodium chloride and potassium chloride; and one or more buffers selected from the group consisting of e buffers and borate buffers; and wherein the composition has a pH from about 4.5 to about 7.5.
28. The composition according to claim 27, wherein the composition further ses one or more preservatives selected from the group consisting of benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, and phenylmercuric nitrate.
29. The composition according to claim 11, wherein the composition further comprises one or more vehicles selected from the group consisting of polyvinyl alcohol, povidone, ypropyl methyl cellulose, and purified water; one or more tonicity adjusters selected from the group consisting of sodium de and ium chloride; and one or more buffers selected from the group consisting of phosphate buffers and citrate buffers; and wherein the composition has a pH from about 4.5 to about 7.5.
30. The composition according to claim 29, wherein the composition further comprises one or more preservatives selected from the group consisting of benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, and phenylmercuric nitrate.
31. The composition according to claim 11, wherein the composition further comprises one or more vehicles selected from the group consisting of polyvinyl alcohol, ne, hydroxypropyl methyl cellulose, and ed water; one or more tonicity ers selected from the group consisting of mannitol and glycerin; and one or more buffers selected from the group consisting of ate buffers and citrate buffers; and wherein the composition has a pH from about 4.5 to about 7.5.
32. The composition according to claim 31, wherein the composition r comprises one or more preservatives selected from the group consisting of benzalkonium chloride, butanol, thimerosal, phenylmercuric acetate, and phenylmercuric nitrate.
33. The composition according to claim 11, wherein the composition further comprises one or more vehicles ed from the group consisting of poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose, and purified water; one or more ty adjusters selected from the group consisting of sodium chloride and potassium chloride; and one or more buffers selected from the group consisting of acetate buffers and borate buffers; and wherein the composition has a pH from about 4.5 to about 7.5.
34. The composition according to claim 33, wherein the composition further comprises one or more preservatives selected from the group consisting of benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, and phenylmercuric nitrate.
35. The composition according to claim 11, wherein the composition further comprises one or more vehicles selected from the group consisting of poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose, and purified water; one or more tonicity adjusters selected from the group ting of sodium chloride and potassium chloride; and one or more buffers ed from the group ting of phosphate buffers and citrate s; and n the ition has a pH from about 4.5 to about 7.5.
36. The composition according to claim 35, wherein the composition further comprises one or more preservatives selected from the group consisting of benzalkonium chloride, chlorobutanol, osal, phenylmercuric acetate, and phenylmercuric nitrate.
37. The composition according to claim 41, wherein the composition further comprises one or more vehicles selected from the group consisting of poloxamers, carboxymethyl cellulose, hydroxyethyl ose, and ed water; one or more tonicity adjusters selected from the group ting of mannitol and glycerin; and one or more buffers selected from the group consisting of phosphate buffers and citrate buffers; and wherein the composition has a pH from about 4.5 to about 7.5.
38. The composition according to claim 37, wherein the composition further comprises one or more preservatives selected from the group consisting of benzalkonium chloride, chlorobutanol, thimerosal, mercuric acetate, and phenylmercuric nitrate.
39. A use, in the manufacture of a medicament for treating an ocular condition associated with glucocorticoid and or locorticoid receptor modulation in a patient in need thereof, of; (8S,9S,10R,11S,13S,14S,17R)glycoloylhydroxy-10,13-dimethyloxo- 2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrenyl butyrate; wherein the ocular condition is ed from elevated intraocular pressure, glaucoma, uveitis, retinal vein occlusions, macular degeneration, diabetic pathy, s forms of macular edema, post-surgical inflammation, inflammatory conditions of the palpebral and bulbar conjunctiva, cornea, and anterior segment of the globe, such as allergic conjunctivitis, ocular rosacea, dry eye, retinal detachment, meibomian gland dysfunction, superficial punctate keratitis, herpes zoster keratitis, iritis, cyclitis, selected infective conjunctivitis, corneal injury from chemical, radiation, or thermal burns, penetration of foreign , allergy, and combinations thereof.
40. The use according to claim 39 wherein the ocular ion is selected from, ocular rosacea, dry eye, meibomian and gland dysfunction.
41.A composition le for treating an ocular condition associated with glucocorticoid and or mineralocorticoid receptor modulation comprising: (8S,9S,10R,11S,13S,14S,17R)glycoloylhydroxy-10,13-dimethyloxo- 2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrenyl butyrate; wherein the composition is formulated to be topically ophthalmically acceptable; and wherein the ition further ses one or more vehicles selected from the group consisting of polyvinyl alcohol, ne, hydroxypropyl methyl cellulose, mers, carboxymethyl cellulose, yethyl cellulose and purified water.
42. The composition according to claim 41 wherein the ocular condition is selected from ed intraocular pressure, glaucoma, uveitis, retinal vein occlusions, macular degeneration, diabetic retinopathy, various forms of macular edema, post-surgical inflammation, inflammatory conditions of the palpebral and bulbar conjunctiva, cornea, and anterior segment of the globe, such as allergic conjunctivitis, ocular rosacea, dry eye, retinal detachment, ian gland dysfunction, superficial te keratitis, herpes zoster keratitis, , cyclitis, selected infective conjunctivitis, corneal injury from chemical, radiation, or thermal burns, penetration of foreign bodies, allergy, and combinations thereof.
43. The composition according to claim 42 wherein the ocular ion is ed from, ocular rosacea, dry eye, meibomian and gland dysfunction.
44. The composition according to any one of claims 41-43, wherein the composition further comprises one or more tonicity adjusters selected from the group consisting of sodium chloride, potassium chloride, mannitol, and glycerin.
45. The composition according to any one of claims 41-44, wherein the composition further comprises one or more buffers selected from the group consisting of acetate buffers, citrate s, phosphate buffers, and borate buffers.
46. The composition according to any one of claims 41-45, wherein the composition further comprises one or more vatives selected from the group consisting of konium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, and phenylmercuric nitrate.
47. The composition according to any one of claims 41-46, wherein the composition has a pH from about 4.5 to about 7.5.
48. The ition according to claim 41, wherein the composition r comprises one or more vehicles selected from the group consisting of polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, and purified water; one or more tonicity adjusters selected from the group consisting of sodium chloride and potassium chloride; and one or more buffers selected from the group consisting of acetate buffers and borate buffers; and wherein the composition has a pH from about 4.5 to about 7.5.
49. The composition according to claim 48, wherein the composition further ses one or more preservatives selected from the group consisting of benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, and phenylmercuric nitrate.
50. The composition according to claim 41, wherein the composition further comprises one or more vehicles selected from the group consisting of polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, and purified water; one or more tonicity adjusters selected from the group consisting of sodium chloride and potassium chloride; and one or more buffers selected from the group consisting of phosphate s and citrate buffers; and wherein the composition has a pH from about 4.5 to about 7.5.
51. The composition according to claim 50, wherein the composition further comprises one or more preservatives selected from the group consisting of benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric e, and phenylmercuric nitrate.
52. The composition according to claim 41, wherein the composition r comprises one or more vehicles ed from the group consisting of polyvinyl alcohol, povidone, ypropyl methyl cellulose, and purified water; one or more tonicity adjusters selected from the group consisting of mannitol and glycerin; and one or more buffers ed from the group consisting of ate buffers and citrate s; and wherein the composition has a pH from about 4.5 to about 7.5.
53. The composition according to claim 52, wherein the composition further comprises one or more preservatives selected from the group consisting of benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, and phenylmercuric nitrate.
54. The ition according to claim 41, wherein the composition further comprises one or more vehicles ed from the group consisting of poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose, and purified water; one or more tonicity adjusters selected from the group consisting of sodium de and potassium chloride; and one or more buffers selected from the group consisting of acetate buffers and borate s; and wherein the composition has a pH from about 4.5 to about 7.5.
55. The composition according to claim 54, wherein the composition further comprises one or more vatives selected from the group consisting of benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, and phenylmercuric nitrate.
56. The ition according to claim 41, wherein the composition further comprises one or more vehicles selected from the group ting of poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose, and ed water; one or more tonicity adjusters selected from the group consisting of sodium chloride and potassium chloride; and one or more buffers selected from the group consisting of phosphate buffers and citrate buffers; and wherein the composition has a pH from about 4.5 to about 7.5.
57. The composition according to claim 56, wherein the composition further comprises one or more preservatives selected from the group consisting of benzalkonium chloride, butanol, thimerosal, phenylmercuric e, and phenylmercuric nitrate.
58. The composition according to claim 41, wherein the composition further comprises one or more vehicles ed from the group consisting of poloxamers, carboxymethyl cellulose, yethyl cellulose, and purified water; one or more tonicity adjusters ed from the group consisting of mannitol and glycerin; and one or more buffers selected from the group consisting of phosphate buffers and citrate buffers; and wherein the composition has a pH from about 4.5 to about 7.5.
59. The composition according to claim 58, wherein the composition further comprises one or more preservatives selected from the group consisting of benzalkonium de, chlorobutanol, thimerosal, phenylmercuric acetate, and phenylmercuric nitrate.
60. A use as d in claim 1 or 39, substantially as herein described with reference to any example thereof.
61. A composition as claimed in claim 11 or 41, substantially as herein bed with reference to any example thereof.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201161558775P | 2011-11-11 | 2011-11-11 | |
| US61/558,775 | 2011-11-11 | ||
| PCT/US2012/064296 WO2013071010A1 (en) | 2011-11-11 | 2012-11-09 | PHARMACEUTICAL COMPOSITIONS AND METHODS OF USE OF 4-PREGENEN-11ß-17-21-TRIOL-3,20-DIONE DERIVATIVES |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| NZ624920A NZ624920A (en) | 2017-06-30 |
| NZ624920B2 true NZ624920B2 (en) | 2017-10-03 |
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