WO2019123266A1 - Composition ophtalmique comprenant une prostaglandine et un bêta-bloquant - Google Patents

Composition ophtalmique comprenant une prostaglandine et un bêta-bloquant Download PDF

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Publication number
WO2019123266A1
WO2019123266A1 PCT/IB2018/060275 IB2018060275W WO2019123266A1 WO 2019123266 A1 WO2019123266 A1 WO 2019123266A1 IB 2018060275 W IB2018060275 W IB 2018060275W WO 2019123266 A1 WO2019123266 A1 WO 2019123266A1
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typically
composition
cps
prostaglandin
concentration
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PCT/IB2018/060275
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English (en)
Inventor
Brent G. Boudreaux
Theresa LANDRY
Robert Rodstrom
Ruma Sarkar
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Novartis Ag
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Publication of WO2019123266A1 publication Critical patent/WO2019123266A1/fr

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    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
    • 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
    • A61K31/69—Boron compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin

Definitions

  • the present invention is directed to an ophthalmic composition that includes a prostaglandin and a beta-blocker. More particularly, the present invention is directed to an ophthalmic composition that has relatively high viscosity and includes a relatively low concentration of prostaglandin (e.g., travoprost) and a relatively low concentration of beta-blocker (e.g., timolol).
  • a prostaglandin e.g., travoprost
  • beta-blocker e.g., timolol
  • the eyes of humans and animals are responsible for transmitting visual information (e.g., images) to the brain.
  • visual information e.g., images
  • the visual information is transmitted as light through the cornea and the lens of the eye, both of which aid in focusing the visual information on the retina.
  • the visual information is then transmitted to the brain via the optic nerve.
  • Glaucoma is a term associated with multiple different ocular disorders that are each associated with undesirable intraocular pressure (IOP), which can, in turn, cause damage to the optic nerve. If glaucoma goes untreated, it can cause vision loss and eventually blindness.
  • IOP intraocular pressure
  • ophthalmic medicaments that have exhibited ability to lower intraocular pressure, generally in the range of 4 to 9 mm Hg. Multiple different medicaments have been found to exhibit such ability. Examples include, without limitation, prostaglandins, carbonic anhydrase inhibitors, alpha agonists and beta-blockers.
  • a fixed combination that is currently marketed is a combination of a prostaglandin referred to as travoprost, and a beta- blocker referred to as timolol.
  • This combination is sold by Alcon ® Laboratories, Inc., a Novartis ® Corporation, Fort Worth, TX under the tradename DUOTRAV ® .
  • Another example is a combination of the carbonic anhydrase inhibitor referred to as brinzolamide and an alpha agonist referred to as brimonidine.
  • the combination is sold by Alcon ® Laboratories, Inc., a Novartis ® Corporation, Fort Worth, TX under the tradename SIMBRINZA ® .
  • beta-blockers alone and prostaglandins alone have been approved for the treatment of elevated intraocular pressure in the United States, a fixed combination of these two drugs for such treatment has never been approved in the United States. This is the case even though fixed combinations of a prostaglandin and a beta-blocker are sold in many geographies throughout the world.
  • the Food and Drug Administration (FDA) has been cautious regarding such approval since it is known that systemic exposure to a beta-blocker can slow the heart rate of humans and that topical administration of a beta-blocker provides some degree of systemic exposure to the beta-blocker, albeit a relatively low exposure.
  • an ophthalmic composition that includes both a prostaglandin (e.g., travoprost) and a beta-blocker (e.g., timolol) where the composition significantly reduces systemic exposure to the beta-blocker.
  • a prostaglandin e.g., travoprost
  • a beta-blocker e.g., timolol
  • the present invention is directed to an ophthalmic composition.
  • the composition is preferably designed for topical administration to the eye and is designed to lower intraocular pressure.
  • the composition comprises a prostaglandin selected from the group consisting of travoprost, latanoprost and bimatoprost wherein: i) the concentration of the prostaglandin, if the prostaglandin is substantially entirely or entirely travoprost, is at least is at least 0.0008 w/v% (0.24 pg per drop (PD)) , more typically at least 0.0012 w/v% (0.36 pg PD) and even possibly at least 0.0014 w/v% (0.42 pg PD) but is no greater than 0.0025 w/v% (.75 pg PD), more typically no greater than 0.0018 w/v% (0.54 pg PD) and even possibly no greater than 0.0016 w/v% (0.48 pg PD) and/or is at
  • the composition also comprises a beta-blocker selected from the group consisting of timolol and betaxolol or both wherein the concentration of the beta- blocker in the composition is at least 0.03 w/v%, more typically at least 0.06 w/v% and even more typically at least 0.09 w/v% but is no greater than 0.2 w/v%, more typically no greater than 0.13 w/v% and even more typically no greater than 0.11 w/v% and/or is at least 0.03 w/v% but no greater than 0.2 w/v%, more typically at least 0.06 w/v% but no greater than 0.13 w/v% and even more typically at least 0.09 w/v% but no greater than 0.11 w/v%.
  • a beta-blocker selected from the group consisting of timolol and betaxolol or both wherein the concentration of the beta- blocker in the composition is at least 0.03 w/v%, more typically at least 0.06 w/
  • the composition also includes viscosity enhancer and water.
  • the water is typically present in the composition at a concentration that is at least 90 w/v% but no greater than 99.7 w/v%, more typically at least 96 w/v% but no greater than 99.0 w/v% and even more typically at least 97.5 w/v% but no greater than 98.5 w/v%.
  • both the prostaglandin and the beta-blocker are substantially entirely or entirely dissolved in the composition.
  • the viscosity of the composition is at least 30 cps, more typically at least 120 cps and even more typically at least 190 cps and is typically no greater than 500 cps, more typically no greater than 300 cps and even more typically no greater than 240 cp and/or is typically at least 30 cps but no greater than 500 cps, more typically at least 120 cps but no greater than 300 cps and even more typically at least 190 cps but no greater than 240 cps.
  • the topical ophthalmic composition also typically includes borate.
  • the borate is boric acid. It is also preferable that the borate is in composition at a concentration that is typically 0.2 to 2.0 w/v %, more typically at a concentration of 0.2 to 0.6 w/v% even more typically at a concentration of 0.2 to 0.4 w/v %, and still more typically at a concentration of about 0.3 w/v % (i.e., 0.3 w/v% ⁇ 0.02 w/v%).
  • the topical ophthalmic composition also typically comprises polyol and the polyol is preferably entirely or substantially entirely propylene glycol.
  • the polyol is present in the composition at a concentration of at least 0.02 w/v% but no greater than 3 w/v%, more typically at least 0.15 w/v% but no greater than 0.5 w/v%, still more typically at least 0.25% w/v% but no greater than 0.40 w/v% or 0.35 w/v%.
  • the topical ophthalmic composition also preferably includes sodium chloride.
  • the sodium chloride is present in the composition at a concentration that is typically at least about 0.10 w/v %, more typically at least about 0.3 w/v % and even more typically at least about 0.45 w/v % but no greater than about 0.9 w/v %, more typically no greater than about 0.70 w/v % and even possibly no greater than about 0.55 w/v % and/or at least 0.1 w/v% but no greater than 0.9 w/v%, more typically at least 0.30 w/v% but no greater than 0.70 w/v% and even possibly at least 0.45 w/v% but no greater than 0.55 w/v%.
  • the topical ophthalmic composition also typically includes sodium hydroxide, hydrochloric acid or both to adjust pH.
  • the pH is typically at least 6.0, more typically at least 6.2 and even more typically at least 6.4 or 6.5 and is typically no greater than 7.3, more typically no greater than 7.1 and even more typically no greater than 7.0 or 6.8 and/or such pH is typically at least 6.0 but no greater than 7.3, more typically at least 6.2 but no greater than 7.0, and even more typically at least 6.4 but no greater than 7.0 or 6.8.
  • the viscosity enhancer preferably includes carboxyvinyl polymer, which is typically a carbomer.
  • the carboxyvinyl polymer is present in the composition at a concentration that is typically at least about 0.05 w/v%, more typically at least about 0.2 w/v% even more typically at least about 0.35 w/v% and is typically no greater than about 1.0%, more typically no greater than about 0.6% even more typically no greater than about 0.5% and/or is typically at least 0.05 w/v%, but no greater than 1.0 w/v%, more typically at least 0.2 w/v% but no greater than 0.6 w/v% and even more typically at least 0.35 w/v% but no greater than 0.45 w/v%. .
  • the viscosity enhancer preferably also or alternatively includes galactomannan polymer.
  • the galactomannan polymer is native guar.
  • the galactomannan polymer is present in the composition at a concentration that is at least about 0.04 w/v%, more typically at least about 0.13 w/v%, and even more typically at least about 0.18 w/v% and no greater than about 0.6 w/v%, more typically no greater than about 0.25 and even more typically no greater than about 0.22 w/v% and/or is typically at least 0.04 w/v%, but no greater than 0.6 w/v%, more typically at least 0.13 w/v% but no greater than 0.25 w/v% and even more typically at least 0.18 w/v% but no greater than 0.22 w/v%.
  • the beta-blocker can be entirely or substantially entirely timolol.
  • the timolol is provided as timolol maleate.
  • the beta-blocker can also be entirely or substantially entirely betaxolol.
  • betaxolol is provided as betaxolol HC1.
  • the prostaglandin can be substantially entirely or entirely latanoprost.
  • the prostaglandin can also be substantially entirely or entirely travoprost.
  • the prostaglandin can also be substantially entirely or entirely bimatoprost.
  • the present invention also includes a method of reducing intraocular pressure.
  • the method includes reducing intraocular pressure in a subject having elevated intraocular pressure or diagnosed with glaucoma, preferably open angle glaucoma, or ocular hypertension.
  • the method comprises topically applying any one of the compositions described herein to an eye.
  • the eye is a human eye and the step of topical application is performed once a day. It is also preferable that the step of topical application is performed by expelling a single drop of the composition from a container onto the eye.
  • the present invention also includes the use of a composition as recited herein, for use in reducing intraocular pressure in a subject.
  • the compositions recited herein are used in treating diseases and conditions caused by elevated or increased intraocular pressure in a subject. Examples of diseases caused by elevated intraocular pressure include ocular hypertension, and open angle glaucoma.
  • the present invention also include an article comprised of any one of the composition described disposed within packaging wherein the packaging includes instructions for the composition to be administered once daily.
  • the packaging preferably includes a container configured to expel one drop of the composition at a time and the instructions for administration instruct that the composition be administered as a single drop once daily to one eye or both eyes of an individual.
  • the present invention is predicated upon the provision of an ophthalmic pharmaceutical composition for lowering intraocular pressure (IOP).
  • the method includes reducing intraocular pressure in a subject having elevated intraocular pressure or diagnosed with glaucoma, preferably open angle glaucoma, or ocular hypertension.
  • the ophthalmic composition includes a prostaglandin, preferably an FP-receptor agonist prostaglandin, and a beta-blocker. Both the prostaglandin and the beta-blocker are in the composition at relatively low concentrations.
  • the concentration of the prostaglandin and the beta- blocker are below typical concentrations of the prostaglandin and the beta-blocker in marketed ophthalmic fixed dose combination compositions while avoiding loss in efficacy and reducing undesirable side effects of the product.
  • This is accomplished by using a viscous delivery vehicle to retain the prostaglandin and the beta-blocker longer on the surface of the eye resulting in adequate intra-ocular bioavailability and less systemic exposure of the active pharmaceutical ingredients.
  • the composition can be dosed once daily and due to less systemic exposure, may avoid all or at least a portion of the tendency of the beta-blocker to increase the heart rate of a human being.
  • the lower concentration of prostaglandin is believed to avoid a loss of the ability of the prostaglandin to lower intraocular pressure that might otherwise result from providing undesirably high amounts and/or concentrations of prostaglandin to target tissues of the eye.
  • the fixed combination of the relatively low concentration of prostaglandin and the relatively low concentration of beta-blocker may be able to produce similar IOP lowering efficacy to the current fixed combination of these drugs while using less of the two drugs, and while additionally avoiding systemic side effect associated with beta-blockers such as but not limited to decreased heart rates in some patients.
  • compositions of the present invention are typically given in w/v%.
  • concentrations of composition of the present invention are typically given in w/v%.
  • the compositions discussed herein are typically dosed as eye drops having a volume of approximately 35 microliters (m ⁇ )
  • a total weight per dose is also provided. For example, for a range of at least 1 w/v% but no greater than 10 w/v%, a range of at least 350 pg but no greater than 3500 pg per dose is also provided.
  • concentrations for the prostaglandins have also been provided in a per dose (PD) weight as well.
  • PD weights have not been provided for the other ingredients, they are considered to be disclosed based upon the above calculation.
  • a different drop or dose volume or weight could modify the above calculation of PD weight and could be calculated by the skilled artisan.
  • the (PD) weight could be easily calculated for delivery types other than a drop.
  • the phrase“less than” relative to a specified concentration means that the specified component (e.g., antimicrobial preservative) is either not present in the composition at all or is present at a concentration less than the specified limit (e.g., 1 w/v %).
  • the phrase“an effective amount of’ means that a specified component is present in the composition in an amount sufficient to have an impact on the therapeutic capability, the buffering capability, the preservative capability and/or the anti microbial capability of the composition.
  • prostaglandin includes, prostaglandins, prostaglandin derivatives, prostaglandin analogs and prodrugs of prostaglandin (e.g., esters or amides of the corresponding free acid). While it is contemplated that the prostaglandin of the composition of the present invention can be selected from a wide variety of compounds, it is preferable that the prostaglandin be selected from the group consisting of latanoprost, travoprost, bimatoprost and tafluprost and more preferably latanoprost, travoprost and bimatoprost.
  • the prostaglandin may be selected from combinations of the aforementioned prostaglandins. It is also preferable that the prostaglandin be an FP-receptor agonist. In a highly preferred embodiment, the prostaglandin is travoprost.
  • the concentration of the prostaglandin in the composition in general, is at least 0.0005 w/v% (0.15 pg PD) , more typically at least 0.001 w/v% (0.3 pg PD) and even possibly at least 0.0013 w/v% (0.39 pg PD) but is no greater than 0.004 w/v% (1.2 pg PD), more typically no greater than 0.0025 w/v% (0.75 pg PD) and even possibly no greater than 0.0017 w/v% (0.51 pg PD).
  • the concentration of prostaglandin in the composition in general, is at least 0.0005 w/v% (0.15 pg PD) but no greater than 0.004 w/v% (0.6 pg PD) and more typically at least 0.001 w/v% (0.3 pg PD) but no greater than 0.0025 w/v% (0.75 pg PD) and even more typically at least 0.0013 w/v% (0.39 pg PD) but no greater than 0.0017 w/v% (0.51 pg PD).
  • the prostaglandin is entirely or substantially entirely travoprost.
  • the concentration of the prostaglandin in the composition is at least 0.0008 w/v% (0.24 pg PD) , more typically at least 0.0012 w/v% (0.36 pg PD) and even possibly at least 0.0014 w/v% (0.42 pg PD) but is no greater than 0.0025 w/v% (.75 pg PD), more typically no greater than 0.0018 w/v% (0.54 pg PD) and even possibly no greater than 0.0016 w/v% (0.48 pg PD).
  • the concentration of prostaglandin in the composition is at least 0.0008 w/v% (0.24 pg PD) but no greater than 0.0025 w/v% (0.75 pg PD) and more typically at least 0.0012 w/v% (0.36 pg PD) but no greater than 0.0018 w/v% (0.54 pg PD) and even more typically at least 0.0014 w/v% (0.42 pg PD) but no greater than 0.0016 w/v% (0.48 pg PD).
  • an ingredient when “substantially entirely or entirely” according to a particular definition, it means that at least 95 weight percent of the total weight of that particular ingredient or the entirety of that ingredient within the composition is according to that particularly definition. This specifically excludes any more that 5 weight percent of the total weight of that particular ingredient as being outside of the particular definition.
  • the statement “the prostaglandin is substantially entirely or entirely travoprost” means that at least 95 wt% of the total weight of any and all prostaglandin in the composition is travoprost and no more than 5 wt% of the total weight of prostaglandin in the composition is other than travoprost.
  • the concentration of the prostaglandin in the composition is at least 0.0009 w/v% (0.315 pg PD), more typically at least 0.0013 w/v% (0.455 pg PD) and even more typically at least 0.0017 w/v% (0.595 pg PD) but is no greater than 0.0035 w/v% (1.225 pg PD), more typically no greater than 0.0027 w/v% (0.945 pg PD), still more typically no greater than 0.0023 w/v% (0.805 pg PD) and even possibly no greater than 0.0021 w/v% (0.735 pg PD).
  • the concentration of prostaglandin in the composition is at least 0.0009 w/v% (0.315 pg PD) but no greater than 0.0035 w/v% (1.225 pg PD), more typically at least 0.0013 w/v% (0.455 pg PD) but no greater than 0.0027 w/v% (0.945 pg PD) and even more typically at least 0.0017 w/v% (0.595 pg PD) but no greater than 0.0023 w/v% (0.805 pg PD).
  • the concentration of the prostaglandin in the composition is at least 0.003 w/v% (1.05 pg PD), more typically at least 0.006 w/v% (2.10 pg PD) and even more typically at least 0.008 w/v% (0.24 pg PD) but is no greater than 0.02 w/v% (7.00 pg PD), more typically no greater than 0.015 w/v% (5.25 pg PD), even more typically no greater than 0.013 w/v% (4.55 pg PD) and even possibly no greater than 0.011 w/v% (3.85 pg PD).
  • the concentration of prostaglandin in the composition is at least 0.003 w/v% (1.05 pg PD) but no greater than 0.02 w/v% (7.00 pg PD), more typically at least 0.006 w/v% (2.10 pg PD) but no greater than 0.015 w/v% (5.25 pg PD) and even more typically at least 0.008 w/v% (2.80 pg PD) but no greater than 0.013 w/v% (4.55 pg PD).
  • the concentration of the prostaglandin in the composition is at least 0.0003 w/v% (0.105 pg PD), more typically at least 0.0006 w/v% (0.210 pg PD) and even more typically at least 0.0008 w/v% (0.024 pg PD) but is no greater than 0.002 w/v% (0.700 pg PD), more typically no greater than 0.0015 w/v% (0.525 pg PD), even more typically no greater than 0.0013 w/v% (0.455 pg PD) and even possibly no greater than 0.0011 w/v% (0.385 pg PD).
  • the concentration of prostaglandin in the composition is at least 0.0003 w/v% (0.105 pg PD) but no greater than 0.002 w/v% (0.700 pg PD), more typically at least 0.0006 w/v% (0.210 pg PD) but no greater than 0.0015 w/v% (0.525 pg PD) and even more typically at least 0.0008 w/v% (0.280 pg PD) but no greater than 0.0013 w/v% (0.455 pg PD).
  • the beta-blocker is typically selected from the group consisting of timolol, more particularly timolol maleate, betaxalol, more particularly betaxolol hydrochloride, or a combination thereof although it is contemplated that other beta- blockers may also be used.
  • the beta-blocker is present in the composition at a concentration that is at least 0.03 w/v% but no greater than 0.2 w/v%, more typically at least 0.06 w/v% but no greater than 0.13 w/v% and even more typically at least 0.09 w/v% but no greater than 0.11 w/v%.
  • concentrations that are descriptive for the beta-blocker are meant to refer to the concentration of beta-blocker only, not the concentration of the beta-blocker and its salt, unless the description specifically refers to the concentration of the salt form.
  • concentrations of timolol refers only to timolol in the composition, not, for example, timolol maleate, unless otherwise specified.
  • concentrations of betaxolol refer only to concentrations of betaxolol, not, for example, betaxolol HC1, unless otherwise specified.
  • the beta-blocker is entirely or substantially entirely timolol and is preferably provided as timolol maleate.
  • the concentration of the beta-blocker in the composition is at least 0.03 w/v%, more typically at least 0.06 w/v% and even more typically at least 0.09 w/v% but is no greater than 0.2 w/v%, more typically no greater than 0.13 w/v% and even more typically no greater than 0.11 w/v%.
  • the concentration of the timolol in the composition is at least 0.03 w/v% but no greater than 0.2 w/v%, more typically at least 0.06 w/v% but no greater than 0.13 w/v% and even more typically at least 0.09 w/v% but no greater than 0.11 w/v%.
  • the beta-blocker is entirely or substantially entirely betaxolol and is preferably provided as betaxolol hydrochloride.
  • the concentration of the beta- blocker in the composition is at least 0.03 w/v%, more typically at least 0.06 w/v% and even more typically at least 0.09 w/v% but is no greater than 0.2 w/v%, more typically no greater than 0.13 w/v% and even more typically no greater than 0.11 w/v%.
  • the concentration of the betaxolol in the composition is at least 0.03 w/v% but no greater than 0.2 w/v%, more typically at least 0.06 w/v% but no greater than 0.13 w/v% and even more typically at least 0.09 w/v% but no greater than 0.11 w/v%.
  • Both the prostaglandin and the beta-blocker are typically substantially entirely dissolved (i.e., at least 95% by weight of total amount of prostaglandin and at least 95% by weight of the total amount of beta-blocker) or entirely dissolved in the composition.
  • the composition typically additionally includes a viscosity enhancing agent and preferably includes two or more viscosity enhancing agents.
  • viscosity enhancing agents suitable for use in the composition include, without limitation, carboxymethyl cellulose, hydroxyethyl cellulose, guar galactomannan (guar gum) polymer (herein also referred to as guar or galactomannan), carboxyvinyl polymer or a combination thereof.
  • the total concentration of the viscosity enhancing agent[s], is typically at least 0.03 w/v%, more typically at least 0.2 w/v% and even more typically at least 0.4 w/v% but is no greater than 5 w/v%, more typically no greater than 3 w/v%, even more typically no greater than 1.0 w/v% and even possibly no greater than 0.8 w/v%.
  • the total concentration of the viscosity enhancing agent[s], when included in the composition is typically at least 0.03 w/v%, but no greater than 3 w/v%, more typically at least 0.2 w/v% but no greater than 1.0 w/v% and even more typically at least 0.4 w/v% but no greater than 0.8 w/v%.
  • the composition includes guar galactomannan polymer or carboxyvinyl polymer. In a highly preferred embodiment the composition includes a combination of both guar galactomannan polymer and carboxyvinyl polymer.
  • carboxyvinyl polymer is a particularly preferred viscosity enhancing agent. It is contemplated that the viscosity enhancing agent can be substantially entirely or entirely carboxyvinyl polymer. Typically, the carboxyvinyl polymer will have a network of cross-linked polymer chains. The polymers are often characterized as having carboxylic acid functional groups and preferably contain from 2 to 7 carbon atoms per functional group. Preferred carboxyvinyl polymers include carbomers, i.e. synthetic high-molecular-weight polymers of acrylic acid that are crosslinked e.g. with allyl sucrose or allyl ethers of pentaerythritol, particularly water-soluble and water- swellable carbomers. Preferred carbomers are available under the trade name CARBOPOL ® from various suppliers The commercially available polymers CARBOPOL ® 934P (Carbomer 934P), 940 and 974P are highly preferred.
  • the concentration of carboxyvinyl polymer, particularly carbomer, when included in the ophthalmic composition of the present invention is typically at least about 0.05 w/v%, more typically at least about 0.2 w/v% even more typically at least about 0.35 w/v%. Moreover, the concentration of carboxyvinyl polymer, particularly carbomer, when included in the ophthalmic composition of the present invention, is typically no greater than about 1.0%, more typically no greater than about 0.6% even more typically no greater than about 0.5%.
  • the concentration of the carboxyvinyl polymer, particularly carbomer, when included in the composition is typically at least 0.05 w/v%, but no greater than 1.0 w/v%, more typically at least 0.2 w/v% but no greater than 0.6 w/v% and even more typically at least 0.35 w/v% but no greater than 0.45 w/v%.
  • compositions of the present invention preferably includes a galactomannan polymer.
  • galactomannans typically derived from guar gum, locust bean gum and tara gum.
  • galactomannan refers to polysaccharides derived from the above natural gums or similar natural or synthetic gums containing mannose or galactose moieties, or both groups, as the main structural components.
  • Preferred galactomannans of the present invention are made up of linear chains of (l-4)-P-D-mannopyranosyl units with a- D-galactopyranosyl units attached by (1-6) linkages.
  • the ratio of D-galactose to D-mannose varies, but generally will be from about 1:2 to 1:4.
  • Galactomannans having a D- galactose:D-mannose ratio of about 1:2 are most preferred.
  • other chemically modified variations of the polysaccharides are also included in the “galactomannan” definition. For example, hydroxyethyl, hydroxypropyl and carboxymethylhydroxypropyl substitutions may be made to the galactomannans of the present invention.
  • Non-ionic variations to the galactomannans, such as those containing alkoxy and alkyl (C1-C6) groups are particularly preferred when a soft gel is desired (e.g., hydroxylpropyl substitutions).
  • Non-cis hydroxyl positions are most preferred.
  • An example of non-ionic substitution of a galactomannan of the present invention is hydroxypropyl guar, with a molar substitution of about 0.4.
  • Anionic substitutions may also be made to the galactomannans.
  • Anionic substitution is particularly preferred when strongly responsive gels are desired.
  • Preferred galactomannan polymer of the present invention are guar, native guar, and hydroxypropyl guar.
  • Native guar is particularly preferred, for example, USP or general grade native guar powder obtained from TIC Gums, Inc.
  • a process for producing a particularly preferred native guar is disclosed in United States Patent Application 20100196415, entitled “Process for Purifying Guar” filed Feb. 5, 2010.
  • a galactomannan polymer when included, is typically present in the composition of the present invention at a concentration that is at least about 0.04 w/v%, more typically at least about 0.13 w/v%, and even more typically at least about 0.18 w/v%.
  • the galactomannan polymer when included, is typically present in the composition of the present invention at a concentration that is no greater than about 0.6 w/v%, more typically no greater than about 0.25 and even more typically no greater than about 0.22 w/v%. %.
  • the concentration of the galactomann polymer when included in the composition, is typically at least 0.04 w/v%, but no greater than 0.6 w/v%, more typically at least 0.13 w/v% but no greater than 0.25 w/v% and even more typically at least 0.18 w/v% but no greater than 0.22 w/v%.
  • Borate compounds are typically used in the compositions of the present invention and such compounds include, but are not limited to, boric acid and other pharmaceutically acceptable salts such as sodium borate (borax) and potassium borate. Borate is typically present at a concentration of 0.2 to 2.0 w/v %, more typically at a concentration of 0.2 to 0.6 w/v% even more typically at a concentration of 0.2 to 0.4 w/v %, and still more typically at about 0.3 w/v % (i.e., 0.3 w/v% ⁇ 0.02 w/v%).
  • boric acid and other pharmaceutically acceptable salts such as sodium borate (borax) and potassium borate.
  • Borate is typically present at a concentration of 0.2 to 2.0 w/v %, more typically at a concentration of 0.2 to 0.6 w/v% even more typically at a concentration of 0.2 to 0.4 w/v %, and still more typically at about 0.3 w/v % (i.e., 0.3
  • borate refers to all pharmaceutically suitable forms of borates, including but not limited to boric acid, and alkali metal borates such as sodium borate and potassium borate. Boric acid is the preferred borate used with embodiments of the present invention.
  • the borate compound when used in in conjunction with the galactomannan polymer, form a galactomannan-borate system in aqueous solution.
  • a borate anion will condense onto the cis-diol groups of a galactomannan molecule, and may cross-link with a second galactomannan molecule.
  • Cross-linking of borate and galactomannan polymer is influenced by factors such as pH, among others, and such cross-linking in turn influences the viscosity of the solution.
  • the pH of the composition is below common physiologic pH (i.e., about 7.4) of the tear film of the eye such that a significant degree of cross-linking of the galactomannan-borate system occurs upon dosing of the composition topically to the eye.
  • the composition of the present invention will have a pH in the range of 4 to 9, preferably 5.5 to 8.5, and most preferably 5.5 to 8.0.
  • the composition particularly where that composition includes a galactomannan-borate system, will have a pH below that aforementioned common physiologic pH.
  • Such preferred pH is typically at least 6.0, more typically at least 6.2 and even more typically at least 6.4 or 6.5 and is typically no greater than 7.3, more typically no greater than 7.1 and even more typically no greater than 7.0 or 6.8.
  • pH is typically at least 6.0 but no greater than 7.3, more typically at least 6.2 but no greater than 7.0, and even more typically at least 6.4 but no greater than 7.0.
  • Sodium hydroxide (NaOH) and/or hydrochloric acid (HC1) may be used in quantities sufficient to adjust the pH of the composition to its target pH.
  • the viscosity of the composition is at least 30 cps, more typically at least 120 cps and even more typically at least 190 cps.
  • the viscosity of the composition is typically no greater than 500 cps, more typically no greater than 300 cps and even more typically no greater than 240 cps.
  • the viscosity of the composition is typically at least 30 cps but no greater than 500 cps, more typically at least 120 cps but no greater than 300 cps and even more typically at least 190 cps but no greater than 240 cps.
  • Viscosity measurements for the composition of the present application are measured using a Brookfield viscometer set at a high shear rate of 24 sec 1 using spindle CP-52 at 12 rpm. Viscosity is typically measured at room temperature, i.e., 25 °C, as would be understood by the skilled artisan.
  • the viscosity of the composition is particularly important.
  • the viscosity can be critical to the droppability, stability and longer retention of the composition on the surface of the eye as compared to low viscosity compositions. This is particularly the case when the composition includes the aforementioned preferred ingredients at their preferred concentrations.
  • this viscosity is particularly important to achieve the desired ocular bioavailability of the prostaglandin (e.g., travoprost) and the beta-blocker (e.g., timolol) when those active ingredients are included in the composition at their preferred concentrations.
  • the viscosity of the composition is typically at least 90 cps, more typically at least 150 cps and even more typically at least 190 cps.
  • the viscosity of the composition is typically no greater than 300 cps, more typically no greater than 270 cps and even more typically no greater than 250 cps or even 240 cps.
  • the viscosity of the composition is typically at least 90 cps but no greater than 300 cps, more typically at least 150 cps but no greater than 270 cps and even more typically at least 190 cps but no greater than 240 cps.
  • composition of the present invention can also include one or more polyols.
  • polyol includes any compound having at least one hydroxyl group on each of two adjacent carbon atoms that are not in trans configuration relative to each other.
  • the polyols can be linear or cyclic, substituted or unsubstituted, or mixtures thereof, so long as the resultant complex is water soluble and pharmaceutically acceptable. Examples of such compounds include: sugars, sugar alcohols, sugar acids and uronic acids.
  • Preferred polyols are sugars, sugar alcohols and sugar acids, including, but not limited to: mannitol, glycerin, xylitol, sorbitol and propylene glycol.
  • the composition includes propylene glycol, glycerin or a combination thereof. Particularly preferred is propylene glycol and, more particularly, the polyol in the composition is entirely or substantially entirely propylene glycol.
  • the concentration of polyol is at least 0.02 w/v% but no greater than 3 w/v%, more typically at least 0.15 w/v% but no greater than 0.5 w/v%, still more typically at least 0.25% w/v% but no greater than 0.40 w/v% or 0.35 w/v%.
  • propylene glycol as entirely or substantially entirely the only polyol in the composition can avoid complications, which may be caused by other polyols such as sorbitol and mannitol.
  • polyols such as mannitol and sorbitol can complex more significantly with borate in the composition forming an anionic complex that can upset the ionic balance of the composition. In turn, this can affect properties of the composition such as viscosity, preservation efficacy or others.
  • the composition of the present invention will typically include one or more preservatives such that the composition can satisfy preservation efficacy testing as described further below.
  • the composition of the present invention may be self -preserved to allow the composition to satisfy preservation efficacy testing.
  • preservative suitable for the composition of the present invention include, without limitation, biguanides, polymeric quaternary ammonium compounds, benzalkonium chloride (BAC), combinations thereof or the like.
  • BAC is a particularly preferred preservative and it is contemplated that the composition be substantially free or entirely free of any preservatives other than BAC.
  • the compositions of the present invention typically include the preservative benzalkonium chloride.
  • benzalkonium chloride (BAC) shall, unless otherwise specifically stated, mean alkyldimethylbenzylammonium chloride (ADBAC) and all derivatives thereof.
  • Derivatives of ADBAC include compounds where the alkyl group of ADBAC has been shortened or lengthened and/or where one or both of the two methyl groups of ADBAC have been changed to a larger alkyl group.
  • BAC is typically in the compositions of the present invention in an amount that is at least about 0.0008 w/v %, more typically at least about 0.002 w/v % and even more typically at least about 0.004 w/v % but no greater than about 0.01 w/v %, more typically no greater than about 0.008 w/v % and even possibly no greater than about 0.006 or even no greater than about 0.005 w/v % of the ophthalmic composition.
  • the concentration of BAC in the composition is at least 0.0008 w/v % but no greater than 0.01 w/v%, more typically at least 0.002 w/v% but no greater than 0.008 w/v% and even possibly at least 0.004 w/v% but no greater than 0.006 or 0.005 w/v%.
  • a surfactant is included in the pharmaceutical composition of the present invention.
  • the surfactant can increase the solubility of the therapeutic agent, particularly the prostaglandin (e.g., travoprost) and/or at least assist in assuring that the agent is distributed evenly in the composition.
  • the surfactant may also promote the ability of that therapeutic agent to penetrate human tissue (e.g., corneal tissue of the eye) thereby further increasing the bioavailability of the agent.
  • the composition of the present invention will typically include surfactant.
  • the pharmaceutical composition can include at least 0.001 w/v% but no greater than 3 w/v%, more typically at least 0.01 w/v% but no greater than 0.5 w/v%, at least 0.05% w/v% but no greater than 0.2 w/v% or 0.1 w/v% surfactant.
  • the surfactant can include non-ionic, an anionic, a cationic, or an amphoteric or zwitterionic surfactant or a combination of such surfactants. It is highly preferred that at least a portion or substantially the entirety of the surfactant be non-ionic for assisting in providing enhanced bioavailability of the therapeutic agent.
  • the phrase“substantially the entirety of the surfactant” is used to suggest either the entirety of the surfactant or the entirety of the surfactant with the exception of a nominal amount of surfactant or both.
  • surfactant examples include, without limitation, ethers of fatty alcohols and/or polyoxyethylene alkyl ethers, e.g., macrogol ethers such as ceto macrogol 1000, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, e.g., the commercially available TweensTM, polyoxyethylene stearates, combinations thereof or the like.
  • macrogol ethers such as ceto macrogol 1000
  • polyoxyethylene castor oil derivatives such as ceto macrogol 1000
  • polyoxyethylene sorbitan fatty acid esters e.g., the commercially available TweensTM, polyoxyethylene stearates, combinations thereof or the like.
  • the amount of surfactant employed can be chosen so as to increase the bioavailability of the therapeutic agent, particularly the prostaglandin (e.g., travoprost).
  • Surfactant that assists in providing for a desired degree of bioavailability according to the present invention is typically composed of agent that exhibits a relatively high hydrophile/lipophile/balance (HLB).
  • HLB hydrophile/lipophile/balance
  • the surfactant of the pharmaceutical composition, particularly the ophthalmic composition has an HLB value greater than 8, preferably greater than 10 and even possibly greater than 12.
  • the surfactant may include polysorbate 20 (TWEEN 20) (polyoxyethylene 20 sorbitan monolaurate), TWEEN 40, TWEEN 60, polysorbate 80 (TWEEN 80), Zwittergent 312, TEEPOL HB7, SPAN 85, pluronic or poloxamers, especially, PLURONIC L62LF, L101, and L64, F68, L44, L121, F-84 and P-103, PEG1000, and/or TETRONIC 1501, 150R1, 701, 901, 1301, and 130R1, poloxamer 333, poloxamer 334, and poloxamer 335, sorbitan oleate, polysorbate 81, polysorbate 85, polysorbate 120, sodium taurocholates, sodium deoxytaurocholates, chenodeoxycholic acid, ursodeoxycholic acid, or combinations thereof.
  • TWEEN 20 polyoxyethylene 20 sorbitan monolaurate
  • TWEEN 40 polyoxyethylene 20 sorbit
  • the surfactant for the present invention is a non-ionic seed, nut and/or vegetable oil-derived surfactant.
  • seed, nut and/or vegetable oils that have been hydrogenated, ethoxylated or both.
  • Such surfactants include, but are not limited, to babassu oil, almond oil, maize oil, palm kernel oil, castor oil, coconut oil, cotton seed oil, jojoba oil, linseed oil, mustard oil, olive oil, peanut oil, safflower oil sesame oil, soybean oil, sunflower- seed oil and wheat germ oil, their hydrogenated or ethoxylated derivatives or combinations thereof.
  • Preferred oils are castor oil, babassu oil, almond oil, maize oil, cababassu oil and palm kernel oil, most preferably castor oil.
  • Particularly preferred surfactants include Polyoxyethylene (POE) (40) Hydrogenated castor oil (or PEG (40 Hydrogenated castor oil) (HCO-40), POE (60) Hydrogenated castor oil (HCO-60), and POE (200) Hydrogenated castor oil (HCO- 200).
  • the surfactant is entirely or substantially entirely hydrogenated and ethoxylated castor oil and even more particularly, Polyoxyethylene (POE) (40) Hydrogenated castor oil.
  • the composition of the present invention is aqueous and therefore includes a substantial concentration of water.
  • the composition typically includes water at a concentration that is at least 90 w/v% but no greater than 99.7 w/v%, more typically at least 96 w/v% but no greater than 99.0 w/v% and even more typically at least 97.5 w/v% but no greater than 98.5 w/v%.
  • compositions of the present invention will have an osmolality of 200 to 400 or 450 milliosmoles per kilogram (mOsm/kg), more preferably 240 to 360 mOsm/kg.
  • the composition includes a salt (e.g., sodium chloride) to adjust the tonicity and viscosity.
  • a salt e.g., sodium chloride
  • the concentration of sodium chloride is typically at least about 0.10 w/v %, more typically at least about 0.3 w/v % and even more typically at least about 0.45 w/v % but no greater than about 0.9 w/v %, more typically no greater than about 0.70 w/v % and even possibly no greater than about 0.55 w/v % of the ophthalmic composition.
  • the concentration of sodium chloride in the composition is at least 0.1 w/v% but no greater than 0.9 w/v%, more typically at least 0.30 w/v% but no greater than 0.70 w/v% and even possibly at least 0.45 w/v% but no greater than 0.55 w/v%.
  • the concentration of salt in the composition can help provide the desired viscosity and/or droppability of the composition.
  • the concentrations of prostaglandin, viscosity enhancing agent and surfactant specified herein are believed to provide the desired bioavailablity of travoprost while avoiding the tachyphylaxis that has been discovered for prostaglandins (e.g., travoprost).
  • compositions that include prostaglandin have shown that relatively high concentrations of a prostaglandin, particularly travoprost, can cause the prostaglandin to be less efficacious in its ability to lower intraocular pressure. While it is typical for higher concentrations of drugs to have similar or better efficacy in treating (e.g., ameliorating, curing or reducing) a malady or symptoms of a malady, it is believed that higher dosing and/or higher concentrations can cause tachyphylaxis in the ability of the prostaglandin to lower intraocular pressure.
  • prostaglandin e.g., travoprost
  • concentrations of prostaglandin in the composition as specified herein will be as effective or more effective at lowering intraocular pressure in humans when compared to the same prostaglandin dosed once a day at a substantially higher concentration in a different vehicle. It is also believed that these lower concentrations of prostaglandin, particularly in the vehicle described herein, may allow for avoidance of side effects such as hyperemia, which are often associated with prostaglandins.
  • the present invention is particularly directed to the provision of multi-dose ophthalmic compositions that have sufficient antimicrobial activity to allow the compositions to satisfy the USP preservative efficacy requirements, as well as other preservative efficacy standards for aqueous pharmaceutical compositions.
  • PET Preservative Efficacy Test
  • compositions of the present invention will generally be formulated as sterile aqueous compositions.
  • the compositions of the present invention are also formulated so as to be compatible with the eye and/or other tissues to be treated with the compositions.
  • the ophthalmic compositions intended for direct application to the eye will be formulated so as to have a pH and tonicity that are compatible with the eye.
  • the present invention is also directed to a method of reducing intraocular pressure.
  • the method includes reducing intraocular pressure in a subject having elevated intraocular pressure or diagnosed with glaucoma, preferably open angle glaucoma, or ocular hypertension.
  • the method comprises topically applying any one of the compositions described herein topically to an eye.
  • the eye is a human eye and the step of topical application is performed once a day. It is also preferable that the step of topical application is performed by expelling a single drop of the composition from a container onto the eye.
  • the present invention also includes the use of a composition as recited herein, for use in reducing intraocular pressure in a subject.
  • the compositions recited herein are used in treating diseases and conditions caused by elevated or increased intraocular pressure in a subject. Examples of diseases caused by elevated intraocular pressure include ocular hypertension, and open angle glaucoma.
  • the present invention is also directed to an article comprised of the composition described herein, wherein the composition is disposed within packaging and the packaging includes instructions for the composition to be administered once daily.
  • the packaging preferably includes a container configured to expel one drop of the composition at a time and the instructions for administration instruct that the composition be administered as a single drop once daily to one eye or both eyes of an individual.
  • concentrations of Betaxolol (provided as Betaxolol HC1) and Timolol (provided as Timolol Maleate) refer respectively to the concentrations of Betaxolol and Timolol and not the concentrations of the Betaxolol HC1 and Timolol Maleate.
  • Table 1 Aqueous humor Cmax (ng/mL) and AUC0-6h (ng*h/mL) for travoprost add following topical ocular administration to male New Zealand white rabbits
  • Table 2 Aqueous humor Cmax (ng/mL) and AUC0-6h (ng*h/mL) for timolol free base following topical ocular administration to male New Zealand white rabbits
  • Table 3 Plasma Cmax (ng/mL) and AUC0-4h (ng*h/mL) for timolol free base following topical ocular administration to male New Zealand White rabbits
  • the travoprost exposure in aqueous humor of the original marketed composition (Cmax 17.6 ng/mL and AUC 48.1 ng*h/mL) is similar to that of the composition of the present invention with timolol 0.1% (Cmax 15.8 ng/mL and AUC 49.5 ng*h/mL).
  • the timolol aqueous humor levels for composition of the present invention containing 0.1% timolol as presented in Table 2 (Cmax 625 ng/mL and AUC 815 ng*h/mL) are similar to marketed composition containing 0.5% timolol (Cmax 792 ng/mL and AUC 1120 ng*h/mL).
  • the timolol plasma concentrations for marketed composition are about 5x higher than the composition of the present invention (Cmax 2.14 ng/mL and AUC 2.20 ng*h/mL).

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Abstract

La présente invention concerne une composition ophtalmique qui comprend une prostaglandine, un bêta-bloquant et un ou plusieurs agents améliorant la viscosité. L'invention concerne également un article contenant la composition et des procédés d'utilisation de la composition. La composition est typiquement appropriée pour une application topique sur un œil d'un mammifère une fois par jour. En outre, la composition comprend des concentrations du bêta-bloquant et de la prostaglandine qui produisent une diminution souhaitable de la pression intraoculaire.
PCT/IB2018/060275 2017-12-20 2018-12-18 Composition ophtalmique comprenant une prostaglandine et un bêta-bloquant WO2019123266A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100196415A1 (en) 2009-02-05 2010-08-05 Alcon Research, Ltd. Process for purifying guar
US20120122976A1 (en) * 2009-05-14 2012-05-17 Ursapharm Arzneimittel Gmbh Phosphate-free pharmaceutical composition for the treatment of glaucoma
US8268299B2 (en) 2006-09-21 2012-09-18 Alcon Research, Ltd. Self preserved aqueous pharmaceutical compositions

Patent Citations (3)

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Publication number Priority date Publication date Assignee Title
US8268299B2 (en) 2006-09-21 2012-09-18 Alcon Research, Ltd. Self preserved aqueous pharmaceutical compositions
US20100196415A1 (en) 2009-02-05 2010-08-05 Alcon Research, Ltd. Process for purifying guar
US20120122976A1 (en) * 2009-05-14 2012-05-17 Ursapharm Arzneimittel Gmbh Phosphate-free pharmaceutical composition for the treatment of glaucoma

Non-Patent Citations (2)

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Title
RONALD L FELLMAN ET AL: "Comparison of travoprost 0.0015% and 0.004% with timolol 0.5% in patients with elevated intraocular pressure: A 6-month, masked, multicenter trial", OPHTHALMOLOGY., vol. 109, no. 5, 1 January 2002 (2002-01-01), US, pages 998 - 1008, XP055580609, ISSN: 0161-6420, DOI: 10.1016/S0161-6420(02)01010-2 *
URTTI A ET AL: "Minimizing systemic absorption of topically administered ophthalmic drugs", SURVEY OF OPHTHALMOLOGY, SURVEY OF OPHTHALMOLOGY INC, XX, vol. 37, no. 6, 1 May 1993 (1993-05-01), pages 435 - 456, XP026333273, ISSN: 0039-6257, [retrieved on 19930501], DOI: 10.1016/0039-6257(93)90141-S *

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