EP3082427A1 - Zusammensetzungen und verfahren zur behandlung von glaukomen - Google Patents

Zusammensetzungen und verfahren zur behandlung von glaukomen

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Publication number
EP3082427A1
EP3082427A1 EP14872240.8A EP14872240A EP3082427A1 EP 3082427 A1 EP3082427 A1 EP 3082427A1 EP 14872240 A EP14872240 A EP 14872240A EP 3082427 A1 EP3082427 A1 EP 3082427A1
Authority
EP
European Patent Office
Prior art keywords
concentration
pharmaceutical composition
buffer
dexmedetomidine
composition
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP14872240.8A
Other languages
English (en)
French (fr)
Other versions
EP3082427A4 (de
Inventor
Gerald Horn
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
GNT LLC
Original Assignee
GNT LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US14/132,780 external-priority patent/US20140107173A1/en
Application filed by GNT LLC filed Critical GNT LLC
Publication of EP3082427A1 publication Critical patent/EP3082427A1/de
Publication of EP3082427A4 publication Critical patent/EP3082427A4/de
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/186—Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide
    • 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
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics

Definitions

  • Glaucoma is a multifactorial disease which encompasses a spectrum ranging from elevated intraocular pressure ("IOP") to reduced vascular perfusion of the optic nerve.
  • IOP intraocular pressure
  • glaucoma patients require two or more drugs for satisfactory control of their intraocular pressure.
  • the prostaglandins/prostanoids including Xalatan ® (latanoprost; Xalatan is a registered trademark of Pfizer Health AB), Travatan ® (travoprost; Travatan is a registered trademark of Novartis AG) and Lumigan ® (bimatoprost; Lumigan is a registered trademark of Allergan, Inc.
  • the two drugs should have different mechanisms of action.
  • Brimonidine a known alpha-2 (a-2) adrenergic receptor agonist, typically causes moderate peak IOP reduction of about 20-25% in ocular hypertensive eyes and 6-18% in normotensive eyes (less than 21 mm Hg). Its peak effect is within 2 hours of instillation, its duration of effect is typically less than 12 hours, and its moderate efficacy usually requires dosing of 2-3 times a day. It is one of the leading secondary drugs, with a mechanism of action of aqueous suppression that complements the prostaglandin/prostanoids uveal scleral outflow enhancement for significant additive benefit, but about equal to other second line glaucoma drugs such as beta-blockers and carbonic anhydrase inhibitors.
  • brimonidine is the only commercially available a-2 agonist, proving safer and/or more effective than predecessors agonist which it has been compared, including clonidine (i.e. fewer instances of systemic hypotension and/or bradycardia), apraclonidine (i.e. fewer instances of tachyphylaxis), and dexmedetomidine (i.e. less systemic sedation, greater IOP reduction efficacy).
  • clonidine i.e. fewer instances of systemic hypotension and/or bradycardia
  • apraclonidine i.e. fewer instances of tachyphylaxis
  • dexmedetomidine i.e. less systemic sedation, greater IOP reduction efficacy
  • brimonidine may induce substantial local side effects in 10-25% of users, such as conjunctival hyperemia (i.e.
  • brimonidine a-2 agonists, including brimonidine, clonidine and dexmedetomidine, induce substantial systemic effects if absorbed into the circulation, and are specifically known to increase fatigue, decrease blood pressure (i.e. hypotension) and lower the heart rate (i.e. bradycardia).
  • brimonidine has been the only commercially available a-2 agonist, due to its demonstrated combination of superior IOP reduction with greatly reduced risk of systemic side effects versus all other a-2 agonists attempted for this purpose, despite its less than optimal side effect profile and modest efficacy relative to prostaglandins/prostanoids.
  • compositions and methods effective for the treatment of glaucoma in a patient in need thereof are formulated to prevent sedation, eliminate or reduce redness, eliminate or reduce ocular allergy, as well as significantly reduce intraocular pressure.
  • the provided compositions may also have an eye whitening effect.
  • the compositions include all of the above benefits and also have neuroprotective benefits and may be used for optic nerve protection, including the treatment of neurodegenerative conditions, such as ischemic optic neuropathy, diabetic retinopathy, optic ischemia, retinal vascular ischemia, and other optic neuropathies, particularly those involving retinal ganglion cells and/or axons at or near the optic nerve lamina.
  • the formulation preferably has the following non-
  • the elastic modulus increases about 200 to 1000 fold within 1-2 seconds during the low shear force interblink period of each cycle, more preferably at least 2000 fold, and still more preferably at least 4000 fold, and where during the blink phase such modulus is less than 100, preferably less than 10, and more preferably about 0;
  • the invention provides novel formulations of dexmedetomidine, which are surprisingly found to be much more effective for the treatment of glaucoma than brimonidine.
  • These novel inventive formulations share some or all of the following characteristics: a) a high selectivity for a-2 over a-1 adrenergic receptors, such as 1000: 1 or greater; more preferably 1500: 1 or greater; and even more preferably 2000: 1 or greater;
  • c) include an anionic cyclodextrin such as Captisol ® (Captisol is a registered trademark of Cydex Pharmaceuticals), other cyclodextrins, or other nonionic surfactants such as poloxamer or a polyoxyl alkyl at specified concentration range, and one or more specific viscosity enhancers (also interchangeably referred to as a "gelling agents").
  • an anionic cyclodextrin such as Captisol ® (Captisol is a registered trademark of Cydex Pharmaceuticals)
  • other cyclodextrins or other nonionic surfactants such as poloxamer or a polyoxyl alkyl at specified concentration range
  • one or more specific viscosity enhancers also interchangeably referred to as a "gelling agents”
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising: an a-2 adrenergic receptor agonist at a concentration from between about 0.0125% to about 0.125%) weight by volume, wherein said a-2 adrenergic receptor has a Log P value of 2.0 or greater and has a binding affinity of 950 fold or greater for a-2 over a-1 adrenergic receptors;
  • a cyclodextrin or a poloxamer or a polyoxyl alkyl at a concentration of between 2%> and 12% weight by volume or less;
  • the cyclodextrin, poloxamer or polyoxyl alkyl is present at concentration range of 3% to 10% by weight; and more preferably, at 5% to 6% by weight.
  • a surfactant selected from polyoxyl 40 stearate, a cyclodextrin, gamma cyclodextrin and Captisol ® at a concentration from about 1% to about 15% w/v, more preferably polyoxyl 40 stearate or Captisol ® at a concentration of about 5.5% w/v;
  • an antioxidant at a concentration from about 0.005% to about 0.05% w/v, preferaby at 0.015% w/v, preferably the antioxidant is sodium
  • a pH from about 4.0 to about 8.0, preferably from about 6.0 to about 7.0.
  • the present invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising: i. dexmedetomidine at a concentration from about 0.060% to about 0.087% w/v; ii. polyoxyl 40 stearate at a concentration of about 5.5% w/v;
  • benzalkonium chloride at a concentration of about 0.02% w/v
  • sodium lauryl sulfate at a concentration from about 0.01% to about 5.0% w/v, preferably at 0.50%> w/v;
  • EDTA at a concentration of about 0.015% w/v
  • a phosphate buffer at a concentration from about 1 to about 5
  • pH of the composition is from about 6.0 to about 7.0.
  • the present invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising:
  • dexmedetomidine at a concentration from about 0.06% to 0.087% w/v;
  • benzalkonium chloride at a concentration of about 0.02% w/v
  • v. sodium lauryl sulfate at a concentration from about 0.1% to about 1.0% w/v, preferably at 0.50%> w/v;
  • an antioxidant is at a concentration of about 0.015% w/v; and vii. optionally a phosphate buffer at a concentration from about 1 to about 5
  • the present invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising: i. dexmedetomidine at a concentration of about 0.080% w/v;
  • the mucoadhesive is at a concentration from between about
  • inventive compositions may provide optic nerve protection, retinal ganglion cell neuroprotection, an increase in a-2 agonist concentration in the inner retinal plexiform, and additional neuroprotective benefits. They may also increase the outfiow at the trabecular meshwork which is populated with endothelial cells and believed to be populated with a-2a receptors in humans.
  • compositions of the invention may be used to reduce eye redness and/or increase eye whiteness in subjects in need thereof.
  • the concentration of a poloxamer, a polyoxyl alkyl, or a cyclodextrin should be within the 15% to 25% range, at which gelling effect at room temperature is known to occur by which corneal retention is prolonged but with substantial prolonged blurring on instillation of minutes or more, and/or at the physiologic range of tonicity enhancers.
  • a poloxamer, a polyoxyl alkyl, or a cyclodextrin is effective in the provided combinations when it is present at 12% or less, and preferably at more than 3% but less than 10%.
  • a poloxamer, a polyoxyl alkyl, or a cyclodextrin is present at a concentration of 15% or greater or much less than 2%, the compositions are surprisingly less effective or ineffective.
  • viscosity enhancers at too low concentrations resulted in surprisingly more side effects and reduced efficacy, and that viscosities are reduced up to or more than 100 fold within the inventive formulations, such that a 1% CMC solution in water of 2,500 cps will be about 100 to 250 cps on initial instillation of a preferred embodiment. It has also been found that the use of viscosity enhancers by themselves (i.e., without a poloxamer, a polyoxyl alkyl or a cyclodextrin) results in much less effective formulations with prolonged blurring on instillation, greater systemic absorption, and in general less efficacy and more side effects.
  • the tonicity of the provided formulations is at 0 to 200 mOsm/kg, and preferably at 50 to 150 mOsm/kg, a sustained wetting/lubricating effect will result with minimal blurring and the greater comfort for the patients.
  • an ophthalmic vehicle requires 280-310 mOsm/kg, which is achieved through the use of electrolytes or polyols (e.g. mannitol).
  • cyclodextrins and more preferably the sulfobutyl ether derivative of ⁇ -cyclodextrin (Captisol ® ) enhance the topical redness reduction whitening effect of the a-2 agonist, particularly dexmedetomidine; and whereby such preferred cyclodextrins further enhance intraocular pressure reduction.
  • Captisol ® the sulfobutyl ether derivative of ⁇ -cyclodextrin
  • compositions and methods are effective for the treatment of glaucoma.
  • the compositions of the invention are formulated to prevent sedation, eliminate or reduce redness, may increase duration of therapeutic action and reduce the incidence of rebound hyperemia and/or other allergic reaction, as well as more significantly reduce intraocular pressure than prior art formulations of a-2 agonists.
  • contralateral eye IOP is 90-100% of the IOP of the treated eye, due to very high systemic absorption (vs. about 10%> systemic absorption with the compositions of the present invention).
  • formulations of the present invention provide the
  • IOP reduction of about 40% at 4 hours in a treated eye is greater than that found for the most optimized formulation of brimonidine (Alphagan ® P at 0.1%, pH 7.4 or greater), which is about 20%> in a treated eye.
  • brimonidine Alphagan ® P at 0.1%, pH 7.4 or greater
  • Every 1 mm Hg reduction in IOP may result in substantial prevention of visual field loss.
  • the longer duration of effect of the present invention creates a substantial effect over a 24 hour period, while a single dose of the conventional brimonidine formulations provides the IOP reduction effect for only about 12 hours or less.
  • the invention also provides improved wetting and comfort, lasting up to an hour after instillation.
  • the beneficial effects of the provided compositions include:
  • a-2 agonists such as apraclonidine and brimonidine
  • a-2 agonists such as apraclonidine and brimonidine
  • a-2 agonists such as apraclonidine and
  • compositions include selectivity for a-2 versus a-1 adrenergic receptors, lipophilicity, tonicity and solubility.
  • potency, activity or EC50 at an a-1 A receptor can be determined by assaying for intracellular calcium.
  • Intracellular calcium can be assayed, without limitation, in HEK293 cells stably expressing an a-1 A receptor, such as a bovine a-1 A receptor.
  • compositions and methods of the invention include selective a-2 adrenergic receptor agonists which have K; for a-2 over a-1 receptors of 1500 fold or greater and have an octanol-water partition coefficient of about Log P 2.50 - 3.0 adjusted however for topical pH (Log D) to be between 0.75 and 3.08.
  • Gut D topical pH
  • Tears and intraocular fluids are physiologic at pH 7.4, which is equal to pH at Log P and, according to the precepts of the present invention, confers IOP reduction benefits.
  • compositions and methods of the invention include selective a-2 adrenergic receptor agonists which have IQ for a-2 over a-1 receptors of 1000 fold or greater and are at a concentration from between about 0.0035% to about 0.035% weight by volume.
  • Brimonidine, guanfacine, guanabenz, dexmedetomidine and fadolmidine are some of the sufficiently highly selective a-2 agonists to satisfy the selectivity requirement.
  • these highly selective a-2 agonists only dexmedetomidine satisfies other additional preferred formulation characteristics of the present invention, such as lipophilicity.
  • Other a-2 agonists, such as clonidine, may be sufficiently lipophilic but lack sufficient selectivity.
  • a-2 adrenergic receptor agonist suitable for purposes of the invention is dexmedetomidine as either the HC1 salt, or as the citrate salt.
  • Other salts may similarly be substituted for the HC1.
  • compositions and methods of the invention include dexmedetomidine, or another selective a-2 adrenergic receptor agonist, at a concentration from between about 0.0125%) to about 0.125%) weight by volume; preferably, between about 0.025%> to about 0.125% weight by volume; more preferably between about 0.045% and about 0.10% weight by volume and even more preferably between about 0.060%) and about 0.087%.
  • Lipophilicity may be measured, for example, using known measurements, such as
  • Log P log Kow derivation of the octanol-water partition coefficient and/or, a closely related coefficient, XLogP3-AA. See, for example, Tiejun Cheng et al, Computation of Octanol-Water Partition Coefficients by Guiding an Additive Model with Knowledge, J. Chem. Inf. Model., 2007, 47 (6), pp 2140-2148. These measurements represent the intraocular lipophilicity value of topical drugs for intraocular delivery (i.e., once the drug permeates into the anterior chamber and is at a pH of 7.4). A person of ordinary skill in the art is well familiar with these measurements. Thus, the Log P value is the octanol-water coefficient at pH 7.4, i.e., physiologic pH.
  • Log P and/or XLogP3-AA are measured when the formulation at issue is or will be at the physiologic pH of about 7.4.
  • the range between +2.0 and +3.0 typically allows for the best compromise between: a) the need for a highly lipophilic drug to penetrate the lipophilic corneal epithelium, and to a lesser extent, the very thin inner corneal membrane called Descemet's membrane, and b) a highly hydrophilic drug to penetrate the stroma, which is the middle layer of the corneal "sandwich" that must be penetrated for effective ophthalmic absorption.
  • the disclosed combination of a poloxamer, a viscosity enhancer and a hypotonic solution at the disclosed concentration ranges provides a delivery vehicle for dexmedetomidine (and, it is believed, for other mild to highly lipophilic drugs) that is independent of pH and largely independent of the individual drug's lipophilicity.
  • the optimal pH of the provided formulations is such pH that results in a Log "D" value for the drug (the initial topical lipophilicity) of between 0.75 and 3.08, and more preferably between 0.92 and 2.98, representing the maximum pH range of 4.0 to 8.0, and the preferred pH range of 4.5 to 7.0 for optimal comfort and stability.
  • inventive formulations i.e., those formulations including all of the required ingredients at the required concentrations
  • the efficacy of the inventive formulations no longer appears to be reduced by any particular buffers, including phosphate buffer.
  • buffers including phosphate buffer.
  • specific combination of the ingredients in the inventive formulations confers this pH independence and increased solubility range on a variety of active drugs, both for glaucoma and other purposes, as well as provides increased absorption and reduced systemic side effects; including but not limited to steroidals, nonsteroidals, anti-infectives (antivirals and antimicrobials), and macular degeneration drug treatments such as anti-VEGF.
  • the preferred Log P (and XLogP3-AA) values - those that define intraocular performance according to the present invention - that are suitable for the purposes of the invention are between about 1.00 and 4.50; and more preferably, between about 2.0 and 3.50. If the selectivity of a specific a-2 agonist is substantially above 1000: 1 (for example, 1500: 1), additional advantages are believed to be conferred via greater a-2 agonist binding and reduced a- 1 agonist induced ischemia. For example, optic nerve damage progression is known to be highly sensitive to circulation change and ischemia. Because the drug is used over an extended period of time, even small reductions in unintended a-1 agonist-induced ischemia may be beneficial.
  • the a-2 agonist intraocular lipophilicity as represented by Log P, and selectivity as represented by the ⁇ -2: ⁇ -1 receptor recruitment ratio, appear to be very important for greater efficacy of an a-2 agonist glaucoma drug. If the selectivity is above, for example, 2000: 1, then it is possible that this agonist may be effective for the purposes of the invention at slightly reduced lipophilicity, and vice versa.
  • Table 1 provides known XLogP3-AA values (a more accurate Log P) and a2/al binding affinities for several a-2 agonists.
  • Table 1 demonstrates that among the listed a-2 agonists, only dexmedetomidine has an optimal combination of high lipophilicity (XLogP3-AA) and highly selective a2:al coefficient. However, it is possible that formulations including other a-2 agonists can be achieved which meet the defined requirements of the present invention in both selectivity and lipophilicity categories.
  • dexmedetomidine or another selective a-2 adrenergic receptor agonist, has Log P at an intraocular pH 7.4 of about 3.10; preferably, between about 2.0 and 5.00; and more preferably between about 2.75 and 3.50.
  • Log D refers to a lipophilicity value at a given pH
  • this measurement is especially useful to determine the level of topical lipophilicity and resultant corneal permeability of a topical composition through the highly lipophilic corneal epithelium.
  • 0.75 and about 2.20, and more particularly between about 1.00 and about 1.50, are preferred for increased corneal permeation of dexmedetomidine and other similar a-2 agonists in normal saline, preferably below the pH of 6.4 to 6.5, and that the "vehicle" of the present invention including poloxamer, viscosity enhancer and hypotonic saline or sterile water greatly reduces and likely totally eliminates such pH limitations.
  • Tonicity adjusters include, but are not limited to, a salt such as sodium chloride, potassium chloride, dextran, cyclodextrins, mannitol, dextrose, glycerin, or another pharmaceutically or ophthalmically acceptable tonicity adjustor.
  • the tonicity modifying agents are present at a concentration of between 0.1% and 1% weight by volume.
  • Polysorbate 80 0.050% 0.050% 0.050% 0.050% 0.050% 0.050% 0.050% 0.050% 0.050% 0.050% 0.050% 0.050%
  • compositions with lowest side effect profile are those which contain poloxamer at about 5-6%, CMC, sodium chloride and BAK.
  • the peak dose response IOP reduction for preferred embodiments of the present invention appeared to be between about 0.070% - 0.10%.
  • a formulation comprising 0.08% dexmedetomidine, 5.5% polyoxyl 40 stearate,
  • composition C dexmedetomidine at 0.01%, phosphate buffered to pH 6.4 (Composition C); and c) dexmedetomidine at 0.1% with 5% Poloxamer 407 (F127), 0.25% NaCl, CMC high blend 0.75%>, and BAK 0.02%> at pH 6.1 (Composition A) (preferred embodiment).
  • Composition B (20% (16.6% 15 (6.6% (6.6% 33% reduction) reduction) reduction)
  • Composition C (20% (20% (16.6% (13.4% 83% reduction) reduction) reduction)
  • composition A two-fold greater IOP peak % reduction in the treated eye with the inventive formulation
  • Composition B two-fold greater iOP peak % reduction in the treated eye with the inventive formulation
  • composition A two-fold less IOP % reduction in the non-treated eye with the inventive formulation
  • Composition B two-fold less IOP % reduction in the non-treated eye with the inventive formulation
  • composition A inventive formulation
  • Composition C alternative dexmedetomidine formulation
  • composition A Longer duration of action to peak IOP reduction for the inventive formulation (Composition A) increasing from 2.5 hours to 4 hours vs. brimonidine (Composition B).
  • a greater differential of IOP reduction between treated and non-treated eye using the inventive compositions represents a lower systemic side effect profile as it is interpreted to correlate with reduced systemic absorption of drug reaching the non-treated eye.
  • IOP was measured at one or more of 4 hrs, 8 hrs, 12 hrs, 24 hrs, 32 hrs and comfort and side effect profile were qualitatively assessed.
  • the tested inventive formulation achieved a peak IOP reduction effect at about 4 to 8 hours after instillation. Furthermore, in two out of three patients the IOP remained below the baseline 24 hours after instillation.
  • conventional brimonidine formulations achieve a peak IOP reduction effect of only about 15-18% in normotensive eyes about 2-3 hours after instillation.
  • the IOP reduction effect of the inventive formulation was much stronger: from 41.7% to 58.8% at 8 hours after instillation.
  • the formulations of the invention demonstrate improved performance over brimonidine as well as other known glaucoma drugs under similar conditions of testing (1-2 days of use, normotensive eyes).

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EP14872240.8A 2013-12-18 2014-02-11 Zusammensetzungen und verfahren zur behandlung von glaukomen Withdrawn EP3082427A4 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US14/132,780 US20140107173A1 (en) 2011-02-03 2013-12-18 Compositions and Methods for Treatment of Glaucoma
PCT/US2014/015797 WO2015094392A1 (en) 2013-12-18 2014-02-11 Compositions and methods for treatment of glaucoma

Publications (2)

Publication Number Publication Date
EP3082427A1 true EP3082427A1 (de) 2016-10-26
EP3082427A4 EP3082427A4 (de) 2017-08-02

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EP14872240.8A Withdrawn EP3082427A4 (de) 2013-12-18 2014-02-11 Zusammensetzungen und verfahren zur behandlung von glaukomen

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EP (1) EP3082427A4 (de)
JP (1) JP2017501224A (de)
CN (1) CN106455567A (de)
BR (1) BR112016014404A2 (de)
CA (1) CA2934453A1 (de)
MX (1) MX2016007902A (de)
WO (1) WO2015094392A1 (de)

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JP2019508472A (ja) * 2016-03-17 2019-03-28 プレスバイオピア・セラピーズ・エル・エル・シー 老視の処置のための組成物及び方法
CN111481506B (zh) * 2019-01-25 2023-01-24 江苏恒瑞医药股份有限公司 一种包含经鼻给药的右美托咪定组合物的药物制品
CN116474219A (zh) * 2019-06-28 2023-07-25 四川普锐特药业有限公司 保持给药均一度的药物流体分配器及右美托咪定鼻喷器
WO2020259440A1 (zh) * 2019-06-28 2020-12-30 四川普锐特药业有限公司 右美托咪定鼻喷剂、其制备方法及应用
CN111632025A (zh) * 2020-03-04 2020-09-08 吉林大学第一医院 一种贝美前列素眼用温度敏感型原位凝胶及其制备方法与应用
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