WO2011071620A1 - Stable aqueous compositions of prostglandin agonist prodrugs and methods for use thereof - Google Patents

Stable aqueous compositions of prostglandin agonist prodrugs and methods for use thereof Download PDF

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WO2011071620A1
WO2011071620A1 PCT/US2010/055590 US2010055590W WO2011071620A1 WO 2011071620 A1 WO2011071620 A1 WO 2011071620A1 US 2010055590 W US2010055590 W US 2010055590W WO 2011071620 A1 WO2011071620 A1 WO 2011071620A1
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composition
carboxylic acid
alkyl
prostanoid
acute
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PCT/US2010/055590
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English (en)
French (fr)
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Robert M. Burk
Wha Bin Im
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Allergan, Inc.
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Priority to CN201080063225.1A priority Critical patent/CN102762195B/zh
Priority to EP10782082A priority patent/EP2509582A1/en
Priority to CA2783707A priority patent/CA2783707A1/en
Priority to JP2012543111A priority patent/JP5955774B2/ja
Priority to NZ600577A priority patent/NZ600577A/en
Application filed by Allergan, Inc. filed Critical Allergan, Inc.
Priority to AU2010328555A priority patent/AU2010328555B2/en
Priority to RU2012127869/15A priority patent/RU2012127869A/ru
Priority to SG2012042461A priority patent/SG181600A1/en
Priority to MX2012006622A priority patent/MX2012006622A/es
Publication of WO2011071620A1 publication Critical patent/WO2011071620A1/en
Priority to IL220240A priority patent/IL220240A0/en

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    • 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
    • A61K47/12—Carboxylic acids; Salts or anhydrides 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
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
    • 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
    • A61K31/559—Eicosanoids, e.g. leukotrienes or prostaglandins having heterocyclic rings containing hetero atoms other than oxygen
    • 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
    • A61K47/02—Inorganic 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
    • A61K47/06—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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/10—Ophthalmic agents for accommodation disorders, e.g. myopia

Definitions

  • the present invention relates generally to compositions of prodrugs of prostanoid agonists and more specifically to stable aqueous compositions of the prostanoid agonists prodrugs and methods for use thereof.
  • Ocular hypotensive agents are useful in the treatment of a number of various ocular hypertensive conditions, such as post-surgical and post-laser trabeculectomy ocular hypertensive episodes, glaucoma, and as presurgical adjuncts.
  • Glaucoma is a disease of the eye characterized by increased intraocular pressure. On the basis of its etiology, glaucoma has been classified as primary or secondary. For example, primary glaucoma in adults (congenital glaucoma) may be either open-angle or acute or chronic angle-closure. Secondary glaucoma results from pre-existing ocular diseases such as uveitis, intraocular tumor or an enlarged cataract.
  • the underlying causes of primary glaucoma are not yet known.
  • the increased intraocular tension is due to the obstruction of aqueous humor outflow.
  • chronic open- angle glaucoma the anterior chamber and its anatomic structures appear normal, but drainage of the aqueous humor is impeded.
  • acute or chronic angle-closure glaucoma the anterior chamber is shallow, the filtration angle is narrowed, and the iris may obstruct the trabecular meshwork at the entrance of the canal of Schlemm. Dilation of the pupil may push the root of the iris forward against the angle, and may produce pupilary block and thus precipitate an acute attack. Eyes with narrow anterior chamber angles are predisposed to acute angle- closure glaucoma attacks of various degrees of severity.
  • Secondary glaucoma is caused by any interference with the flow of aqueous humor from the posterior chamber into the anterior chamber and subsequently, into the canal of Schlemm.
  • Inflammatory disease of the anterior segment may prevent aqueous escape by causing complete posterior synechia in iris bombe, and may plug the drainage channel with exudates.
  • Other common causes are intraocular tumors, enlarged cataracts, central retinal vein occlusion, trauma to the eye, operative procedures and intraocular hemorrhage.
  • glaucoma occurs in about 2% of all persons over the age of 40 and may be asymptotic for years before progressing to rapid loss of vision.
  • topical -adrenoreceptor antagonists have traditionally been the drugs of choice for treating glaucoma.
  • Eicosanoids and their derivatives have been reported to possess ocular hypotensive activity, and have been recommended for use in glaucoma management.
  • Eicosanoids and derivatives include numerous biologically important compounds such as prostanoids and their derivatives.
  • Prostanoids can be described as derivatives of prostanoic acid which have the following structural formula:
  • prostanoids are known, depending on the structure and substituents carried on the alicyclic ring of the prostanoic acid skeleton. Further classification is based on the number of unsaturated bonds in the side chain indicated by numerical subscripts after the generic type of prostanoid (e.g. prostanoid Ei (PGEi), prostanoid E 2 (PGE 2 )), and on the configuration of the substituents on the alicyclic ring indicated by or (e.g. prostanoid F 2 (PGF 2 )].
  • PGEi prostanoid Ei
  • PGE 2 prostanoid E 2
  • PPF 2 prostanoid F 2
  • Prostanoids were earlier regarded as potent ocular hypertensives, however, evidence accumulated in the last two decades shows that some prostanoids are highly effective ocular hypotensive agents, and are ideally suited for the long-term medical management of glaucoma (see, for example, Bito, L. Z. Biological Protection with Prostanoids, Cohen, M. M., ed., Boca Raton, Fla., CRC Press Inc., 1985, pp. 231-252; and Bito, L. Z., Applied Pharmacology in the Medical Treatment of Glaucomas Drance, S. M. and Neufeld, A. H. eds., New York, Grune & Stratton, 1984, pp. 477-505.
  • Such prostanoids include PGF 2 PGFi , PGE 2 , and certain lipid-soluble esters, such as Ci to C 2 alkyl esters, e.g. l-isopropyl ester, of such compounds.
  • prostanoids appear to be devoid of significant intraocular side effects
  • ocular surface (conjunctival) hyperemia and foreign-body sensation have been consistently associated with the topical ocular use of such compounds, in particular PGF 2 and its prodrugs, e.g., its 1 -isopropyl ester, in humans.
  • the clinical potentials of prostanoids in the management of conditions associated with increased ocular pressure, e.g. glaucoma are greatly limited by these side effects.
  • an ester is a compound which is converted to a therapeutically active compound after administration, and the term should be interpreted as broadly herein as is generally understood in the art. While not intending to limit the scope of the invention, conversion may occur by hydrolysis of an ester group or some other biologically labile group. Generally, but not necessarily, an ester is inactive or less active than the therapeutically active compound to which it is converted.
  • the present invention is based on the discovery that a marked increase in aqueous stability (and thereby shelf life) of prostanoid agonist compositions is achieved by incorporating into the compositions certain well-defined carboxylic acids, and thereafter adjusting the pH of the compositions from about 4.0 to about 8.0.
  • the compositions and methods of the invention provide the aqueous stability required for marketable topical drug treatments of a wide variety of ocular disorders.
  • compositions including an ester of a prostanoid agonist, a carboxylic acid, sodium phosphate dibasic, sodium chloride, a solubilizing agent, and the remainder water, wherein the pH of the composition is adjusted from about 4 to about 8.
  • aqueous stability to a composition including an ester of a prostanoid agonist.
  • Such methods can be performed, for example, by adding a carboxylic acid to the composition and thereby adjusting the pH to from 4 to about 8.
  • methods for treating an ocular disorder can be performed, for example, by administering to a subject in need thereof a therapeutically effective amount of a composition including an ester of a prostanoid agonist, a carboxylic acid, sodium phosphate dibasic, sodium chloride, a solubilizing agent, and the remainder water, wherein the pH of the composition is adjusted from about 4 to about 8.
  • alkyl refers to straight or branched chain hydrocarbyl groups having from 1 up to about 100 carbon atoms. Whenever it appears herein, a numerical range, such as “1 to 100" or “Ci-Cioo”, refers to each integer in the given range; e.g. , "Ci-Cioo alkyl” means that an alkyl group may comprise only 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. , up to and including 100 carbon atoms, although the term “alkyl” also includes instances where no numerical range of carbon atoms is designated.
  • Substituted alkyl refers to alkyl moieties bearing substituents including alkyl, alkenyl, alkynyl, hydroxy, oxo, alkoxy, mercapto, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, halogen, haloalkyl, cyano, nitro, nitrone, amino, lower alkylamino, lower alkyldiamino, amido, azido, -C(0)H, -C(0)R 7 , -CH 2 OR 7 , -C(O)-, -C(O)-, -S-,
  • R 7 is H or lower alkyl, acyl, oxyacyl, carboxyl, carbamate, sulfonyl, sulfonamide, sulfuryl, and the like.
  • lower alkyl refers to alkyl moieties having from 1 to about 6 carbon atoms.
  • cycloalkyl refers to cyclic (i.e., ring-containing) alkyl moieties typically containing in the range of about 3 up to about 8 carbon atoms
  • substituted cycloalkyl refers to cycloalkyl groups further bearing one or more substituents as set forth above.
  • alkenyl refers to straight or branched chain hydrocarbyl groups having at least one carbon-carbon double bond, and having in the range of about 2 up to about 100 carbon atoms
  • substituted alkenyl refers to alkenyl groups further bearing one or more substituents as set forth above.
  • lower alkenyl refers to alkenyl moieties having from 2 to about 6 carbon atoms
  • oxyalkyl refers to an alkyl moiety wherein at least one methylene unit has been replaced by an oxygen atom.
  • oxyalkenyl refers to an alkenyl moiety wherein at least one methylene unit has been replaced by an oxygen atom.
  • hydroxyalkyl refers to an alkyl moiety bearing at least one hydroxyl group.
  • hydroxyalkenyl refers to an alkenyl moiety bearing at least one hydroxyl group.
  • arylene refers to divalent aromatic groups having in the range of 6 up to 14 carbon atoms and "substituted arylene” refers to divalent aryl groups further bearing one or more substituents as set forth above
  • heteroarylene refers to aromatic moieties containing one or more heteroatoms (e.g., N, O, S, or the like) as part of the ring structure and having in the range of 5 up to 14 total atoms in the ring structure (i.e., carbon atoms and heteroatoms).
  • heteroatoms e.g., N, O, S, or the like
  • Substituted heteroarylene refers to heteroarylene groups further bearing one or more substituents as set forth above.
  • halogen or halide refers to fluoride, chloride, bromide or iodide.
  • the invention provides compositions including an ester of a prostanoid agonist, a carboxylic acid, sodium phosphate dibasic, sodium chloride, a solubilizing agent, and the remainder water, wherein the pH of the composition is adjusted from about 4 to about 8. In some embodiments, the pH of the composition is adjusted to from about 4.5 to about 6.5. In one embodiment, the pH of the composition is adjusted to about 6.0.
  • compositions described herein exhibit remarkable aqueous stability, thereby resulting in increased shelf life for a pharmaceutical formulation containing invention compositions.
  • aqueous stability means
  • ester prodrugs of the prostanoid agonists disclosed herein are contemplated.
  • An ester may be derived from a carboxylic acid of CI (i.e. the terminal carboxylic acid of a natural prostanoid), or an ester may be derived from a carboxylic acid functional group on another part of the molecule, such as on a phenyl ring. While not intending to be limiting, an ester may be an alkyl ester, an aryl ester, or a heteroaryl ester.
  • Ci_ 6 alkyl esters are contemplated for use in the practice of the invention, wherein the alkyl part of the ester has from 1 to 6 carbon atoms and includes, but is not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, t- butyl, pentyl isomers, hexyl isomers, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and combinations thereof having from 1-6 carbon atoms, etc.
  • Prostanoid agonist prodrugs contemplated for use in the compositions of the invention have the structure:
  • each of Zi to Z 6 is independently C, N, O, or S;
  • A is -(CH 2 ) m -Ar-(CH 2 ) 0 - wherein Ar is arylene or heteroarylene, the sum of m and o is from 1 to 4, and wherein one CH 2 may be substituted with S or O;
  • Ri is alkyl, cycloalkyl, oxyalkyl, hydroxyalkyl,
  • alkenyl oxyalkenyl, or hydroxyalkenyl
  • R 2 is alkyl, hydroxyl, halide, or oxo
  • J is alkyl, cycloalkyl, oxyalkyl, hydroxyalkyl
  • E is C 1-12 alkyl, R 3 , or -Y-R 3 wherein Y is CH 2 , S, or O, and R 3 is aryl or heteroaryl; n is 0 or 1 ;
  • the prostanoid agonist prodrugs have the structure wherein n is
  • the prostanoid agonist prodrugs have the structure wherein Ri is alkyl or hydroxyalkyl. In certain embodiments, Ri is isopropyl or -CH 2 -CH 2 -OH.
  • Exemplary prostanoid agonist prodrugs include, but are not limited to, compounds having the structure:
  • carboxylic acids are contemplated for use in the compositions of the invention.
  • the carboxylic acid is a Ci to C 10 carboxylic acid.
  • the carboxylic acid is citric acid.
  • the carboxylic acid is typically present in the composition at a concentration of about 0.05 wt % to about 0.2 wt %. In some embodiments, the carboxylic acid is present in the composition at a concentration of about 0.1 wt% to about 0.15 wt %. In one embodiment, the carboxylic acid is present in the composition at a concentration of 0.135 wt % carboxylic acidA
  • Sodium phosphate dibasic is typically present in the composition at a concentration of about 1.0 wt % to about 2.0 wt %. In some embodiments, sodium phosphate dibasic is present in the composition at a concentration of about 1.2 wt % to about 1.6 wt %. In one embodiment, sodium phosphate dibasic is present in the composition at a concentration of about 1.42 wt %
  • Sodium chloride is typically present in the composition at a concentration of about 0.05 wt % to about 0.2 wt %. In some embodiments, sodium chloride is present in the composition at a concentration of about 0.1 wt % to about 0.15 wt %. In one embodiment, sodium chloride is present in the composition at a concentration of about 0.135 wt %.
  • solubilizing agents are contemplated for use in the practice of the invention, such as for example, polysorbate 80, pluronic F127, and the like.
  • aqueous stability to a formulation comprising an ester of a prostanoid agonist.
  • Such methods are performed, for example, by adding a carboxylic acid to the formulation and thereby adjusting the pH to from 4 to about 8.
  • the pH is adjusted from about 4.5 to about 6.5.
  • the pH is adjusted to about 6.0.
  • methods for treating an ocular disorder can be performed, for example, by administering to a subject in need thereof a therapeutically effective amount of a composition including an ester of a prostanoid agonist, a carboxylic acid, sodium phosphate dibasic, sodium chloride, a solubilizing agent, and the remainder water, wherein the pH of the composition is adjusted from about 4 to about 8.
  • the term "therapeutically effective 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.
  • the subject in need thereof is a mammal. In some embodiments, the mammal is human.
  • Disorders that can be treated using the methods of the invention include, but are not limited to, glaucoma, elevated intraocular pressure, optic neuropathy, corneal pain, diabetic retinopathy, retinal dystrophies, macular degeneration, non-exudative age related macular degeneration (ARMD), exudative Age Related Macular Degeneration (ARMD), Lebers optic neuropathy, optic neuritis often associated with multiple sclerosis, retinal vein occlusions, ischemic neuropathies and other neurodegenerative diseases, choroidal neovascularization, central serous chorioretinopathy, cystoid macular edema, diabetic macular edema, myopic retinal degeneration, acute multifocal placoid pigment epitheliopathy, Behcet's disease, birdshot retinochoroidopathy, intermediate uveitis (pars planitis), multifocal choroiditis, multiple evanescent white dot syndrome (MEWDS), ocular s

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PCT/US2010/055590 2009-12-09 2010-11-05 Stable aqueous compositions of prostglandin agonist prodrugs and methods for use thereof WO2011071620A1 (en)

Priority Applications (10)

Application Number Priority Date Filing Date Title
MX2012006622A MX2012006622A (es) 2009-12-09 2010-11-05 Composiciones acuosas estables de profarmacos de agonista de prostaglandina y metodos para el uso de estas.
EP10782082A EP2509582A1 (en) 2009-12-09 2010-11-05 Stable aqueous compositions of prostglandin agonist prodrugs and methods for use thereof
CA2783707A CA2783707A1 (en) 2009-12-09 2010-11-05 Stable aqueous compositions of prostglandin agonist prodrugs and methods for use thereof
JP2012543111A JP5955774B2 (ja) 2009-12-09 2010-11-05 プロスタグランジンアゴニストのプロドラッグの安定した水性組成物およびその使用方法
NZ600577A NZ600577A (en) 2009-12-09 2010-11-05 Stable aqueous compositions of prostglandin agonist prodrugs and methods for use thereof
CN201080063225.1A CN102762195B (zh) 2009-12-09 2010-11-05 前列腺素激动剂前药的稳定水性组合物及其使用方法
AU2010328555A AU2010328555B2 (en) 2009-12-09 2010-11-05 Stable aqueous compositions of prostglandin agonist prodrugs and methods for use thereof
RU2012127869/15A RU2012127869A (ru) 2009-12-09 2010-11-05 Устойчивые водные композиции пролекарств агонистов простагладина и способы их применения
SG2012042461A SG181600A1 (en) 2009-12-09 2010-11-05 Stable aqueous compositions of prostglandin agonist prodrugs and methods for use thereof
IL220240A IL220240A0 (en) 2009-12-09 2012-06-07 Stable aqueous compositions of prostglandin agonist prodrugs and methods for use thereof

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US26789709P 2009-12-09 2009-12-09
US61/267,897 2009-12-09

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EP (1) EP2509582A1 (es)
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KR (1) KR20120106788A (es)
CN (1) CN102762195B (es)
AR (1) AR078929A1 (es)
AU (1) AU2010328555B2 (es)
CA (1) CA2783707A1 (es)
CL (1) CL2012001545A1 (es)
IL (1) IL220240A0 (es)
MX (1) MX2012006622A (es)
NZ (1) NZ600577A (es)
RU (1) RU2012127869A (es)
SG (1) SG181600A1 (es)
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Publication number Priority date Publication date Assignee Title
WO2015175075A1 (en) * 2014-02-20 2015-11-19 Allergan, Inc. Reduced central corneal thickening by use of hydrophilic ester prodrugs of beta-chlorocyclopentanes
US9427401B2 (en) 2012-08-27 2016-08-30 Allergan, Inc. Reduced central corneal thickening by use of hydrophilic ester prodrugs of beta-chlorocyclopentanes
US10329284B2 (en) 2014-10-02 2019-06-25 Allergan, Inc. Ester prodrugs of gamma-lactams and their use

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Publication number Priority date Publication date Assignee Title
KR101535825B1 (ko) 2012-09-25 2015-07-10 엘지디스플레이 주식회사 표시장치 및 이의 라인결함 검출방법

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