WO2011140203A2 - Stabilized ophthalmic galactomannan formulations - Google Patents
Stabilized ophthalmic galactomannan formulations Download PDFInfo
- Publication number
- WO2011140203A2 WO2011140203A2 PCT/US2011/035165 US2011035165W WO2011140203A2 WO 2011140203 A2 WO2011140203 A2 WO 2011140203A2 US 2011035165 W US2011035165 W US 2011035165W WO 2011140203 A2 WO2011140203 A2 WO 2011140203A2
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- WO
- WIPO (PCT)
- Prior art keywords
- formulation
- present
- formulations
- concentration
- galactomannan
- Prior art date
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Classifications
-
- 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
- A61K9/08—Solutions
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/736—Glucomannans or galactomannans, e.g. locust bean gum, guar gum
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
- 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
-
- 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
- A61P27/04—Artificial tears; Irrigation solutions
Definitions
- the present invention relates to ophthalmic formulations comprising galactomannans, and more specifically to formulations comprising galactomannan and a diol alcohol compound in a quantity sufficient to stabilize the viscosity of the formulation.
- Ophthalmic formulations often comprise compounds that provide desirable properties to the formulation. When these formulations are instilled in the eye, the properties of such compounds can help prevent ophthalmic problems such as bioadhesion and the formation of friction-induced tissue damage, as well as encourage the natural healing and restoration of previously damaged tissues.
- Formulations are typically developed with a target viscosity to ensure that they are comfortable for the user and do not cause undesirable side effects such as blurring.
- a suitable formulation viscosity can help ensure that an ophthalmic formulation used in dry eye disorders will relieve dry eye-associated symptoms and/or treat the underlying disorder.
- the viscosity of ophthalmic formulations may be chosen to ensure that a pharmaceutical agent carried in the formulation remains in the eye for a desired length of time. Given its criticality, the viscosity of ophthalmic formulations should remain as stable as possible over time.
- the viscosity of formulations can be affected by storage conditions (e.g., environmental temperature, time of storage, ambient light, etc.). Also, ophthalmic formulations must be sterilized before use, and the sterilization process, particularly heat sterilization, can dramatically affect the viscosity of such formulations.
- Ophthalmic formulations have been previously described that utilize galactomannan-borate systems.
- U.S. Patent No. 6,403,609 to Asgharian entitled “Ophthalmic compositions containing galactomannan polymers and borate,” describes such systems and is herein incorporated by reference in its entirety.
- the cross-linking of galactomannan and borate is responsible for the gel-forming behavior of the described formulations.
- Magnesium has been utilized in guar formulations to assist in the hydration of guar. See Vega-Cantu et al., "Effect of Magnesium and Iron on the Hydration and Hydrolysis of Guar Gum” Biomacromolecules, Vol. 7:441-445, 2006.
- Embodiments of the invention generally relate to ophthalmic formulations comprising galactomannan.
- the present inventors have unexpectedly discovered that diol alcohols can be included in such ophthalmic formulations to stabilize the viscosity of such solutions.
- the stabilization of the ophthalmic formulations by diol alcohols minimizes viscosity loss at elevated temperatures and ensures that the formulations can be stored safely for longer periods of time without viscosity loss.
- Galactomannans of the present invention include, but are not limited to, galactomannans such as guar and guar derivatives.
- the formulations of the present invention also comprise a borate source such as boric acid.
- formulations of the present invention optionally comprise a pharmaceutically acceptable salt of a divalent cation such as magnesium, zinc and calcium that have also been discovered to stabilize galactomannan formulations.
- a pharmaceutically acceptable salt of a divalent cation such as magnesium, zinc and calcium that have also been discovered to stabilize galactomannan formulations.
- Preferred formulations comprise guar or a guar derivative, magnesium chloride, and sorbitol.
- Formulations of the present invention may be used, among other applications, as drug delivery vehicles for ophthalmic therapeutics, artificial tear solutions, and as dry eye therapeutics.
- Another embodiment of the present invention is a method for stabilizing ophthalmic formulations comprising galactomannan and borate.
- the method comprises adding a diol alcohol and, optionally, a pharmaceutically acceptable divalent cation salt such as magnesium chloride.
- the formulations of the present invention comprise a galactomannan and a borate in aqueous solution.
- the cross-linking behavior of the galactomannan and the borate contributes to the viscosity of the formulations.
- the present invention is directed to the use of diol alcohols such as sorbitol and propylene glycol to stabilize the viscosity of ophthalmic formulations, presumably by modifying the cross-linking of the borate and galactomannan.
- the use of such diol alcohols also stabilizes the molecular weight of galactomannan polymers during sterilization of formulations comprising such polymers.
- the diol alcohol sorbitol is used in preferred formulations of the present invention.
- the diol alcohol compounds that may be used with embodiments of the present invention include, but are not limited to, hydrophilic carbohydrates such as sorbitol or mannitol that comprise cis-diol groups (hydroxyl groups attached to adjacent carbon atoms).
- Other diol alcohol compounds of the present invention include polyethylene glycols, polypropylene glycols, and glycerol.
- Particularly preferred diol compounds are sorbitol and mannitol.
- the diol compounds are present at concentrations of about 0.5 to 5.0 w/v% in the formulations of the present invention, and are preferably present at a concentration of about 0.5 to 2.0 w/v%.
- the formulations of the present invention optionally comprise a pharmaceutically acceptable divalent cation salt such as magnesium chloride.
- Divalent cations include, but are not limited to, magnesium, chloride, and zinc cations.
- concentrations of divalent cations should be greater than 0.05 w/v%, with a preferred concentration of 0.05 w/v% to 0.25 w/v%.
- 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, hydroxy ethyl, 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). Substitutions in the 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.
- a galactomannan is typically present in a formulation of the present invention at a concentration of about 0.01 to about 10 w/v%, preferably at about 0.05 w/v% to about 2.0 w/v%, and most preferably at about 0.05 to about 0.5 w/v%.
- Preferred galactomannans of the present invention are guar, hydroxypropyl guar, and hydroxypropyl guar galactomannan.
- Native guar such as the guar produced by a process set forth in U.S. Patent Application Publication No. 2010/0196415 entitled "Process for Purifying Guar” filed February 5, 2010 (the entire contents of which are herein incorporated by reference) is also a preferred galactomannan.
- Borate is typically present at a concentration of about 0.05 to about 2.0 w/v%, and preferably about 0.1 to 1.5 w/v%.
- the term "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.
- Borate compounds which may be used in the compositions of the present invention are boric acid and other pharmaceutically acceptable salts such as sodium borate (borax) and potassium borate.
- the term "borate” refers to all pharmaceutically suitable forms of borates. Borates are common excipients in ophthalmic formulations due to weak buffering capacity at physiological pH and well known safety and compatibility with a wide range of drugs and preservatives. Borates also have inherent bacteriostatic and fungistatic properties, and therefore aid in the preservation of the compositions.
- the formulations of the present invention may optionally comprise one or more additional excipients and/or one or more additional active ingredients.
- Excipients commonly used in pharmaceutical formulations include, but are not limited to, demulcents, tonicity agents, preservatives, chelating agents, buffering agents, and surfactants.
- Other excipients comprise solubilizing agents, stabilizing agents, comfort-enhancing agents, polymers, emollients, pH-adjusting agents and/or lubricants.
- excipients may be used in formulations of the present invention including water, mixtures of water and water-miscible solvents, such as vegetable oils or mineral oils comprising from 0.5 to 5% non-toxic water-soluble polymers, natural products, such as alginates, pectins, tragacanth, karaya gum, xanthan gum, carrageenin, agar and acacia, starch derivatives, such as starch acetate and hydroxypropyl starch, and also other synthetic products such as polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl methyl ether, polyethylene oxide, and preferably cross-linked polyacrylic acid and mixtures of those products.
- vegetable oils or mineral oils comprising from 0.5 to 5% non-toxic water-soluble polymers
- natural products such as alginates, pectins, tragacanth, karaya gum, xanthan gum, carrageenin, agar and acacia
- starch derivatives such as
- Demulcents used with embodiments of the present invention include, but are not limited to, glycerin, polyvinyl pyrrolidone, polyethylene oxide, polyethylene glycol, propylene glycol and polyacrylic acid. Particularly preferred demulcents are propylene glycol and polyethylene glycol 400.
- Suitable tonicity-adjusting agents include, but are not limited to, mannitol, sodium chloride, glycerin, and the like.
- Suitable buffering agents include, but are not limited to, phosphates, acetates and the like, and amino alcohols such as 2-amino-2- methyl-l-propanol (AMP).
- Suitable surfactants include, but are not limited to, ionic and nonionic surfactants (though nonionic surfactants are preferred), RLM 100, POE 20 cetylstearyl ethers such as Procol ® CS20, poloxamers such as Pluronic ® F68, and block copolymers such as poly(oxyethylene)-poly(oxybutylene) compounds set forth in U.S. Patent Application Publication No. 2008/0138310 entitled “Use of PEO-PBO Block Copolymers in Ophthalmic Compositions" filed December 10, 2007 (the entire contents of which are herein incorporated by reference).
- the formulations set forth herein may comprise one or more preservatives.
- preservatives include p-hydroxybenzoic acid ester, sodium perborate, sodium chlorite, alcohols such as chlorobutanol, benzyl alcohol or phenyl ethanol, guanidine derivatives such as polyhexamethylene biguanide, sodium perborate, polyquaternium-1, or sorbic acid.
- the formulation may be self-preserved so that no preservation agent is required.
- Formulations of the present invention are ophthalmically suitable for application to a subject's eyes.
- aqueous typically denotes an aqueous formulation wherein the excipient is >50%, more preferably >75% and in particular >90% by weight water.
- These drops may be delivered from a single dose ampoule which may preferably be sterile and thus render bacteriostatic components of the formulation unnecessary.
- the drops may be delivered from a multi- dose bottle which may preferably comprise a device which extracts any preservative from the formulation as it is delivered, such devices being known in the art.
- the formulations of the present invention are preferably isotonic, or slightly hypotonic in order to combat any hypertonicity of tears caused by evaporation and/or disease. This may require a tonicity agent to bring the osmolality of the formulation to a level at or near 210-320 milliosmoles per kilogram (mOsm/kg).
- the formulations of the present invention generally have an osmolality in the range of 220-320 mOsm/kg, and preferably have an osmolality in the range of 235-300 mOsm/kg.
- the ophthalmic formulations will generally be formulated as sterile aqueous solutions.
- compositions of the present invention can also be used to administer pharmaceutically active compounds.
- pharmaceutically active compounds include, but are not limited to, glaucoma therapeutics, pain relievers, anti-inflammatory and anti-allergy medications, and anti-microbials. More specific examples of pharmaceutically active compounds include betaxolol, timolol, pilocarpine, carbonic anhydrase inhibitors and prostglandins; dopaminergic antagonists; post-surgical antihypertensive agents, such as para-amino clonidine (apraclonidine); anti-infectives such as ciprofloxacin, moxifloxacin, and tobramycin; non-steroidal and steroidal anti-inflammatories, such as naproxen, diclofenac, nepafenac, suprofen, ketorolac, tetrahydrocortisol and dexamethasone; dry eye therapeutics such as PDE4 inhibitors; and anti-allergy medications such
- concentrations of the ingredients comprising the formulations of the present invention can vary.
- concentrations can vary depending on the addition, substitution, and/or subtraction of ingredients in a given formulation.
- Preferred formulations are prepared using a buffering system that maintains the formulation at a pH of about 6.5 to a pH of about 8.0.
- Topical formulations are preferred which have a physiological pH matching the tissue to which the formulation will be applied or dispensed.
- a formulation of the present invention is administered once a day.
- the formulations may also be formulated for administration at any frequency of administration, including once a week, once every
- Such dosing frequency is also maintained for a varying duration of time depending on the therapeutic regimen.
- the duration of a particular therapeutic regimen may vary from one-time dosing to a regimen that extends for months or years.
- One of ordinary skill in the art would be familiar with determining a therapeutic regimen for a specific indication.
- Example 1 is a formulation according to an embodiment of the present invention.
- Example 2 summarizes studies performed on formulations of the present invention.
- the viscosity of various solutions of the present invention and control solutions was evaluated using a controlled stress rheometer (AR 2000ex, TA Instruments, Inc.).
- the measurement system was a 40mm acrylic 2° cone and plate with a sample volume of 0.58mL. A temperature of 25 °C +/- 0.1 °C was maintained and a cover was placed over the measurement system to prevent evaporation of the solutions.
- Solution 89A is the control for this experiment.
- the dissolved 0 2 level at ambient conditions is constant at 7 ppm.
- the initial viscosity of Solution 89A at a shear rate of 10s "1 is at 10.97cP. After 5 weeks at room temperature, there is a small drop in viscosity of 3.65%. After 5 weeks at elevated temperatures of 40°C there is a much greater drop in viscosity of 14.77%.
- Solution 89B has the highest initial viscosity of the formulations tested.
- 89B is the formulation with just the removal of dissolved 0 2 .
- the initial viscosity of solution 89B at a shear rate of 10s "1 is 17.62cP. After 5 weeks at room temperature, there is a small drop in viscosity of 3.22%. After 5 weeks at 40°C, there is a much greater drop in viscosity of 15.95%.
- 89B has a similar breakdown through the stability. However the initial viscosity is maintained at a level of 0.1 ppm dissolved 0 2 .
- Solution 89C has 0.19 w/v% MgCl 2 added to the formulation.
- the initial viscosity of solution 89C at a shear rate of 10s "1 is 14.55cP. After 5 weeks at room temperature, there is a small drop in viscosity of 1.51%. After 5 weeks at 40°C, there is a drop in viscosity of 7.91%.
- Solution 89C with magnesium demonstrates a greater initial viscosity and enhanced stability compared to the control solution (solution 89A) at both room and elevated temperature.
- Solution 89D comprising 1.0 w/v% sorbitol shows the best stability of the tested formulations.
- the initial viscosity of solution 89D at a shear rate of 10s "1 is 13.30cP. After 5 weeks at room temperature there is a small drop in viscosity of 0.68%). After 5 weeks at 40°C there is a drop in viscosity of 2.85%.
- Native guar with a molecular weight of 3.0M Daltons manufactured according to the process described in U.S. Patent Application Publication No. 2010/0196415 was formulated in test formulations A-C set forth in Table 4 below. Following sterilization by autoclaving, the molecular weight of native guar in each formulation was measured. Compared to formulations B and C, the native guar in formulation A not containing a diol compound (sorbitol or glycerol) had a significantly lower measured molecular weight. The use of diol compounds in the guar formulations has a preservation effect on the molecular weight of guar during the sterilization process. Table 4
Abstract
Description
Claims
Priority Applications (13)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2011800292803A CN102939074A (en) | 2010-05-05 | 2011-05-04 | Stabilized ophthalmic galactomannan formulations |
MX2012012826A MX2012012826A (en) | 2010-05-05 | 2011-05-04 | Stabilized ophthalmic galactomannan formulations. |
ES11720357T ES2809304T3 (en) | 2010-05-05 | 2011-05-04 | Stabilized ophthalmic formulations of galactomannan |
AU2011248129A AU2011248129B2 (en) | 2010-05-05 | 2011-05-04 | Stabilized ophthalmic galactomannan formulations |
SG2012081386A SG185422A1 (en) | 2010-05-05 | 2011-05-04 | Stabilized ophthalmic galactomannan formulations |
CA2798069A CA2798069C (en) | 2010-05-05 | 2011-05-04 | Stabilized ophthalmic galactomannan formulations |
JP2013509217A JP5794744B2 (en) | 2010-05-05 | 2011-05-04 | Stabilized ophthalmic galactomannan formulation |
KR1020177037138A KR20180001587A (en) | 2010-05-05 | 2011-05-04 | Stabilized ophthalmic galactomannan formulations |
KR1020127031590A KR20130060228A (en) | 2010-05-05 | 2011-05-04 | Stabilized ophthalmic galactomannan formulations |
BR112012028308-1A BR112012028308B1 (en) | 2010-05-05 | 2011-05-04 | STABILIZED GALACTOMANAN OPTHALMIC FORMULATIONS AND THEIR MANUFACTURING METHOD |
EP11720357.0A EP2566447B1 (en) | 2010-05-05 | 2011-05-04 | Stabilized ophthalmic galactomannan formulations |
NZ603345A NZ603345A (en) | 2010-05-05 | 2011-05-04 | Stabilized ophthalmic galactomannan formulations |
ZA2012/08199A ZA201208199B (en) | 2010-05-05 | 2012-10-31 | Stabilized ophthalmic galactomannan formulations |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US33151110P | 2010-05-05 | 2010-05-05 | |
US61/331,511 | 2010-05-05 |
Publications (2)
Publication Number | Publication Date |
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WO2011140203A2 true WO2011140203A2 (en) | 2011-11-10 |
WO2011140203A3 WO2011140203A3 (en) | 2012-04-19 |
Family
ID=44626461
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2011/035165 WO2011140203A2 (en) | 2010-05-05 | 2011-05-04 | Stabilized ophthalmic galactomannan formulations |
Country Status (16)
Country | Link |
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US (2) | US20110275593A1 (en) |
EP (1) | EP2566447B1 (en) |
JP (1) | JP5794744B2 (en) |
KR (2) | KR20130060228A (en) |
CN (2) | CN102939074A (en) |
AR (1) | AR081015A1 (en) |
AU (1) | AU2011248129B2 (en) |
BR (1) | BR112012028308B1 (en) |
CA (1) | CA2798069C (en) |
ES (1) | ES2809304T3 (en) |
MX (1) | MX2012012826A (en) |
NZ (1) | NZ603345A (en) |
SG (2) | SG185422A1 (en) |
TW (1) | TWI606841B (en) |
WO (1) | WO2011140203A2 (en) |
ZA (1) | ZA201208199B (en) |
Cited By (6)
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JP2015509933A (en) * | 2012-02-10 | 2015-04-02 | アルコン リサーチ, リミテッド | Aqueous pharmaceutical composition with enhanced stability |
WO2017035408A1 (en) | 2015-08-26 | 2017-03-02 | Achillion Pharmaceuticals, Inc. | Compounds for treatment of immune and inflammatory disorders |
WO2018005552A1 (en) | 2016-06-27 | 2018-01-04 | Achillion Pharmaceuticals, Inc. | Quinazoline and indole compounds to treat medical disorders |
WO2020041301A1 (en) | 2018-08-20 | 2020-02-27 | Achillion Pharmaceuticals, Inc. | Pharmaceutical compounds for the treatment of complement factor d medical disorders |
WO2020081723A1 (en) | 2018-10-16 | 2020-04-23 | Georgia State University Research Foundation, Inc. | Carbon monoxide prodrugs for the treatment of medical disorders |
EP4053117A1 (en) | 2015-08-26 | 2022-09-07 | Achillion Pharmaceuticals, Inc. | Aryl, heteroaryl, and heterocyclic compounds for treatment of medical disorders |
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CA2722508C (en) * | 2008-04-26 | 2016-08-16 | Alcon Research Ltd. | Polymeric artificial tear system |
TWI492769B (en) * | 2009-09-23 | 2015-07-21 | Alcon Res Ltd | Injectable aqueous ophthalmic composition and method of use therefor |
UA113434C2 (en) * | 2012-05-04 | 2017-01-25 | Алкон Рісерч, Лтд. | Ophthalmic compositions with improved dessication protection and retention |
US11583496B2 (en) | 2016-10-12 | 2023-02-21 | PS Therapy Inc. | Drug vehicle compositions and methods of use thereof |
US11260035B2 (en) | 2016-10-12 | 2022-03-01 | Ps Therapies Ltd | Topical compositions and methods of use thereof |
CN110114119B (en) * | 2016-10-12 | 2022-05-31 | Ps治疗有限公司 | Artificial tears, contact lenses, and drug carrier compositions and methods of use thereof |
TWI757773B (en) | 2019-06-28 | 2022-03-11 | 瑞士商愛爾康公司 | Ophthalmic compositions |
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US6403609B1 (en) | 1997-07-29 | 2002-06-11 | Alcon Manufacturing, Ltd. | Ophthalmic compositions containing galactomannan polymers and borate |
US20080138310A1 (en) | 2006-12-11 | 2008-06-12 | Alcon Manufacturing, Ltd. | Use of PEO-PBO block copolymers in ophthalmic compositions |
US20100196415A1 (en) | 2009-02-05 | 2010-08-05 | Alcon Research, Ltd. | Process for purifying guar |
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US8028A (en) * | 1851-04-08 | Hokse-poweb | ||
US4136173A (en) * | 1977-01-31 | 1979-01-23 | American Home Products Corp. | Mixed xanthan gum and locust beam gum therapeutic compositions |
DE3827561C1 (en) * | 1988-08-13 | 1989-12-28 | Lts Lohmann Therapie-Systeme Gmbh & Co Kg, 5450 Neuwied, De | |
US5505953A (en) * | 1992-05-06 | 1996-04-09 | Alcon Laboratories, Inc. | Use of borate-polyol complexes in ophthalmic compositions |
GB9808461D0 (en) * | 1998-04-22 | 1998-06-17 | Innovative Tech Ltd | Solid borate-diol interaction products |
US7084130B2 (en) * | 2001-12-11 | 2006-08-01 | Alcon, Inc. | Intraocular irrigating solution having improved flow characteristics |
TWI336257B (en) * | 2003-06-13 | 2011-01-21 | Alcon Inc | Ophthalmic compositions containing a synergistic combination of three polymers |
US20100021561A1 (en) * | 2006-09-21 | 2010-01-28 | Chowhan Masood A | Self-preserved aqueous pharmaceutical compositions |
AR066901A1 (en) * | 2007-05-18 | 2009-09-23 | Alcon Mfg Ltd | PHODFOLIPID COMPOSITIONS FOR THE CLOSURE OF CONTACT LENSES AND PRESERVATION OF PHARMACEUTICAL COMPOSITIONS |
CA2722508C (en) * | 2008-04-26 | 2016-08-16 | Alcon Research Ltd. | Polymeric artificial tear system |
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2011
- 2011-05-04 US US13/100,439 patent/US20110275593A1/en not_active Abandoned
- 2011-05-04 CA CA2798069A patent/CA2798069C/en active Active
- 2011-05-04 WO PCT/US2011/035165 patent/WO2011140203A2/en active Application Filing
- 2011-05-04 TW TW100115587A patent/TWI606841B/en active
- 2011-05-04 AU AU2011248129A patent/AU2011248129B2/en active Active
- 2011-05-04 KR KR1020127031590A patent/KR20130060228A/en active Application Filing
- 2011-05-04 SG SG2012081386A patent/SG185422A1/en unknown
- 2011-05-04 BR BR112012028308-1A patent/BR112012028308B1/en active IP Right Grant
- 2011-05-04 JP JP2013509217A patent/JP5794744B2/en active Active
- 2011-05-04 MX MX2012012826A patent/MX2012012826A/en active IP Right Grant
- 2011-05-04 NZ NZ603345A patent/NZ603345A/en not_active IP Right Cessation
- 2011-05-04 CN CN2011800292803A patent/CN102939074A/en active Pending
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JP2015509933A (en) * | 2012-02-10 | 2015-04-02 | アルコン リサーチ, リミテッド | Aqueous pharmaceutical composition with enhanced stability |
WO2017035408A1 (en) | 2015-08-26 | 2017-03-02 | Achillion Pharmaceuticals, Inc. | Compounds for treatment of immune and inflammatory disorders |
EP4053117A1 (en) | 2015-08-26 | 2022-09-07 | Achillion Pharmaceuticals, Inc. | Aryl, heteroaryl, and heterocyclic compounds for treatment of medical disorders |
WO2018005552A1 (en) | 2016-06-27 | 2018-01-04 | Achillion Pharmaceuticals, Inc. | Quinazoline and indole compounds to treat medical disorders |
EP3939591A1 (en) | 2016-06-27 | 2022-01-19 | Achillion Pharmaceuticals, Inc. | Quinazoline and indole compounds to treat medical disorders |
WO2020041301A1 (en) | 2018-08-20 | 2020-02-27 | Achillion Pharmaceuticals, Inc. | Pharmaceutical compounds for the treatment of complement factor d medical disorders |
WO2020081723A1 (en) | 2018-10-16 | 2020-04-23 | Georgia State University Research Foundation, Inc. | Carbon monoxide prodrugs for the treatment of medical disorders |
Also Published As
Publication number | Publication date |
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TW201141524A (en) | 2011-12-01 |
CN102939074A (en) | 2013-02-20 |
CN106389325A (en) | 2017-02-15 |
US8846641B2 (en) | 2014-09-30 |
SG10201804305SA (en) | 2018-06-28 |
ZA201208199B (en) | 2014-01-29 |
EP2566447B1 (en) | 2020-07-15 |
BR112012028308B1 (en) | 2021-09-28 |
BR112012028308A2 (en) | 2016-11-01 |
US20130244971A1 (en) | 2013-09-19 |
KR20130060228A (en) | 2013-06-07 |
AR081015A1 (en) | 2012-05-30 |
JP5794744B2 (en) | 2015-10-14 |
AU2011248129B2 (en) | 2014-10-09 |
EP2566447A2 (en) | 2013-03-13 |
MX2012012826A (en) | 2013-01-28 |
CA2798069A1 (en) | 2011-11-10 |
WO2011140203A3 (en) | 2012-04-19 |
TWI606841B (en) | 2017-12-01 |
US20110275593A1 (en) | 2011-11-10 |
SG185422A1 (en) | 2012-12-28 |
JP2013525493A (en) | 2013-06-20 |
AU2011248129A1 (en) | 2012-11-29 |
NZ603345A (en) | 2014-12-24 |
ES2809304T3 (en) | 2021-03-03 |
CA2798069C (en) | 2016-07-05 |
KR20180001587A (en) | 2018-01-04 |
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