WO2015134510A1 - Lipoic acid choline ester compositions and methods of use - Google Patents
Lipoic acid choline ester compositions and methods of use Download PDFInfo
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- WO2015134510A1 WO2015134510A1 PCT/US2015/018505 US2015018505W WO2015134510A1 WO 2015134510 A1 WO2015134510 A1 WO 2015134510A1 US 2015018505 W US2015018505 W US 2015018505W WO 2015134510 A1 WO2015134510 A1 WO 2015134510A1
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- lipoic acid
- choline ester
- acid choline
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- 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
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/385—Heterocyclic compounds having sulfur as a ring hetero atom having two or more sulfur atoms in the same ring
-
- 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
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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
- A61K47/10—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
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- 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
- 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
- A61P27/10—Ophthalmic agents for accommodation disorders, e.g. myopia
Definitions
- the present invention generally relates to pharmaceutical compositions comprising lipoic acid choline ester or derivatives thereof and a non-aqueous excipient and uses thereof for treating ocular diseases or disorders (e.g., presbyopia).
- ocular diseases or disorders e.g., presbyopia
- a lens fiber cell fluid layer formed during accommodation by aquaporin-0 has been implicated in presbyopia.
- the diagram shows, when the ciliary muscle contracts (Helmholtz theory of accommodation), tension on the zonules is released and the potential energy stored in the lens capsule is released and creates kinetic force at the equatorial plane of the lens. As shown by finite element analysis of the lens, this force originates adjacent to the zonular lens attachments at the perilenticular equatorial position.
- the lens is made-up of long fiber cells with "new" cells made at the surface.
- Fiber cells form a microfluidic path that resemble "tubes.” This works to maintain lens accommodative function. Dysfunctional "old” fiber cells are displaced inward. This provides an efficient means to move outer "fluid compartment” fluid, when zonular tension is released, toward the middle (central optical axis) of the lens to increase geometric curvature (optical power). This fluid movement is facilitated by a special phenomena similar to that reported for blood flow through microcapillaries ( ⁇ 10 um). A small plasma layer (a phenomenon described by Fahraeus-Lindqvist) is formed along the periphery of blood vessels. This lowers the apparent or effective measured hematocrit viscosity and improves blood flow with lower backpressure.
- lens fiber cells also about 10 um diameter
- Abundant aquaporin-0 lining the cell wall/membrane in lens fiber cells allows water flow out of the cell during accommodation for near vision focus.
- Dissolved micronutrients are supplied to the lens occur through these same interstitial water channels.
- part of their undocumented intrinsic function facilitates accommodative amplitude that requires aforementioned fluid movement to change lens geometry.
- the water layer formed along the intracellular fiber cell membrane wall reduces impedence or resistance and gives "lubrication" to the inner core cytosol protein; a previously overlooked phenomena.
- the protein core (inside the inner portion of the lens fiber cell) may have higher intrinsic viscosity, the "lubrication factor” or microlayer ( ⁇ 1 nm) formed between the core and the inner membrane, significantly lowers the extrinsic viscosity (as with blood hematocrit apparent viscosity). This allows the lens cytosol to move forward to the central visual axis within confines of limited zonular force to increase optical power.
- LACE lipoic acid choline ester
- Patent No. 8,410,462 can restore this critical fluid layer responsible for fluid movement, restore near vision, and reduce the core lens cytosol modulus that is affected by disulfide cross-linking.
- LACE formulations are in need for treating ocular diseases or disorders (e.g., presbyopia) where the critical fluid layer is lost or where disulfide cross- linking is an issue.
- the invention provides a pharmaceutical composition comprising a therapeutically effective amount of lipoic acid choline ester or derivatives thereof and a non-aqueous excipient.
- the therapeutically effective amount of lipoic acid choline ester and the non-aqueous excipient are mixed in an aqueous solution having a pH of 4 to 8 (e.g., 4.0, 4.2, 4.4, 4.6, 4.8, 5.0, 5.2, 5.4, 5.6, 5.8, 6.0, 6.2, 6.4, 6.6, 6.8, 7.0, 7.2, 7.4, 7.6, 7.8, 8.0, or any ranges based on these specified numeric values).
- the aqueous solution comprises a buffer agent.
- the pharmaceutical composition is free of a buffer agent.
- the pharmaceutical composition comprises a therapeutically effective amount of lipoic acid choline ester and a non-aqueous excipient, mixed in an aqueous solution having a pH of 4 to 6, wherein at least 95% of the lipoic acid choline ester is present in the pharmaceutical composition, as measured by HPLC, following storage at 25 °C under 40% relative humidity for 3 months.
- the pharmaceutical composition is characterized in that less than 2% of the lipoic acid choline ester in the composition is degraded following storage at 25 °C under 40% relative humidity for 3 months.
- the pharmaceutical composition is characterized in that the pharmaceutical composition has less than 12% total drug related impurities based on area-under-the-curve as determined by HPLC following storage at 25 °C under 40% relative humidity for 3 months. In some embodiments, the pharmaceutical composition is characterized in that the pharmaceutical composition has less than 7% of a drug related impurity based on area-under-the-curve as determined by HPLC following storage at 25 °C under 40% relative humidity for 3 months, wherein the drug related impurity is characterized by a relative retention time of 1.12 to 1.14.
- the pharmaceutical composition is characterized in that the pharmaceutical composition has 4% of a drug related impurity based on area- under-the-curve as determined by HPLC following storage at 25 °C under 40% relative humidity for 3 months, wherein the drug related impurity is characterized by a relative retention time of 0.65 to 0.66.
- the pharmaceutical composition is characterized by one or more of the following:
- the preservative is benzalkonium chloride and the biochemical energy source is alanine.
- the lipoic acid choline ester has a counter ion selected from the group consisting of chloride, bromide, iodide, sulfate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, hydrogen fumarate, tartrate (e.g., (+)-tartrate, (-)-tartrate, or a mixture thereof), succinate, benzoate, and anions of an amino acid such as glutamic acid.
- a counter ion selected from the group consisting of chloride, bromide, iodide, sulfate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, hydrogen fumarate, tartrate (e.g., (+)-tartrate, (-)-tartrate, or a mixture thereof), succinate, benzoate, and anions of an amino acid such as glutamic acid.
- the pharmaceutical composition is prepared by mixing the therapeutically effective amount of lipoic acid choline ester and the non-aqueous excipient sequentially or simultaneously with the aqueous solution.
- the pharmaceutical composition is prepared by first mixing the therapeutically effective amount of lipoic acid choline ester and the non-aqueous excipient to form a non-aqueous composition, and then mixing the non-aqueous composition with the aqueous solution.
- the non-aqueous composition can be a solution, an emulsion, or a suspension formed by mixing lipoic acid choline ester and the non-aqueous excipient. The mixing can be conducted under heat for a sustained period of time.
- the pharmaceutical composition prepared by either method can have a shelf-stability of at least 3 months (e.g., 3 months, 6 months, 9 months, 1 year, or more than 1 year).
- the invention provides a non-aqueous composition comprising lipoic acid choline ester or derivatives thereof and a non-aqueous excipient.
- the non-aqueous excipient is substantially miscible with water.
- the non-aqueous excipient is a non-hydrolytic solvent.
- the non-aqueous excipient is an alcohol.
- the alcohol is a polyol, e.g., glycerol or propylene glycol.
- the nonaqueous excipient is a semifluorinated alkane.
- the non-aqueous composition comprises a non-aqueous solution obtained by mixing lipoic acid choline ester with the non-aqueous excipient.
- the mixing is conducted at a temperature of 20 °C to 100 °C.
- the mixing is conducted at a temperature of 37 °C to 80 °C.
- the concentration of lipoic acid choline ester or derivatives thereof in the non-aqueous composition is in a range of 0.1% to 40% by weight.
- the lipoic acid choline ester has a counter ion selected from the group consisting of chloride, bromide, iodide, sulfate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, hydrogen fumarate, tartrate (e.g., (+)-tartrate, (-)-tartrate, or a mixture thereof), succinate, benzoate, and anions of an amino acid such as glutamic acid.
- the invention provides an ophthalmic formulation comprising the non-aqueous composition mixed in an aqueous solution.
- the aqueous solution comprises a buffer.
- the ophthalmic formulation has a pH of 4 to 8.
- the ophthalmic formulation has a pH of 4.5.
- the ophthalmic formulation comprises at least one ingredient selected from the group consisting of a biochemically acceptable energy source, a preservative, a buffer agent, a tonicity agent, a surfactant, a viscosity modifying agent, and an antioxidant.
- the non-aqueous composition is sterilized before mixing in the aqueous solution.
- the aqueous solution is a sterilized solution.
- the ophthalmic formulation is characterized by one or more of:
- the preservative is benzalkonium chloride and the biochemical energy source is alanine.
- the invention also provides a system or method of long- term storage of the pharmaceutical composition by storing the non-aqueous composition separately from the aqueous solution, for example, in a two-part device (e.g., as described herein) or in a kit.
- the separately stored non-aqueous composition can then be mixed with the aqueous solution prior to use.
- the system comprises a first compartment, a second compartment, and a seal separating the first and second compartments, wherein the first compartment comprises a non-aqueous composition of an active ingredient and a non- aqueous excipient, the second compartment comprises an aqueous solution, and wherein the system is activated upon breaking the seal and mixing the non-aqueous solution with the aqueous solution.
- the active ingredient is lipoic acid choline ester or derivatives thereof and the non-aqueous excipient is an ophthalmically acceptable excipient.
- the aqueous solution comprises a buffer. In some embodiments, both the non-aqueous composition and the aqueous solution are sterilized.
- the active ingredient in the system has a shelf-stability of more than 3 months. In some embodiments, the active ingredient in the system has a shelf- stability of more than 6 months. In some embodiments, the active ingredient in the system after activation has a shelf-stability of more than 3 months.
- the invention provides a method of storing an active ingredient that is susceptible to hydrolysis in an aqueous solution, the method comprising (a) providing the active ingredient in a first compartment; (b) providing the aqueous solution in a second compartment; and (c) separating the first and second compartments with a seal, wherein the active ingredient in the first compartment is not in contact with the aqueous solution until just prior to usage by breaking the seal.
- the active ingredient in the first compartment is a lyophilized powder or mixed with a non-hydrolytic solvent.
- the active ingredient is lipoic acid choline ester or derivatives thereof, or a peptide.
- the invention also provides a method of treating or preventing presbyopia in a subject in need thereof, the method comprising administering to a lens or an eye of the subject an effective amount of any of the pharmaceutical composition described herein.
- FIG. 1 shows the formation of a lens fiber cell fluid layer during accommodation by aquaporin-0.
- FIG. 2 A shows lipoic acid choline ester metabolites distribution in rabbit eyes following treatment of the rabbit eyes each with 1 drop of a 3% lipoic acid choline ester formulation for 45 minutes.
- FIG. 2B is a schematic drawing of metabolism and clearance of lipoic acid choline ester.
- FIG. 3 shows a comparison of delivering of lipoic acid following administration of a lipoic acid formulation and a lipoic acid choline ester formulation.
- FIG. 4 shows a design of a two-part eye drop bottle with an insert that can be used for long term storage of lipoic acid choline ester formulations.
- numeric values disclosed herein are understood as within a range of normal tolerance in the art, for example, within 10% of the stated value.
- EV06 lipoic acid choline ester
- the counter ion (i.e., Z " ) of LACE can be any pharmaceutically acceptable anions.
- Non- limiting examples of counter ions include chloride, bromide, iodide, sulfate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, hydrogen fumarate, tartrate (e.g., (+)-tartrate, (-)-tartrate, or a mixture thereof), succinate, benzoate, and anions of an amino acid such as glutamic acid.
- the counter ion is chloride.
- the counter ion is tartrate.
- DioptinTM formulations refer to lipoic acid choline ester formulations.
- DioptinTM 3% formulation refers to a formulation having 3% lipoic acid choline ester by weight of the formulation.
- a "derivative" of lipoic acid choline ester is understood as any compound or a mixture of compounds, excluding lipoic acid and choline, formed from reacting lipoic acid choline ester with a non-aqueous pharmaceutical excipient.
- the derivative is a product formed from reacting lipoic acid choline ester with propylene glycol.
- the derivative is a product formed from reacting lipoic acid choline ester with glycerol.
- excipient refers to pharmaceutically acceptable excipient.
- treating refers to administering a therapy in an amount, manner, or mode effective to improve a condition, symptom, or parameter associated with a disease or disorder.
- preventing refers to precluding a patient from getting a disorder, causing a patient to remain free of a disorder for a longer period of time, or halting the progression of a disorder, to either a statistically significant degree or to a degree detectable to one skilled in the art.
- the term "therapeutically effective amount” refers to that amount of an active ingredient (e.g., LACE or derivatives thereof), which results in prevention or delay of onset or amelioration of symptoms of an ocular disease or disorder (e.g., presbyopia) in a subject or an attainment of a desired biological outcome, such as improved accommodative amplitude or another suitable parameter indicating disease state.
- an active ingredient e.g., LACE or derivatives thereof
- a desired biological outcome such as improved accommodative amplitude or another suitable parameter indicating disease state.
- Methods for determining the therapeutically effective amount for ocular applications are known, for example, as described in U.S. Patent No. 8,410,162, the content of which is herein incorporated by reference in its entirety.
- the therapeutically effective amount for treating or preventing presbyopia can be determined by measuring clinical outcomes including, but not limited to, the elasticity, stiffness, viscosity, density, or opacity of a lens.
- shelf-stability or “shelf stable” is understood as a character of or to characterize a composition or an active ingredient (e.g., LACE or derivatives thereof) that is substantially unchanged upon storing at 25 °C under 40% relative humidity (RH) for a period of time (e.g., 3 months).
- RH relative humidity
- Methods for determining such shelf-stability are known, for example, shelf-stability can be measured by HPLC to determine the percentage of the composition or active ingredient (e.g., lipoic acid choline ester) that remains or has been degraded in a formulation following storing the formulation for a certain period of time.
- shelf stable pharmaceutical composition can refer to a composition, which after being stored at 25 °C under 40% RH for 3 months, has at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or greater than 99%) of the active ingredient (e.g., lipoic acid choline ester) present in the composition as measured by HPLC.
- the active ingredient e.g., lipoic acid choline ester
- Shelf stable pharmaceutical composition can also refer to a composition, which after being stored at 25 °C under 40% RH for 3 months, has 5%> or less (e.g., less than 4%, less than 3%, less than 2%, less than 1%, or less than 0.5%)) of the active ingredient (e.g., lipoic acid choline ester) being degraded as measured by HPLC.
- the active ingredient e.g., lipoic acid choline ester
- RRT relative retention time
- subject generally refers to an animal (e.g., a pet) or human, including healthy human or a patient with certain diseases or disorders (e.g., presbyopia).
- animal e.g., a pet
- human including healthy human or a patient with certain diseases or disorders (e.g., presbyopia).
- the invention provides a pharmaceutical composition comprising a therapeutically effective amount of lipoic acid choline ester or derivatives thereof.
- the pharmaceutical composition comprises a lyophilized powder comprising a therapeutically effective amount of lipoic acid choline ester or derivatives thereof.
- the lyophilized powder also includes a nonaqueous excipient.
- the lyophilized powder is obtained by lyophilizing any of the pharmaceutical compositions described herein.
- the pharmaceutical composition comprises a therapeutically effective amount of lipoic acid choline ester or derivatives thereof and a non-aqueous excipient.
- the therapeutically effective amount of lipoic acid choline ester and the non-aqueous excipient are mixed in an aqueous solution having a pH of 4 to 8 (e.g., 4.0, 4.2, 4.4, 4.6, 4.8, 5.0, 5.2, 5.4, 5.6, 5.8, 6.0, 6.2, 6.4, 6.6, 6.8, 7.0, 7.2, 7.4, 7.6, 7.8, 8.0, or any ranges based on these specified numeric values).
- the aqueous solution comprises a buffer agent.
- the pharmaceutical composition is free of a buffer agent.
- the aqueous solution is substantially oxygen free.
- the pharmaceutical composition is prepared by mixing the therapeutically effective amount of lipoic acid choline ester and the non-aqueous excipient sequentially or simultaneously with the aqueous solution. In some embodiments, the pharmaceutical composition is prepared by first mixing the therapeutically effective amount of lipoic acid choline ester and the non-aqueous excipient to form a non-aqueous composition, and then mixing the non-aqueous composition with the aqueous solution.
- the pharmaceutical composition prepared by either method can have a shelf- stability of at least 3 months (e.g., 3 months, 6 months, 9 months, 1 year, or more than 1 year).
- the pharmaceutical composition after being stored at 25 °C under 40% RH for 3 months, has at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or greater than 99%) of the lipoic acid choline ester or derivatives thereof present in the composition as measured by HPLC.
- the pharmaceutical composition after being stored at 25 °C under 40%> RH for 3 months, has 5% or less (e.g., less than 4%, less than 3%, less than 2%, less than 1%, or less than 0.5%) of the lipoic acid choline ester or derivatives thereof been degraded as measured by HPLC.
- the pharmaceutical composition can also have favorable profiles of drug related degradant (e.g., total drug related impurities, or amount of a specific drug related impurity) following storage at 25 °C under 40% RH for a certain period of time.
- drug related degradant e.g., total drug related impurities, or amount of a specific drug related impurity
- Analytical tools e.g., HPLC
- the pharmaceutical composition is characterized by having 12% or less (e.g., less than 10%, less than 8%, less than 6%, less than 4%), less than 2%, or less than 1%) total drug related impurities based on area-under- the-curve as determined by HPLC following storage at 25 °C under 40% RH for 3 months.
- the pharmaceutical composition is characterized by having 7% or less (e.g., less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1%) of a drug related impurity based on area-under-the-curve as determined by HPLC following storage at 25 °C under 40% RH for 3 months, wherein the drug related impurity is characterized by a relative retention time of 1.12 to 1.14.
- the pharmaceutical composition is characterized by having 4% or less (e.g., less than 3%, less than 2%, or less than 1%) of a drug related impurity based on area-under-the-curve as determined by HPLC following storage at 25 °C under 40% RH for 3 months, wherein the drug related impurity is characterized by a relative retention time of 0.65 to 0.66.
- Concentration of lipoic acid choline ester or derivatives thereof in the pharmaceutical composition can be any concentration of from 1% to 10% (e.g., 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or any ranges based on these specified numeric values) by weight of the composition.
- the concentration of the lipoic acid choline ester in the pharmaceutical composition is 1%. In some embodiments, the concentration of the lipoic acid choline ester in the pharmaceutical composition is 3%. In some embodiments, the concentration of the lipoic acid choline ester in the pharmaceutical composition is 4%.
- the non-aqueous excipient can be an ophthalmically acceptable excipient.
- the non-aqueous excipient is non-hydro lytic.
- the non-aqueous excipient is substantially miscible with water.
- the non-aqueous excipient forms an emulsion upon mixing with water.
- the non-aqueous excipient is an ionic liquid (e.g., glycerol-choline).
- the non-aqueous excipient that is substantially miscible with water is an alcohol (e.g., ethanol, sorbitol, propylene glycol, polyethylene glycol, glycerol, or a mixture thereof).
- the alcohol is a polyol (e.g., propylene glycol, glycerol, ethylene glycol, diethylene glycol, erythritol, lactitol, maltitol, mannitol, sorbitol, xylitol, pentaerythritol, or sucrose).
- the polyol is glycerol.
- the polyol is propylene glycol.
- the non-aqueous excipient is a semifluormated alkane.
- Semifluormated alkanes are known, for example, as described in U.S. Patent Application Publication 2013/0046014, the content of which is incorporated by reference in its entirety.
- Semifluormated alkanes are linear or branched alkanes some of whose hydrogen atoms have been replaced by fluorine.
- the semifluormated alkanes are composed of at least one non-fluorinated hydrocarbon segment and at least one perfluorinated hydrocarbon segment.
- the semifluormated alkanes have one non-fluorinated hydrocarbon segment attached to one perfluorinated hydrocarbon segment, according to the general formula F(CF 2 )n(CH 2 )mH, or two perfluorinated hydrocarbon segments separated by one non-fluorinated hydrocarbon segment, according to the general formula F(CF 2 ) n (CH 2 ) m (CF 2 ) 0 F, wherein n, m, and o are independently selected in the range from 3 to 20.
- Concentrations of the non-aqueous excipient (e.g., glycerol) in the pharmaceutical composition can be from 0.1% to 10% (e.g., 0.1%, 0.2, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or any ranges based on these specified numeric values) by weight of the composition.
- the non-aqueous excipient is glycerol
- the concentration of glycerol is in the range of 0.1% to 5% (e.g., 0.1%>, 0.2%>, 0.5%>, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, or any ranges based on these specified numeric values) by weight of the composition.
- the concentration of glycerol is 0.1%, 0.4%, 1.3%, or 2.7% by weight of the composition.
- the pharmaceutical composition can also contain other suitable ingredients.
- suitable ingredients include one or more ingredients selected from the group consisting of a biochemically acceptable energy source, a preservative, a buffer agent, a tonicity agent, a surfactant, a viscosity modifying agent, and an antioxidant.
- Suitable biochemically acceptable energy source can be any of those known in the art.
- the biochemical acceptable energy source can be any of those that can facilitate reduction by participating as an intermediate of energy metabolic pathways, particularly the glucose metabolic pathway.
- suitable biochemically acceptable energy source include amino acids or derivative thereof (e.g., alanine, glycine, valine, leucine, isoleucine, 2-oxoglutarate, glutamate, and glutamine, etc.), a sugar or metabolites thereof (e.g., glucose, glucose-6-phosphate (G6P)), pyruvate (e.g., ethyl pyruvate), lactose, lactate, or derivatives thereof), a lipid (e.g., a fatty acid or derivatives thereof such as mono-, di-, and tri-glycerides and phospholipids), and others (e.g., NADH).
- amino acids or derivative thereof e.g., alanine, glycine, valine, le
- Suitable amount of a biochemically acceptable energy source can be in the range of 0.01% to 5% (e.g., 0.05%, 0.1%, 0.2%, 0.5%, 1%, 2%, 3%, 4%, 5%, or any ranges based on these specified numeric values) by weight of the composition.
- the biochemical energy source is ethyl pyruvate.
- the biochemical energy source is alanine.
- the amount of ethyl pyruvate or alanine is in the range of 0.05% to 5% (e.g., 0.05%, 0.1%, 0.2%, 0.5%, 1%, 2%, 3%, 4%, 5%, or any ranges based on these specified numeric values) by weight of the composition. In some embodiments, the amount of alanine is 0.5% by weight of the composition. In any of the embodiments described herein, the biochemically acceptable energy source is in an amount that is ophthalmically acceptable.
- Suitable preservatives can be any of those known in the art. Non-limiting examples include benzalkonium chloride (BAK), cetrimonium, chlorobutanol, edetate disodium (EDTA), polyquaternium-1 (Polyquad®), polyhexamethylene biguanide (PHMB), stabilized oxychloro complex (PURITE®), sodium perborate, and SofZia®.
- Suitable amount of a preservative in the pharmaceutical composition can be in the range of 0.005% to 0.1% (e.g., 0.005, 0.01, 0.02%, 0.05%, 0.1%, or any ranges based on these specified numeric values) by weight of the composition.
- the preservative is benzalkonium chloride.
- the benzylalkonium chloride is in the amount of 0.005% to 0.1% (e.g., 0.005, 0.01, 0.02%, 0.05%, 0.1%, or any ranges based on these specified numeric values) by weight of the composition.
- the benzylalkonium chloride is in the amount of 0.01% by weight of the composition.
- the preservative is in an amount that is ophthalmically acceptable.
- the pharmaceutical composition is free of a preservative. Even though lipoic acid choline ester or a derivative thereof may function as a preservative, as used herein, it is not categorized as a preservative.
- Suitable buffer agent can be any of those known in the art that can achieve a desired pH (e.g., described herein) for the pharmaceutical composition.
- Non-limiting examples include phosphate buffers (e.g., sodium phosphate monobasic monohydrate, sodium phosphate dibasic anhydrous), acetate buffer, citrate buffer, borate buffers, and HBSS (Hank's Balanced Salt Solution).
- Suitable amount of a buffer agent can be readily calculated based on a desired pH.
- the buffer agent is in an amount that is ophthalmically acceptable.
- the pharmaceutical composition does not include a buffer agent.
- the pH of the aqueous solution or the final pharmaceutical composition is adjusted with an acid (e.g., hydrochloride acid) or a base (e.g., sodium hydroxide) to the desired pH range (e.g., as described herein).
- an acid e.g., hydrochloride acid
- a base e.g., sodium hydroxide
- Suitable tonicity agent can be any of those known in the art. Non-limiting examples include sodium chloride, potassium chloride, mannitol, dextrose, glycerin, propylene glycol and mixtures thereof. Suitable amount of tonicity agent in the pharmaceutical composition is any amount that can achieve an osmolality of 200-460 mOsm (e.g., 260-360 mOsm, or 260-320 mOsm). In some embodiments, the pharmaceutical composition is an isotonic composition.
- the amount of a tonicity agent e.g., sodium chloride
- the tonicity agent is in an amount that is ophthalmically acceptable.
- Suitable surfactant can be any of those known in the art, including ionic surfactants and nonionic surfactants.
- Non- limiting ionic surfactants include ammonium lauryl sulfate, sodium lauryl sulfate, sodium laureth sulfate, sodium myreth sulfate, dioctyl sodium sulfosuccinate, perfluorooctanesulfonate, perfluorobutanesulfonate, linear alkylbenzene sulfonates, sodium lauroyl sarcosinate, perfluorononanoate, perfluorooctanoate, octenidine dihydrochloride, cetyl trimethylammonium bromide, cetyl trimethylammonium chloride, cetylpyridinium chloride (CPC), benzalkonium chloride (BAC), benzethonium chloride (BZT), dimethyldioctadec
- Non-limiting examples of useful nonionic surfactants include polyoxyethylene fatty esters (e.g., polysorbate 80 [poly(oxyethylene)sorbitan monooleate], polysorbate 60 [poly(oxyethylene)sorbitan monostearate], polysorbate 40 [poly(oxyethylene)sorbitan monopalmitate], poly(oxyethylene)sorbitan monolaurate, poly(oxyethylene)sorbitan trioleate, or polysorbate 65 [poly(oxyethylene)sorbitan tristearate]), polyoxyethylene hydrogenated castor oils (e.g., polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, or polyoxyethylene hydrogenated castor oil 60), polyoxyethylene polyoxypropylene glycols (e.g., polyoxyethylene (160) polyoxypropylene (30) glycol [Pluronic F681], polyoxyethylene (42) polyoxypropylene (67) glycol [Pluronic PI 23], polyoxyethylene (5
- the surfactant is polysorbate 80.
- Suitable amount of surfactant in the pharmaceutical composition can be in the range of 0.01% to 5% (e.g., 0.05, 0.1, 0.2%, 0.5%, 1%, 2%, 3%, 4%, 5%, or any ranges based on these specified numeric values) by weight of the composition.
- the surfactant is polysorbate 80, and the amount of polysorbate 80 is in the range of 0.05% to 5% (e.g., 0.05, 0.1, 0.2%, 0.5%, 1%, 2%, 3%, 4%, 5%, or any ranges based on these specified numeric values) by weight of the composition.
- the amount of polysorbate 80 is 0.5% by weight of the composition.
- the surfactant is in an amount that is ophthalmically acceptable.
- the pharmaceutical composition is free of a surfactant. Even though lipoic acid choline ester or a derivative thereof may function as a surfactant, as used herein, it is not categorized as a surfactant.
- Suitable viscosity modifying agent can be any of those known in the art. Non- limiting examples include carbopol gels, cellulosic agents (e.g., hydroxypropyl methylcellulose), polycarbophil, polyvinyl alcohol, dextran, gelatin glycerin, polyethylene glycol, poloxamer 407, polyvinyl alcohol and polyvinyl pyrrolidone and mixtures thereof. Suitable amount of viscosity modifying agent can be in the range of 0.1% to 5% (e.g., 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, or any ranges based on these specified numeric values) by weight of the composition.
- the viscosity modifying agent is in an amount that is ophthalmically acceptable.
- the pharmaceutical composition is free of a viscosity modifying agent (e.g., a polymeric viscosity modifying agent such as hydroxypropyl methylcellulose).
- Suitable antioxidant can be any of those known in the art.
- the redox potential of the antioxidant is less than 0.5 mv (e.g., less than 0.4 mv, less than 0.3 mv, less than 0.2 mv, or less than 0.1 mv).
- the redox potential of the antioxidant is less than 0.28 mv, the redox potential for dihydrolipoic acid (DHLA).
- Non-limiting examples include ascorbic acid, L-ascorbic acid stearate, alphathioglycerin, ethylenediaminetetraacetic acid, erythorbic acid, cysteine hydrochloride, N-acetylcysteine, L-carnitine, citric acid, tocopherol acetate, potassium dichloroisocyanurate, dibutylhydroxytoluene, 2,6-di-t-butyl-4-methylphenol, soybean lecithin, sodium thioglycollate, sodium thiomalate, natural vitamin E, tocopherol, ascorbyl pasthyminate, sodium pyrosulfite, butylhydroxyanisole, 1,3-butylene glycol, pentaerythtyl tetrakis[3-(3,5-di-t-butyl-4-hydroxyphenyl)]propionate, propyl gallate, 2- mercaptobenzimidazole and oxyquinoline s
- Suitable amount of antioxidant can be in the range of 0.1% to 5% (e.g., 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, or any ranges based on these specified numeric values) by weight of the composition. In any of the embodiments described herein, the antioxidant is in an amount that is ophthalmically acceptable. [0055] In some embodiments, the pharmaceutical composition is characterized by one or more of the following:
- composition having a concentration of the lipoic acid choline ester from 1% to 10% (e.g., 1%, 1.5%, 3%), 4%), 5%>, or any ranges between the specified numeric values) by weight of the composition;
- composition having a concentration of a preservative (e.g., benzalkonium chloride) of 0.005% to 0.1%) (e.g., 0.01%)) by weight of the composition;
- a preservative e.g., benzalkonium chloride
- composition having a biochemical energy source (e.g., alanine) of 0.1 % to 5% (e.g., 0.5%>) by weight of the composition; and
- a biochemical energy source e.g., alanine
- the lipoic acid choline ester in the pharmaceutical composition has a counter ion selected from the group consisting of chloride, bromide, iodide, sulfate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, hydrogen fumarate, tartrate (e.g., (+)-tartrate, (-)-tartrate, or a mixture thereof), succinate, benzoate, and anions of an amino acid such as glutamic acid.
- the counter ion is chloride.
- the pharmaceutical composition contains a non-aqueous excipient, which is glycerol in a concentration of 2.7% by weight of the composition. In some embodiments, the concentration of glycerol is 3% by weight of the composition.
- the pharmaceutical composition consists essentially of
- edetate disodium dehydrate 1.3% by weight of glycerin, 0.5% by weight of alanine, 0.01% by weight of benzalkanium chloride, 1% by weight of lipoic acid choline ester, and water, wherein the pH of the pharmaceutical composition is 4.3 to 4.7.
- the pharmaceutical composition consists essentially of
- edetate disodium dehydrate 0.025%) by weight of edetate disodium dehydrate, 0.4 % by weight of glycerin, 0.5% by weight of alanine, 0.01% by weight of benzalkanium chloride, 3% by weight of lipoic acid choline ester, and water, wherein the pH of the pharmaceutical composition is 4.3 to 4.7.
- the pharmaceutical composition consists essentially of
- edetate disodium dehydrate 0.1% by weight of glycerin, 0.5% by weight of alanine, 0.01% by weight of benzalkanium chloride, 4% by weight of lipoic acid choline ester, and water, wherein the pH of the pharmaceutical composition is 4.4 to 4.6.
- the pharmaceutical compositions described herein can be formed by premixing the therapeutically effective amount of lipoic acid choline ester with a nonaqueous excipient to form a non-aqueous composition.
- the non-aqueous composition can then be further mixed with an aqueous solution, e.g., to form an ophthalmic formulation.
- the invention also provides a system or method of long- term storage of the pharmaceutical composition by storing the non-aqueous composition separately from the aqueous solution, for example, in a two-part device (e.g., as described herein) or in a kit.
- the separately stored non-aqueous composition can then be mixed with the aqueous solution to form an "activated" formulation prior to use.
- the non-aqueous composition can be a solution, an emulsion, or a suspension formed by mixing lipoic acid choline ester and the non-aqueous excipient.
- the mixing can be conducted under heat for a sustained period of time.
- the mixing is conducted at a temperature of 20 °C to 100 °C (e.g., 20 °C, 30 °C, 40 °C, 50 °C, 60 °C, 70 °C, 80 °C, 90 °C, 100 °C, or any ranges based on these specified numeric values) for a period of 1 hour to 24 hours (e.g., 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, or any ranges based on these specified numeric values).
- the mixing is conducted at a temperature of 37 °C to 80 °C. In some embodiments, the mixing is carried out for 8 hours.
- the non-aqueous composition is a solution.
- the solution contains lipoic acid choline ester.
- the solution contains a derivative of lipoic acid choline ester (e.g., a reaction product formed from lipoic acid choline ester and a non-aqueous excipient (e.g., propylene glycol or glycerol).
- the concentration of lipoic acid choline ester or derivatives thereof in the solution can be up to the solubility limit in the non-aqueous excipient (e.g., propylene glycol or glycerol).
- the concentration of lipoic acid choline ester or derivatives thereof is in a range of 0.1% to 40% (e.g., 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%), or any ranges based on these specified numeric values) by weight of the solution.
- the non-aqueous compositions described herein can be mixed with an aqueous solution having a pH of 4 to 8 (e.g., 4.2, 4.4, 4.6, 4.8, 5.0, 5.2, 5.4, 5.6, 5.8, 6.0, 6.2, 6.4, 6.6, 6.8, 7.0, 7.2, 7.4, 7.6, 7.8, 8.0, or any ranges based on these specified numeric values) to form an ophthalmic formulation.
- mixing the non-aqueous composition does not substantially change the pH of the aqueous solution, i.e., the ophthalmic formulation also has a pH of 4 to 8.
- the ophthalmic formulation has a pH of 4 to 6 (e.g., 4.2, 4.4, 4.6, 4.8, 5.0, 5.2, 5.4, 5.6, 5.8, 6.0, or any ranges based on these specified numeric values). In some embodiments, the ophthalmic formulation has a pH of 4.2 to 4.7 (e.g., 4.5).
- the ophthalmic formulations can be sterilized.
- the nonaqueous composition is sterilized before mixing with the aqueous solution.
- the aqueous solution is also sterilized.
- the nonaqueous composition is mixed with the aqueous solution (e.g., a sterilized aqueous solution, or a non-sterilized aqueous solution) and then sterilized.
- the ophthalmic formulation can include one or more ingredients selected from the group consisting of a biochemically acceptable energy source, a preservative, a buffer agent, a tonicity agent, a surfactant, a viscosity modifying agent, and an antioxidant. Suitable biochemically acceptable energy sources, preservatives, buffer agents, tonicity agents, surfactants, viscosity modifying agents, and antioxidants are those described herein.
- the one or more ingredients are mixed in the aqueous solution before mixing with the non-aqueous composition.
- the one or more ingredients are mixed in the non-aqueous composition before mixing with the aqueous solution.
- ophthalmic formulation can also be free of a buffer agent, a surfactant, a viscosity modifying agent, a preservative, or a combination thereof.
- the ophthalmic formulation is characterized by one or more of: (a) having a concentration of the lipoic acid choline ester or derivatives thereof from 1% to 10% (e.g., 1%), 1.5%, 3%), 4%, 5%, or any ranges based on the specified numeric values) by weight of the formulation;
- biochemical energy source e.g., alanine
- 0.1%> to 5% e.g., 0.5%) by weight of the formulation
- (f) having a shelf-life stability of greater than 3 months e.g., 3 months, 6 months, 9 months, or 12 months.
- the ophthalmic formulation contains a non-aqueous excipient, which is glycerol in a concentration of 2.7% by weight of the composition. In some embodiments, the concentration of glycerol is 3% by weight of the formulation.
- the ophthalmic formulation consists essentially of 0.025% by weight of edetate disodium dehydrate, 1.3% by weight of glycerin, 0.5% by weight of alanine, 0.01% by weight of benzalkanium chloride, 1% by weight of lipoic acid choline ester or derivatives thereof, and water, wherein the pH of the ophthalmic formulation is 4.3 to 4.7.
- the ophthalmic formulation consists essentially of 0.025% by weight of edetate disodium dehydrate, 0.4 % by weight of glycerin, 0.5% by weight of alanine, 0.01% by weight of benzalkanium chloride, 3% by weight of lipoic acid choline ester or derivatives thereof, and water, wherein the pH of the ophthalmic formulation is
- the ophthalmic formulation consists essentially of 0.025% by weight of edetate disodium dehydrate, 0.1% by weight of glycerin, 0.5% by weight of alanine, 0.01% by weight of benzalkanium chloride, 4% by weight of lipoic acid choline ester or derivatives thereof, and water, wherein the pH of the ophthalmic formulation is
- the invention provides a method for storing lipoic acid choline ester in a non-aqueous environment, an oxygen free environment, and/or with reduced light exposure.
- the lipoic acid choline ester is stored in a non-aqueous environment.
- the lipoic acid choline ester is stored in the non-aqueous environment as a lyophilized powder.
- the lipoic acid choline ester is stored in the non-aqueous environment as a non-aqueous composition (e.g., as described herein).
- the lipoic acid choline ester is stored in a non-aqueous environment in an opaque container.
- the non-aqueous environment is substantially oxygen free.
- the lipoic acid choline ester is stored in an aqueous environment (e.g., after mixing a non-aqueous composition with an aqueous solution), wherein the aqueous environment is free of oxygen.
- the lipoic acid choline ester is stored in the aqueous environment with reduced light exposure (e.g., in an opaque container).
- the invention also provides a system for storing a pharmaceutical composition comprising an active ingredient in an aqueous solution, wherein the active ingredient (e.g., lipoic acid choline ester or derivatives thereof) is susceptible to hydrolysis in the aqueous solution.
- the active ingredient e.g., lipoic acid choline ester or derivatives thereof
- the system comprises a first compartment, a second compartment, and a seal separating the first and second compartments, wherein the first compartment comprises a non-aqueous composition comprising the active ingredient (e.g., lipoic acid choline ester or derivatives thereof), the second compartment comprises an aqueous solution.
- the active ingredient in the first compartment is in a solid form (e,g., a powder, e.g., a lyophilized powder).
- the active ingredient in the first compartment is mixed with a non-aqueous excipient (e.g., as described herein).
- the system is activated upon breaking the seal and mixing the non-aqueous solution with the aqueous solution.
- part 1 of the eye drop bottle contains any of the non-aqueous compositions described herein (e.g., lipoic acid choline ester or derivatives thereof mixed with glycerol).
- part 1 of the eye drop bottle contains a non-aqueous composition comprising an active ingredient (e.g., a peptide) that is susceptible to hydrolysis in an aqueous solution.
- part 1 of the eye drop bottle contains lipoic acid choline ester or derivatives thereof in glycerol (e.g., 150 mg LACE/1.03 uL glycerol).
- part 2 of the eye drop bottle contains an aqueous solution (4.8 mL) having the following excipients: 0.01 % by weight of Benzalkonium Chloride; 2.6 % by weight of Glycerin, USP; and 0.5% by weight of Alanine, USP, wherein the pH of the solution is 4.5 ⁇ 0.2.
- the insert separates the non-aqueous composition from part 2 until activation, which allows long-term storage until short-term ocular treatment is started.
- the insert includes a main insert stationary holder; an inner tube; and a lower seal, wherein the inner tube is configured to contain the non-aqueous composition and the lower seal is configured to prevent contact of the non-aqueous composition with the aqueous solution.
- the eye drop bottle includes a dropper tip, which seals the insert.
- the eye drop bottle is configured such that compressing or squeezing the bottle is sufficient to move the lower seal upward, whereby exposing the inner tube perforations to release the non-aqueous composition into the aqueous solution.
- the non-aqueous composition comprising the active pharmaceutical ingredient (e.g., lipoic acid choline ester or derivatives thereof), prior to releasing into the aqueous solution, is shelf-stable for at least 3 months (e.g., 6 months, 9 months, 12 months, 2 years, or more than 2 years).
- the non-aqueous composition is characterized by having 2% or less (e.g., 1.5%, 1%), 0.5%), or 0.2%o) of the active pharmaceutical ingredient degraded.
- the non-aqueous composition is characterized by having 10%> or less (e.g., 9%, 8%, 7%, 6%, 5%, 4%, 35, 2%, 1%, 0.5%, or 0.2%) of the active pharmaceutical ingredient degraded.
- the pharmaceutical composition formed by releasing the non-aqueous composition into the aqueous solution is shelf-stable for at least 3 months (e.g., 6 months, 9 months, or 12 months).
- the invention also provides a method of storing an active ingredient that is susceptible to hydrolysis in an aqueous solution, the method comprising (a) providing the active ingredient in a first compartment; (b) providing the aqueous solution in a second compartment; and (c) separating the first and second compartments, e.g., with a seal, wherein the active ingredient in the first compartment is not in contact with the aqueous solution until just prior to usage, e.g., by breaking the seal.
- the active ingredient in the first compartment is mixed with a non-aqueous excipient (e.g., as described herein).
- the active ingredient is lipoic acid choline ester or derivatives thereof, or a peptide. Suitable methods for configuring the first compartment and the second compartment include those described herein.
- compositions comprising lipoic acid choline ester or derivatives thereof (e.g., as described herein) can be employed in a method for treating or preventing a disease or disorder associated with oxidative damage.
- Diseases or disorders associated with oxidative damage are known.
- the invention provides a method of treating an ocular disease in a subject in need thereof, comprising administering to a lens or an eye of the subject a therapeutically effective amount of any of the pharmaceutical compositions described herein.
- the ocular diseases are presbyopia, cataract, macular degeneration (including age-related macular degeneration), retinopathies (including diabetic retinopathy), glaucoma, or ocular inflammations.
- the ocular disease is presbyopia.
- Suitable amount of pharmaceutical compositions for the methods of treating or preventing an ocular disease herein can be any therapeutically effective amount.
- the method comprises administering to the lens or eye of the subject an amount of the pharmaceutical composition effective to increase the accommodative amplitude of the lens by at least 0.1 diopters (D) (e.g., 0.1, 0.2, 0.5, 1, 1.2, 1.5, 1.8, 2, 2.5, 3, or 5 diopters).
- the method comprises administering to the lens or eye of the subject 1-5 drops (about 40 uL per drop) of the pharmaceutical composition.
- the lens or eye of the subject is treated with the pharmaceutical composition 1, 2, 3, 4, 5, or more than 5 times a day, each time with 1-5 drops (about 40 uL per drop). In some embodiments, the lens or eye of the subject is treated with the pharmaceutical composition 1, 2, 3, 4, 5, or more than 5 drops each time. In some embodiments, the lens or eye of the subject is treated with the pharmaceutical composition herein twice or three times per day, each time with 1 or 2 drops (about 40 uL per drop).
- the methods include preventative methods that can be performed on patients of any age.
- the methods also include therapeutic methods that can be performed on patients of any age, particularly patients that are 20, 25, 30, 35, 40, 45, 50, 52, 55, 57, 60, 70, 75, or 80 years of age or older.
- HPLC systems that were used in the performance of the HPLC assays were qualified by CGMP with IQ, OQ and PQ. Each system that was used consisted of a Waters 2695 Separations Module and Waters 2487 Dual ⁇ Absorbance Detector.
- the HPLC method to analyze LACE Chloride used a Phenomenex Luna CN column with a 5 um particle size, 100 A pore size, 2.0 mm inner diameter, and 50 mm length (PN: 00B-4255-B0).
- the mobile phase consisted of 50% of 0.1 M Sodium Acetate and 50 % Acetonitrile.
- the flow rate was 1.0 mL/min
- the detection wavelength was 225 nm
- the column temperature was 40 °C
- the injection volume was 20 uL
- the run time was 50 minutes.
- the working LACE chloride concentration was 0.1 mg/mL and plastic HPLC vials were used for the analysis.
- Table 1 shows the detailed formulations of LACE chloride ophthalmic formulations at pH 5.5 and 7.0 (BCL442-110).
- LACE Chloride 1.5% 3.0% 5.0% 1.5% 3.0% 5.0% [0100]
- the pH, osmolality, appearance, and LACE chloride concentration were measured in solutions containing LACE chloride at 1.5 %, 3.0 %, and 5.0% at pH 5.5 or pH 7.0.
- the LACE chloride assay was performed four days after preparation. The solutions showed that the LACE chloride is not very stable at pH 7 over four days from the time of preparation until the assay was performed. But the solutions at pH 5.5 resulted in a percent recovery from 86% to 109%, which showed that low pH is more stable for LACE chloride formulations.
- a solution of LACE chloride in propylene glycol was prepared to determine its stability.
- a solution of 1.0%> LACE chloride in propylene glycol was prepared and stored at -20 °C(ambient RH), 5 °C(ambient RH), and 25 °C (40% RH). The solutions were tested for LACE chloride potency after storage for 3 months.
- Waters 2695 Separation Module or equivalent containing a pump capable of delivering a gradient flow rate of 1.0 mL/min or equivalent and an autosampler.
- the run time and the retention time may vary based on the age of the column and the type of the instrument used
- DioptinTM the lenses of the treated eyes of the old mice were more elastic than the lenses of untreated eyes, i.e. the relative force required for similar Z displacements was higher in the untreated eyes' lenses. In most instances the lenses of the treated eyes were even more elastic than the lenses of the 8 week old mice.
- Draize Test is an acute toxicity test devised in 1944 by Food and Drug Administration (FDA) toxicologists John H. Draize and Jacob M. Spines. Initially used for testing cosmetics, the procedure involves applying 0.5 mL or 0.5g of a test substance to the eye or skin of a restrained, conscious animal, and then leaving it for set amount of time before rinsing it out and recording its effects. Corneal, iris, and conjunctival responses were evaluated using the scale described by Draize et al, J. Pharmacol. & Exp. Therapeutics, 52:377-390 (1944)].
- Draize score is based on corneal damage. A normal score was 0, increasing amounts of damage result in a higher score, with the maximum score possible being 110. A Draize score was computed at each observation time by averaging the total scores of all rabbits tested. Observations were made and recorded 24, 48, and 72 hours after treatment.
- This test consists of instilling 30 to 50 ⁇ of the product into one eye of 6 New
- DioptinTM ophthalmic formulations were well tolerated in rabbit eyes. No dose- related ocular signs of toxicity were observed at any timepoint in the GLP study. Ophthalmic exams were normal, with the exception of mild (1+) conjunctival congestion and (1+) discharge observed in some of animals dosed with 3% or 4% DioptinTM on the first day of dosing, which persisted throughout the dosing period, but did not worsen. No systemic effects or adverse events were reported. Plasma levels of EV06 were at or below the limits of detection, indicating rapid metabolism.
- DioptinTM is a promising new treatment for presbyopia, with the potential to restore several diopters of accommodation.
- EV06 has been shown to be effective at increasing lens elasticity through reduction of lens protein disulfides.
- the ophthalmic formulation is non-irritating, and systemic and ocular safety have been demonstrated in a 90 day GLP ocular toxicology study at topical doses up to 4% three times daily.
- DioptinTM Eye Drop to Treat Presbyopia corneal penetration and ocular
- esters of lipoic acid were evaluated in rabbits for corneal penetration. Rabbits were also used to examine the metabolism, absorption, and distribution of LACE (LA prodrug) using HPLC-ESI/MS/MS (LOD > 2 ng/ml).
- LACE was found to improve penetration over lipoic acid.
- a prototypic ocular eye drop formulation of LACE was tested as DioptinTM. It is rapidly degraded by endogenous butycholinesterases and provides elevated ocular tissue levels of LA.
- Lens DHLA (measured as LA) and LACE are both significantly elevated [P ⁇ 0.05] using 3% DioptinTM treated compared to untreated contralateral eye; 22.6 +/- 9.1(5) and 142.3 +/- 31.9 (5) nM/L, respectively.
- DioptinTM elevates LACE (prodrug) and LA (active) in ocular tissue samples (ESI/LC/MS/MS); importantly in the lens. LA can be cleared away in the form of 6,8-bismethylthio-octanoic acid (BMOA).
- BMOA 6,8-bismethylthio-octanoic acid
- LACE molecule into the cornea is converted into non-surfactant natural products (lipoic acid and choline) in the cornea by pseudochlolinesterases (PCHE), which minimizes corneal damage during transit into the aqueous. Importantly, this corneal cleavage process then allows for transfer of these intermediates into the aqueous.
- PCHE pseudochlolinesterases
- This rapid degradation into lipoic acid allows applying a higher concentration of LACE to an eye compared to that of a non-degradable cationic surfactants, for example, the safety limit for ocular use of BAK is ⁇ 0.01%.
- DioptinTM provides a convenient ocular delivery platform for improved aqueous delivery of a dithiol compound to reduce protein disulfides in order to soften the lens and restore accommodative amplitude, which is useful for treatment of Presbyopia.
- Lipoic acid choline ester was mixed in neat glycerol (no water) with brief heating to 80 °C for 8 hours. High concentrations of lipoic acid choline ester in a final clear solution were found. The final clear solution is stable.
- a single bottle 2-part delivery system is described for the 2-part stable long-term manufactured formulation.
- This delivery bottle uses commercially available bottle, dropper tip, and cap.
- An insert is placed into the commercially available standard bottle (Fig. 4, left top), which separates the 2-parts until activation.
- the insert shown in Fig. 4 has the following assembly components: the main insert stationary holder 1; the inner tube 2 that contains the non-hydro lytic solvent and also contains a filter to remove particulates; the lower seal 3 that contains the liquid within the inner tube; and the dropper tip 5 for sealing the insert prior to sterilization.
- the active agent in part-1 composition is added to the inner tube 2, as shown in 4.
- the dropper tip is then placed. Part 1 is sterilized using gamma-irradiation.
- Part-2 contains the aqueous solution that is separately sterilized. Once the insert and aqueous solution are properly sterilized, they are combined (cap removed) under a sterile controlled manufacturing environment (Fig. 4, middle drawing). Part-1 insert is placed into the Part-2 container. Once assembled, long-term storage is possible without need for carefully controlled temperature conditions ( ⁇ 45 °C).
- the final formulation is sufficiently stable to maintain predicted outcome.
- the final formulation is stable when refrigerated (5 °C) for 30 days without degradation >
- Parts 1 and 2 maintained in the 2-part bottle provides a long-term shelf life resistant to thermal degradation ⁇ 45 °C for 2 years.
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Abstract
Description
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Priority Applications (13)
Application Number | Priority Date | Filing Date | Title |
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US15/118,910 US20160354340A1 (en) | 2014-03-03 | 2015-03-03 | Lipoic acid choline ester compositions and methods of use |
CA2941518A CA2941518A1 (en) | 2014-03-03 | 2015-03-03 | Lipoic acid choline ester compositions and methods of use |
BR112016020181A BR112016020181A8 (en) | 2014-03-03 | 2015-03-03 | choline ester lipoic acid compositions and methods of use. |
KR1020167026593A KR20160145558A (en) | 2014-03-03 | 2015-03-03 | Lipoic acid choline ester compositions and methods of use |
EP15758583.7A EP3113613A4 (en) | 2014-03-03 | 2015-03-03 | Lipoic acid choline ester compositions and methods of use |
JP2016573672A JP6526066B2 (en) | 2014-03-03 | 2015-03-03 | Lipoic acid choline ester composition and method of use |
AU2015227307A AU2015227307A1 (en) | 2014-03-03 | 2015-03-03 | Lipoic acid choline ester compositions and methods of use |
MX2016011290A MX2016011290A (en) | 2014-03-03 | 2015-03-03 | Lipoic acid choline ester compositions and methods of use. |
RU2016137784A RU2735790C2 (en) | 2014-03-03 | 2015-03-03 | Compositions and methods of using choline ester of lipoic acid |
CN201580012000.6A CN106455563A (en) | 2014-03-03 | 2015-03-03 | Lipoic acid choline ester compositions and methods of use |
IL247529A IL247529B (en) | 2014-03-03 | 2016-08-29 | Lipoic acid choline ester compositions and methods of use |
US16/578,368 US11426381B2 (en) | 2014-03-03 | 2019-09-22 | Lipoic acid choline ester compositions and methods of use |
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Cited By (3)
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---|---|---|---|---|
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WO2018055572A1 (en) * | 2016-09-23 | 2018-03-29 | Encore Vision, Inc. | Lipoic acid choline ester compositions and methods to stabilize into pharmaceutically relevant drug products |
WO2021181361A1 (en) * | 2020-03-13 | 2021-09-16 | Novartis Ag | Pharmaceutical compositions of lipoic acid choline ester salts and methods of treatment using same |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060275278A1 (en) * | 2005-06-02 | 2006-12-07 | Choy Camus K M | Method and ophthalmic formulation for eye protection or treatment |
EP2179736A1 (en) * | 2007-08-09 | 2010-04-28 | Senju Pharmaceutical Co., Ltd. | Two-component eye drops containing pirenoxine |
US20100317725A1 (en) | 2009-06-15 | 2010-12-16 | Encore Health Llc | Choline Esters |
WO2011104037A2 (en) * | 2010-02-26 | 2011-09-01 | Kist-Europe Forschungsgesellschaft Mbh | Process for preparing a ready-to-use product which can be metered |
WO2012093113A1 (en) * | 2011-01-04 | 2012-07-12 | Novaliq Gmbh | O/w-emulsions comprising semifluorinated alkanes |
US8410462B2 (en) | 2006-12-29 | 2013-04-02 | Endress + Hasuer Gmbh + Co. Kg | Optoelectronic apparatus for transmission of an electrical signal |
WO2013110621A1 (en) * | 2012-01-23 | 2013-08-01 | Novaliq Gmbh | Stabilised protein compositions based on semifluorinated alkanes |
WO2013126597A1 (en) * | 2012-02-22 | 2013-08-29 | Stealth Peptides International, Inc. | Methods and compositions for preventing or treating ophthalmic conditions |
Family Cites Families (80)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB935962A (en) | 1960-06-17 | 1963-09-04 | Fujisawa Pharmaceutical Co | Improvements in or relating to the production of 6.8-dithiooctanamides |
US3855240A (en) | 1969-04-28 | 1974-12-17 | Exxon Research Engineering Co | Sulfur containing heterocycles |
US4210667A (en) | 1979-04-19 | 1980-07-01 | Pfizer Inc. | Pharmaceutical preparations containing coumarin carboxylic acid derivatives |
US4755528A (en) | 1984-12-06 | 1988-07-05 | Alcon Laboratories, Inc. | High energy ionizing protective 2,3-diamino-1,4-butanedithiol; 4,5-diamino-1,2-dithiane; and N-acyl and N-alkyl derivatives thereof, compositions and method of use therefor |
US6030950A (en) | 1987-07-09 | 2000-02-29 | Ohlenschlaeger; Gerhard | Pharmaceutical therapeutic use of glutathione derivative |
US5599903A (en) | 1992-04-03 | 1997-02-04 | Terrapin Technologies, Inc. | Glutathione analogs and paralog panels comprising glutathione mimics |
FR2638970A1 (en) | 1988-11-16 | 1990-05-18 | Corbiere Jerome | NOVEL PHARMACEUTICAL COMPOSITIONS ACTING ON PRESBYTIA AND METHOD OF OBTAINING THEM |
WO1993002639A1 (en) | 1991-08-06 | 1993-02-18 | Autogenesis Technologies, Inc. | Injectable collagen-based compositions for making intraocular lens |
US5466680A (en) | 1992-03-26 | 1995-11-14 | Cytologics, Inc. | Method and compositions for enhancing white blood cell functioning on a mucosal or cutaneous surface |
US5459133A (en) | 1992-06-05 | 1995-10-17 | Telor Ophthalmic Pharmaceuticals, Inc. | Methods and products for treating presbyopia |
AU4633793A (en) | 1992-06-10 | 1994-01-04 | Summit Technology, Inc. | Correction of presbyopia by photorefractive keratectomy |
AU4653993A (en) | 1992-07-02 | 1994-01-31 | Telor Ophthalmic Pharmaceuticals, Inc. | Methods and products for treating presbyopia |
US6313274B1 (en) | 1992-07-06 | 2001-11-06 | Thomas R. Sykes | Photoactivation of proteins for conjugation purposes |
US5465737A (en) | 1992-07-15 | 1995-11-14 | Schachar; Ronald A. | Treatment of presbyopia and other eye disorders |
US5354331A (en) | 1992-07-15 | 1994-10-11 | Schachar Ronald A | Treatment of presbyopia and other eye disorders |
BR9306848A (en) | 1992-08-07 | 1998-12-08 | Keravision Inc | Split polymeric ring for introduction into the stroma |
DE4345199C2 (en) * | 1993-05-22 | 1995-10-12 | Asta Medica Ag | Use of dihydrolipoic acid to suppress intolerance reactions in the border area of implants with living body tissue |
US5395356A (en) | 1993-06-04 | 1995-03-07 | Summit Technology, Inc. | Correction of presbyopia by photorefractive keratectomy |
US5527774A (en) | 1993-07-12 | 1996-06-18 | Girard; Louis J. | Dislocation of cataractous lens by enzymatic zonulolysis |
US5665770A (en) | 1993-11-05 | 1997-09-09 | Gakko Hojin Kinki Daigaku | Method for treatment of cataract with radical scavenger |
EP0754046A1 (en) | 1994-04-04 | 1997-01-22 | FREEMAN, William R. | Use of phosphonylmethoxyalkyl nucleosides for the treatment of raised intraocular pressure |
US6063116A (en) | 1994-10-26 | 2000-05-16 | Medarex, Inc. | Modulation of cell proliferation and wound healing |
US6743779B1 (en) | 1994-11-29 | 2004-06-01 | Imarx Pharmaceutical Corp. | Methods for delivering compounds into a cell |
US5624955A (en) | 1995-05-03 | 1997-04-29 | Regents Of The University Of Minnesota | Compounds that enhance the concentration of glutathione in tissues |
US5686450A (en) | 1995-06-07 | 1997-11-11 | Alcon Laboratories, Inc. | Use of N,N'-bis(mercaptoacetyl) hydrazine derivatives as anticataract agents |
US6007510A (en) | 1996-10-25 | 1999-12-28 | Anamed, Inc. | Implantable devices and methods for controlling the flow of fluids within the body |
US5817630A (en) | 1997-03-18 | 1998-10-06 | Austin Nutriceutical Corporation | Glutathione antioxidant eye drops |
IL123887A0 (en) | 1997-04-02 | 1998-10-30 | Sankyo Co | Dithiolan derivatives their use and pharmaceutical compositions containing the same |
US5843184A (en) | 1998-01-26 | 1998-12-01 | Cionni; Robert J. | Endocapsular tension ring and method of implanting same |
US6153647A (en) | 1998-11-12 | 2000-11-28 | My-Tech, Inc. | Method for augmenting the inotropic effects of β-adrenergic agonists using pyruvate therapy |
US6472541B2 (en) | 1998-11-20 | 2002-10-29 | The Regents Of The University Of California | Protecting groups with increased photosensitivities |
EP1133317A1 (en) | 1998-11-26 | 2001-09-19 | Pentapharm AG | Transport system conjugate |
US6288106B1 (en) | 1999-05-25 | 2001-09-11 | Chronorx, Llc | Processes for the synthesis and use of various α-lipoic acid complexes |
AU5601300A (en) | 1999-06-09 | 2000-12-28 | Department Of The Army, U.S. Government | Method and compositions for treating and preventing retinal damage |
JP4476435B2 (en) * | 1999-07-22 | 2010-06-09 | 株式会社細川洋行 | Partition member, multi-chamber infusion container, and method for producing multi-chamber infusion container with drug |
US6890896B1 (en) | 1999-11-18 | 2005-05-10 | Ceremedix, Inc. | Compositions and methods for counteracting effects of reactive oxygen species and free radicals |
US6387945B2 (en) | 2000-04-11 | 2002-05-14 | The Regents Of The University Of California | Lipoic acid analogs |
EP1303215A1 (en) | 2000-07-10 | 2003-04-23 | Koninklijke Philips Electronics N.V. | Geometry matching for imaging medical apparatus |
WO2002010151A2 (en) | 2000-08-02 | 2002-02-07 | Basf Aktiengesellschaft | Method for producing lipoic acid and dihydrolipoic acid |
US6923955B2 (en) | 2000-08-16 | 2005-08-02 | Newlens, Llc | Presbyopia treatment by lens alteration |
US7914815B2 (en) | 2000-08-16 | 2011-03-29 | Encore Health, Llc | Method for delivery of pharmaceuticals for treating or preventing presbyopia |
US8647612B2 (en) | 2008-03-05 | 2014-02-11 | Encore Health, Llc | Dithiol compounds, derivatives, and treatment of presbyopia |
US7935332B2 (en) | 2000-08-16 | 2011-05-03 | Encore Health, Llc | Presbyopia treatment by lens alteration |
US8697109B2 (en) | 2000-08-16 | 2014-04-15 | Encore Health, Llc | Caged mercaptan and seleno-mercaptan compounds and methods of using them |
US20050112113A1 (en) | 2000-08-16 | 2005-05-26 | Till Jonathan S. | Presbyopia treatment by lens alteration |
AU2001283386A1 (en) | 2000-08-16 | 2002-02-25 | Refocus, Llc. | Presbyopia treatment by lens alteration |
DE10045059A1 (en) | 2000-09-12 | 2002-03-21 | Basf Ag | Therapeutic combination of lipoic acid and conjugate acids for the treatment of diabetic disorders |
US6273092B1 (en) | 2000-09-22 | 2001-08-14 | Gerard M. Nolan | Methods for treating various eye disorders |
US6703039B2 (en) | 2000-12-06 | 2004-03-09 | Bausch & Lomb Incorporated | Reversible gelling system for ocular drug delivery |
EP1370237A2 (en) | 2001-01-19 | 2003-12-17 | Newlens, LLC | Presbyopia treatment by lens alteration |
US7700080B2 (en) | 2001-03-19 | 2010-04-20 | Senju Pharmaceutical Co., Ltd. | Method of suppressing melanin production by metal chelates of lipoyl amino acid derivatives |
WO2002096360A2 (en) | 2001-05-25 | 2002-12-05 | Ceremedix, Inc. | Single amino acid based compounds for counteracting effects of reactive oxygen species and free radicals |
FR2832637B1 (en) | 2001-06-07 | 2004-07-30 | Lefaix Marie Therese Droy | USE OF AN ANTIOXIDANT FOR THE MANUFACTURE OF A MEDICAMENT FOR THE TREATMENT OF EYE SURFACE CONDITIONS |
ITMI20011232A1 (en) | 2001-06-12 | 2002-12-12 | St Microelectronics Srl | METHOD OF REPROGRAMMING SUBSEQUENT TO A CANCELLATION OPERATION OF A MATRIX OF NON-VOLATILE MEMORY CELLS, IN PARTICULAR OF |
AU2002254546A1 (en) | 2002-04-03 | 2003-10-20 | Mitchell A. Avery | Lipoic acid analogs useful as provitamins and antioxidants |
US20050137124A1 (en) | 2002-08-09 | 2005-06-23 | Vitreo-Retinal Technologies, Inc. A California Corporation | Agents for intravitreal administration to treat or prevent disorders of the eye |
KR100973451B1 (en) | 2002-09-13 | 2010-08-02 | 유겐가이샤 오가 리서치 | Melanin extinguisher |
US7795203B2 (en) * | 2002-09-30 | 2010-09-14 | Babizhayev Mark A | Method for topical treatment of eye disease and composition and device for said treatment |
US20060177430A1 (en) | 2002-12-20 | 2006-08-10 | Chakshu Research Inc | Treatment of ocular disorders with ophthalmic formulations containing methylsulfonylmethane as a transport enhancer |
US7941211B2 (en) | 2003-11-17 | 2011-05-10 | Zeavision, Llc. | Preloading with macular pigment to improve photodynamic treatment of retinal vascular disorders |
CA2547086A1 (en) | 2003-11-25 | 2005-06-09 | University Of Rochester | Compounds for delivering amino acids or peptides with antioxidant activity into mitochondria and use thereof |
US7718697B2 (en) | 2003-12-17 | 2010-05-18 | Alcon, Inc. | Method for treating glaucoma comprising administering α-lipoic acid |
GB0404693D0 (en) | 2004-03-02 | 2004-04-07 | Univ London | Pharmaceutical preparations for the treatment of ocular surface and other disorders |
FR2869531B1 (en) | 2004-04-30 | 2006-07-14 | Optis France Sa Sa | OCULAR IONTOPHORESIS DEVICE REDUCING IRRITATION |
US7264279B2 (en) | 2004-07-08 | 2007-09-04 | Fab-Tech, Inc. | Segmented conduit having a monolithic lining |
US20080038316A1 (en) | 2004-10-01 | 2008-02-14 | Wong Vernon G | Conveniently implantable sustained release drug compositions |
US20060188492A1 (en) | 2005-01-13 | 2006-08-24 | Chronorx Llc, An Alaska Limited Liability Company | Topical management of ocular and periocular conditions |
EP1904108B1 (en) | 2005-07-15 | 2011-11-30 | Chakshu Research, Inc. | Ophthalmological formulation comprising methylsulfonylmethane and ciprofloxacin |
US20070055070A1 (en) | 2005-09-07 | 2007-03-08 | Lawrence Lowell J | Novel esters of lipoic acid |
US20070207116A1 (en) * | 2006-03-01 | 2007-09-06 | Brown David C | Antioxidant compositions for the eye |
CN101522658A (en) | 2006-06-16 | 2009-09-02 | 因迪基恩药物公司 | Metformin R-(+) lipoate as an antidiabetic agent for control of diabetic hyperglycemia and diabetic complications |
WO2008067403A2 (en) | 2006-11-28 | 2008-06-05 | Encore Health Llc | Presbyopia treatment by lens alteration |
US20100031772A1 (en) * | 2006-12-08 | 2010-02-11 | Djamschid Amirzadeh-Asl | Molded body containing titanium |
ES2732293T3 (en) | 2007-02-22 | 2019-11-21 | Childrens Hospital & Res Center At Oakland | Fatty acid formulations and methods for using them |
JP2010520333A (en) | 2007-03-01 | 2010-06-10 | セダーズ−シナイ メディカル センター | Antioxidant polymer containing [1,2] -dithiolane moiety and use thereof |
UA86441C2 (en) | 2007-03-30 | 2009-04-27 | Акционерное Общество Открытого Типа "Галичфарм" | (2-hydroxyethyl)trimethylammonium thiooctate (choline thioctate), having hepatoprotective, hypoamoniemic and detoxic action, method for production thereof and pharmaceutical compositions based on it |
WO2009111635A2 (en) | 2008-03-05 | 2009-09-11 | Encore Health, Llc | Dithiol compounds, derivatives, and uses therefor |
US9044439B2 (en) * | 2008-03-05 | 2015-06-02 | Encore Health, Llc | Low dose lipoic and pharmaceutical compositions and methods |
WO2010147957A2 (en) | 2009-06-15 | 2010-12-23 | Encore Health, Llc | Dithiol compounds, derivatives, and uses therefor |
DK2547323T3 (en) | 2010-03-17 | 2016-05-02 | Novaliq Gmbh | PHARMACEUTICAL COMPOSITION FOR TREATMENT OF INCREASED INTRAOCULAR PRESSURE |
-
2015
- 2015-03-03 WO PCT/US2015/018505 patent/WO2015134510A1/en active Application Filing
- 2015-03-03 RU RU2016137784A patent/RU2735790C2/en active
- 2015-03-03 CA CA2941518A patent/CA2941518A1/en not_active Abandoned
- 2015-03-03 CN CN202011555416.1A patent/CN112641720A/en active Pending
- 2015-03-03 JP JP2016573672A patent/JP6526066B2/en not_active Expired - Fee Related
- 2015-03-03 AU AU2015227307A patent/AU2015227307A1/en not_active Abandoned
- 2015-03-03 EP EP15758583.7A patent/EP3113613A4/en not_active Withdrawn
- 2015-03-03 CN CN201580012000.6A patent/CN106455563A/en active Pending
- 2015-03-03 KR KR1020167026593A patent/KR20160145558A/en not_active Application Discontinuation
- 2015-03-03 MX MX2016011290A patent/MX2016011290A/en unknown
- 2015-03-03 US US15/118,910 patent/US20160354340A1/en not_active Abandoned
- 2015-03-03 BR BR112016020181A patent/BR112016020181A8/en not_active IP Right Cessation
-
2016
- 2016-08-29 IL IL247529A patent/IL247529B/en active IP Right Grant
-
2019
- 2019-09-22 US US16/578,368 patent/US11426381B2/en active Active
- 2019-10-02 AU AU2019240641A patent/AU2019240641B2/en not_active Ceased
Patent Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060275278A1 (en) * | 2005-06-02 | 2006-12-07 | Choy Camus K M | Method and ophthalmic formulation for eye protection or treatment |
US8410462B2 (en) | 2006-12-29 | 2013-04-02 | Endress + Hasuer Gmbh + Co. Kg | Optoelectronic apparatus for transmission of an electrical signal |
EP2179736A1 (en) * | 2007-08-09 | 2010-04-28 | Senju Pharmaceutical Co., Ltd. | Two-component eye drops containing pirenoxine |
US20100317725A1 (en) | 2009-06-15 | 2010-12-16 | Encore Health Llc | Choline Esters |
US8410162B2 (en) | 2009-06-15 | 2013-04-02 | Encore Health Llc | Choline esters |
WO2011104037A2 (en) * | 2010-02-26 | 2011-09-01 | Kist-Europe Forschungsgesellschaft Mbh | Process for preparing a ready-to-use product which can be metered |
WO2012093113A1 (en) * | 2011-01-04 | 2012-07-12 | Novaliq Gmbh | O/w-emulsions comprising semifluorinated alkanes |
WO2013110621A1 (en) * | 2012-01-23 | 2013-08-01 | Novaliq Gmbh | Stabilised protein compositions based on semifluorinated alkanes |
WO2013126597A1 (en) * | 2012-02-22 | 2013-08-29 | Stealth Peptides International, Inc. | Methods and compositions for preventing or treating ophthalmic conditions |
Non-Patent Citations (2)
Title |
---|
DRAIZE ET AL., J. PHARMACOL. & EXP. THERAPEUTICS, vol. 82, 1944, pages 377 - 390 |
See also references of EP3113613A4 |
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US20200281891A1 (en) | 2020-09-10 |
BR112016020181A8 (en) | 2021-06-29 |
CA2941518A1 (en) | 2015-09-11 |
RU2016137784A3 (en) | 2018-10-18 |
JP6526066B2 (en) | 2019-06-05 |
AU2019240641B2 (en) | 2020-10-29 |
IL247529A0 (en) | 2016-11-30 |
AU2015227307A1 (en) | 2016-10-13 |
RU2735790C2 (en) | 2020-11-09 |
MX2016011290A (en) | 2017-04-27 |
CN106455563A (en) | 2017-02-22 |
CN112641720A (en) | 2021-04-13 |
AU2019240641A1 (en) | 2019-10-24 |
JP2017511816A (en) | 2017-04-27 |
BR112016020181A2 (en) | 2017-08-15 |
US11426381B2 (en) | 2022-08-30 |
IL247529B (en) | 2020-10-29 |
RU2016137784A (en) | 2018-04-03 |
US20160354340A1 (en) | 2016-12-08 |
EP3113613A1 (en) | 2017-01-11 |
EP3113613A4 (en) | 2019-03-13 |
KR20160145558A (en) | 2016-12-20 |
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