US20130296264A1 - Ophthalmic compositions with improved dessication protection and retention - Google Patents

Ophthalmic compositions with improved dessication protection and retention Download PDF

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Publication number
US20130296264A1
US20130296264A1 US13/886,788 US201313886788A US2013296264A1 US 20130296264 A1 US20130296264 A1 US 20130296264A1 US 201313886788 A US201313886788 A US 201313886788A US 2013296264 A1 US2013296264 A1 US 2013296264A1
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Prior art keywords
compositions
composition according
present
hyaluronic acid
guar
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US13/886,788
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James W. Davis
Howard Allen Ketelson
Elaine E. Campbell
David L. Meadows
Rekha Rangarajan
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Alcon Research LLC
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Alcon Research LLC
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Priority to US13/886,788 priority Critical patent/US20130296264A1/en
Assigned to ALCON RESEARCH, LTD. reassignment ALCON RESEARCH, LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: DAVIS, JAMES W., CAMPBELL, ELAINE E., KETELSON, HOWARD ALLEN, MEADOWS, DAVID L., RANGARAJAN, REKHA
Publication of US20130296264A1 publication Critical patent/US20130296264A1/en
Priority to US15/421,513 priority patent/US20170136057A1/en
Priority to US16/721,443 priority patent/US10828320B2/en
Priority to US17/060,343 priority patent/US11376275B2/en
Priority to US17/664,143 priority patent/US11672820B2/en
Priority to US18/319,196 priority patent/US20230285443A1/en
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
    • 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
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/728—Hyaluronic acid
    • 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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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 artificial tear compositions and compositions for ophthalmic drug delivery, and more specifically to compositions comprising a galactomannan such as guar, hyaluronic acid, and a cis-diol.
  • a galactomannan such as guar, hyaluronic acid, and a cis-diol.
  • Ophthalmic compositions for topical application comprise compounds that lubricate and protect the ocular surface.
  • artificial tear compositions can prevent symptoms such as pain and discomfort and can prevent bioadhesion and tissue damage induced by friction.
  • a large number of potential compounds are available that are useful as lubricants and ocular surface protectants.
  • certain marketed artificial tear products contain natural polymers such as galactomannans.
  • Other lubricants and ocular surface protectants include, for example, carboxymethylcellulose, glucomannan, glycerol, and hydroxypropylmethylcellulose.
  • the present invention relates to ophthalmic dry eye compositions comprising guar and hyaluronic acid.
  • a cis-diol such as sorbitol or propylene glycol, is also present in the compositions.
  • a borate compound is also present in the compositions.
  • the compositions of the invention provide improved desiccation protection and retention characteristics.
  • the compositions of the present invention are also useful as drug delivery vehicles for ophthalmic therapeutics.
  • the present inventors have discovered that the combination of guar and hyaluronic acid demonstrates a synergistic effect relative to desiccation protection and ocular surface retention when compared to compositions containing either polymer alone.
  • compositions of the present invention demonstrated improved stability when subjected to elevated temperatures such as those encountered during sterilization processes such as autoclaving.
  • FIG. 1 is a bar chart comparing desiccation performance of a composition comprising both hydroxypropyl guar and hyaluronic acid to compositions comprising either hydroxypropyl guar or hyaluronic acid;
  • FIG. 2 is a is a bar chart comparing retention performance of a composition comprising hydroxypropyl guar and hyaluronic acid to compositions comprising hydroxypropyl guar and hyaluronic acid alone;
  • FIG. 3 is a bar chart comparing retention of fluorescently-tagged polymer compositions.
  • FIG. 4 is a bar chart comparing retention of a hydroxypropyl guar/hyaluronic acid composition with a hyaluronic acid/carboxymethylcellulose composition.
  • compositions of the present invention comprise a galactomannan such as guar, hyaluronic acid, and a cis-diol.
  • a galactomannan such as guar, hyaluronic acid, and a cis-diol.
  • the types of galactomannans that may be used in the present invention are typically derived from guar gum, locust bean gum and tam gum.
  • the term “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 (1-4)- ⁇ -D-mannopyranosyl units with ⁇ -D-galactopyranosyl units attached by (1-6) linkages.
  • the ratio of D-galactose to D-mannose varies, but generally will be from about 1:2 to 1:4.
  • Galactomannans having a D-galactose:D-mannose ratio of about 1:2 are most preferred.
  • other chemically modified variations of the polysaccharides are also included in the “galactomannan” definition. For example, hydroxyethyl, hydroxypropyl and carboxymethylhydroxypropyl substitutions may be made to the galactomannans of the present invention.
  • Non-ionic variations to the galactomannans such as those containing alkoxy and alkyl (C1-C6) groups are particularly preferred when a soft gel is desired (e.g., hydroxylpropyl substitutions). 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 composition of the present invention at a concentration of about 0.025 to about 0.8 w/v %, preferably at about 0.1 w/v % to about 0.2 w/v %, and more preferably at about 0.17 to about 0.18 w/v %.
  • hydroxypropyl guar is present at a concentration of about 0.175 w/v %.
  • Preferred galactomannans of the present invention are guar and hydroxypropyl guar. Hydroxypropyl guar is particularly preferred.
  • Glycosaminoglycans such as hyaluronic acid are negatively charged molecules.
  • Hyaluronic acid is an unsulphated glycosaminoglycan composed of repeating disaccharide units of N-acetylglucosamine (GlcNAc) and giucuronic acid (GlcUA) linked together by alternating beta-1,4 and beta-1,3 glycosidic bonds.
  • Hyaluronic acid is also known as hyaluronan, hyaluronate, or HA.
  • the term hyaluronic acid also includes salt forms of hyaluronic acid such as sodium hyaluronate.
  • compositions of the present invention comprise from about 0.05 to about 0.5 w/v % hyaluronic acid.
  • hyaluronic acid is present at a concentration of about 0.1 to about 0.2 w/v %, and more preferably at a concentration of about 0.13 to 0.17 w/v %.
  • sodium hyaluronate is present at a concentration of about 0.15 w/v %.
  • a preferred hyaluronic acid is sodium hyaluronate.
  • the molecular weight of the hyaluronic acid used in compositions of the present invention may vary, but is typically 0.5 to 2.0M Daltons. In one embodiment, the hyaluronic acid has a molecular weight of 900,000 to 1M Daltons. In another embodiment, the hyaluronic acid has a molecular weight of 1.9 to 2.0 M Daltons.
  • the cis-diol 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).
  • Preferred cis-diol compounds of the present invention include polyethylene glycols, polypropylene glycols, and polyethyleneoxide-polybutyleneoxide block copolymers. Particularly preferred cis-diol compounds are sorbitol and mannitol.
  • the cis-diol compounds are present at concentrations of about 0.5 to 5.0 w/v % in the compositions of the present invention, and are preferably present at a concentration of about 1.0 to 2.0 w/v %. In one embodiment, sorbitol is present at a concentration of about 1.4%. Generally, the molecular weight of such cis-diol compounds is between 400 g/mol to 5 million g/mol.
  • borate When present in a composition of the present invention, borate is typically at a concentration of about 0.1 to about 1.8 w/v %. In a preferred embodiment, borate is present at a concentration of 0.3 to 0.4 w/v %. In one embodiment of the present invention, boric acid is present at a concentration of about 0.35 w/v %.
  • boric acid 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.
  • compositions 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 compositions 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.
  • compositions of the present invention including water, mixtures of water and water-miscible solvents, such as C1-C7-alkanols, 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, preferably cross-linked polyacrylic acid and mixtures of those products.
  • water-miscible solvents such as C1-C7-alkanols, 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, x
  • 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-1-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 and poloxamers such as Pluronic® F68.
  • compositions 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, polyquatemium-1, or sorbic acid.
  • the composition may be self-preserved so that no preservation agent is required.
  • compositions of the present invention are ophthalmically suitable for application to a subject's eyes.
  • aqueous typically denotes an aqueous composition 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 composition unnecessary.
  • the drops may be delivered from a multi-dose bottle which may preferably comprise a device which extracts any preservative from the composition as it is delivered, such devices being known in the art.
  • compositions 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 composition to a level at or near 210-320 milliosmoles per kilogram (mOsm/kg).
  • the compositions 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 compositions will generally be formulated as sterile aqueous solutions.
  • compositions of the present invention can also be used to administer pharmaceutically active compounds for the treatment of, for example, ophthalmic diseases such as glaucoma, macular degeneration, and ocular infections.
  • ophthalmic diseases such as glaucoma, macular degeneration, and ocular infections.
  • Such compounds include, but are not limited to, glaucoma therapeutics, pain relievers, anti-inflammatory and anti-allergy medications, and anti-microbials.
  • 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 as H1/H4 inhibitors, H4 inhibitors, and olopatadine.
  • post-surgical antihypertensive agents such as para-amino clonidine (apraclonidine); anti-infectives such as ciprofloxacin
  • concentrations of the ingredients comprising the compositions of the present invention can vary.
  • concentrations can vary depending on the addition, substitution, and/or subtraction of ingredients in a given composition.
  • compositions are prepared using a buffering system that maintains the composition at a pH of about 6.5 to a pH of about 8.0.
  • Topical compositions are preferred which have a physiological pH matching the tissue to which the composition will be applied or dispensed.
  • a composition of the present invention is administered once a day.
  • the compositions may also be formulated for administration at any frequency of administration, including once a week, once every 5 days, once every 3 days, once every 2 days, twice a day, three times a day, four times a day, five times a day, six times a day, eight times a day, every hour, or greater frequency.
  • 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.
  • Guar and hyaluronate compositions of the present invention were autoclaved under standard conditions. As shown below in Table 1, the composition comprising sorbitol has a stabilized molecular weight when compared with the composition that did not contain sorbitol.
  • compositions of the present invention to protect human epithelial cells from desiccating stress was evaluated as follows.
  • Human transformed corneal epithelial cells were plated at 0.09 ⁇ 10 6 cells/mL onto collagen-coated 48-well plates (BD Biosciences #35-4505) and grown to confluence in EpiLife media (Invitrogen #MEPI500CA) supplemented with Human Corneal Growth Supplement (HCGS Invitrogen #S0095) for 48 hours. Cells were treated with test solutions for 30 minutes at 37° C. then rinsed 1 ⁇ (250 ⁇ L) with supplement free media. All solutions were gently removed and the cells were subjected to desiccation at 45% humidity, 37° C.
  • HPG hydroxypropyl guar composition
  • HA hyaluronic acid composition
  • HPG/HA hydroxypropyl guar and hyaluronic acid
  • the DPS composition demonstrated significantly greater desiccation protection than either the HPG solution or the HA solution.
  • the HPG/HA solution also demonstrated greater retention to the epithelial surface than either the HPG solution or the HA solution.
  • a synergistic effect was noted relative to both desiccation protection and retention behavior of the HPG/HA solution.
  • the mean retention time of a composition of the present invention was compared to its components alone. Briefly, a fluorescein labeled dextran tracer of approximately 70 kD (Molecular Probes, Eugene, Oreg.) was added to each test formulation at a concentration of 0.1 w/v %. A scanning fluorophotometer (Ocumetrics, Mountain View, Calif.) was used to monitor signal decay corresponding to elimination of the formulations. As shown in FIG. 3 and TABLE 4 below, individual fluorescent tagging of the polymer components of the HPG/HA solution demonstrates an increase in the amount of polymer bound to the epithelial surface when the polymers hydroxypropyl guar and hyaluronic acid are combined. FIG. 4 and TABLE 5 demonstrate that this improved retention effect was not noted in a dual polymer formulation comprising hyaluronic acid and carboxymethylcellulose (HA/CMC).
  • HA/CMC carboxymethylcellulose
  • TABLE 7 presents the results of a hyaluronic acid dose response study which compares the desiccation protection of compositions with hyaluronic acid alone to compositions comprising hyaluronic acid and hydroxypropyl guar.

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US13/886,788 2012-05-04 2013-05-03 Ophthalmic compositions with improved dessication protection and retention Abandoned US20130296264A1 (en)

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US13/886,788 US20130296264A1 (en) 2012-05-04 2013-05-03 Ophthalmic compositions with improved dessication protection and retention
US15/421,513 US20170136057A1 (en) 2012-05-04 2017-02-01 Ophthalmic compositions with improved dessication protection and retention
US16/721,443 US10828320B2 (en) 2012-05-04 2019-12-19 Ophthalmic compositions with improved dessication protection and retention
US17/060,343 US11376275B2 (en) 2012-05-04 2020-10-01 Ophthalmic compositions with improved dessication protection and retention
US17/664,143 US11672820B2 (en) 2012-05-04 2022-05-19 Ophthalmic compositions with improved dessication protection and retention
US18/319,196 US20230285443A1 (en) 2012-05-04 2023-05-17 Ophthalmic compositions with improved dessication protection and retention

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US16/721,443 Active US10828320B2 (en) 2012-05-04 2019-12-19 Ophthalmic compositions with improved dessication protection and retention
US17/060,343 Active US11376275B2 (en) 2012-05-04 2020-10-01 Ophthalmic compositions with improved dessication protection and retention
US17/664,143 Active US11672820B2 (en) 2012-05-04 2022-05-19 Ophthalmic compositions with improved dessication protection and retention
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US17/060,343 Active US11376275B2 (en) 2012-05-04 2020-10-01 Ophthalmic compositions with improved dessication protection and retention
US17/664,143 Active US11672820B2 (en) 2012-05-04 2022-05-19 Ophthalmic compositions with improved dessication protection and retention
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Cited By (4)

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