WO2021156856A1 - Topical opthalmological composition containing hyaluronate and taurine having non-newtonian rheological properties - Google Patents
Topical opthalmological composition containing hyaluronate and taurine having non-newtonian rheological properties Download PDFInfo
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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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
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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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
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- 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
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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
- A61K31/70—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
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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
- A61K31/74—Synthetic polymeric materials
- A61K31/765—Polymers containing oxygen
- A61K31/78—Polymers containing oxygen of acrylic acid or derivatives thereof
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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
- A61K47/02—Inorganic compounds
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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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
- A61K47/16—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
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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
- A61K47/30—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
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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
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- 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
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- 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
- This invention rates in general to compositions and methods for prevention and treatment of dry eye symptoms. It relates specifically to compositions containing hyaluronate and taurine that have non-Newtonian rheological properties and their use in the treatment or prevention of dry eye conditions that are due to a decreased rate of blinking, to the Meibomian glands not producing sufficient oily-wax secretion to the surface of cornea, or to occupational or environmental conditions that cause rapid evaporation of the tear film.
- Taurine is an amino acid present in the human body that is recognized as having antioxidant and cell stabilizing properties.
- the protective effects of ophthalmic formulations based on taurine and sodium hyaluronate on the ocular surface have been assessed (Bucolo, C.; Fidilio, A.; Platania, C.B.M.; Geraci, F.; Lazzara, F.; and Drago, F., "Antioxidant and Osmoprotecting Activity of Taurine in Dry Eye Models," J. Ocul. Pharmacol. Ther. 2018, 34, 188 - 194).
- Compositions containing 0.5% taurine and 0.4% sodium hyaluronate were discovered to reduce the production of reactive oxygen species on the ocular surface following oxidative stress to rabbit corneal epithelial cells.
- Eye drops containing a 4% (isotonic) solution of taurine for treatment of cataracts and injuries to the cornea are marketed by EndoPharm under the trade name TAUFON.
- Japanese Pat. Appl. Pub. No. 2002020279 discloses an eye drop formulation that contains 0.1% (w/v) sodium hyaluronate, 3% (w/v) taurine and about 1% inorganic salt. The inventors claim that a taurine concentration above 3% is irritating to the eyes.
- the present invention provides an answer for this long-felt need.
- the invention discloses a topical ophthalmic composition, the primary active ingredients of which are an anionic polymer and taurine.
- taurine is present in isotonic or near isotonic concentration in the absence of any salt other than taurate and the salt of the anionic polymer.
- the combination of the effects of the relatively high concentration of taurate and the non-Newtonian viscosity profile provided by the anionic polymer yields an improved composition that is effective for treatment, prevention, and alleviation of conditions such as Occupational Dry Eye Syndrome, Computer Vision Syndrome, and Meibomian Gland Dysfunctions.
- a topical ophthalmic composition wherein said topical ophthalmic composition comprises an aqueous solution comprising (a) a salt of at least one anionic polymer; (b) at least 1% (w/v) taurine; and, (c) ⁇ 0.10% (w/v) of any salt other than said salt of said at least one anionic polymer.
- said composition consists of an aqueous solution consisting of (a) a salt of at least one anionic polymer; (b) at least 1% (w/v) taurine; and, (c) ⁇ 0.10% (w/v) of any salt other than said salt of said at least one anionic polymer.
- said composition comprises (a) a salt of at least one anionic polymer selected from the group consisting of hyaluronates, carbomers, and anionic polysaccharides; (b) >3% - 5% (w/v) taurine; and (c) ⁇ 0.10% (w/v) of any salt other than said salt of said at least one anionic polymer.
- said composition comprises (a) a salt of at least one anionic polymer selected from the group consisting of hyaluronates, carbomers, and anionic polysaccharides; (b) 3.5% - 5% (w/v) taurine; and (c) ⁇ 0.10% (w/v) of any salt other than said salt of said at least one anionic polymer.
- said composition consists of (a) a salt of at least one anionic polymer selected from the group consisting of hyaluronates, carbomers, and anionic polysaccharides; (b) >3% - 5% (w/v) taurine; (c) ⁇ 0.10% (w/v) of any salt other than said salt of said at least one anionic polymer; and, optionally, (d) an effective amount of a preservative.
- said least one anionic polymer is characterized by a molecular weight of at least 10,000 Dalton. In some especially preferred embodiments of the invention, said at least one anionic polymer is characterized by a molecular weight of at least 500,000 Dalton.
- said solution comprises at least one anionic polymer and is characterized by a polymer concentration of between 0.05% and 5.0% (w/v). In some especially preferred embodiments of the invention, said solution comprises at least one anionic polymer and is characterized by a polymer concentration of between 0.1% and 0.2% (w/v). In some preferred embodiments of the invention, said salt of said anionic polymer is present in a concentration sufficient to bring an aqueous solution of said salt of said anionic polymer to a predetermined viscosity at a shear rate of 1 s 1 and a non-Newtonian viscosity profile.
- said predetermined viscosity at a shear rate of 1 s 1 is between 0.1 and 0.2 Pa-s. In some yet more preferred embodiments of the invention, said predetermined viscosity at a shear rate of 1 s 1 is between 0.1 and 0.15 Pa-s. In some especially preferred embodiments of the invention, said predetermined viscosity at a shear rate of 1 s 1 is about 0.13 Pa-s. [0013] It is a further object of this invention to disclose the topical ophthalmic composition as defined in any of the above, wherein said composition does not contain any polymer other than hyaluronate. In some preferred embodiments of the invention, said solution is characterized by a hyaluronate concentration of 0.15% (w/v).
- aqueous solution is characterized by a taurine concentration of between 1% and 5% (w/v).
- said aqueous solution is characterized by a taurine concentration in the range of >3% to 4% (w/v).
- aqueous solution comprises glycerol.
- said aqueous solution is characterized by a glycerol concentration of between 0.05% and 4% (w/v).
- compositions as defined in any of the above, wherein said composition is characterized by a pH that is within a normal pH range of tears. In some preferred embodiments of the invention, said composition is characterized by a pH of between 6.5 and 7.6.
- composition as defined in any of the above, wherein said composition comprises an effective amount of preservative.
- said composition consists of an aqueous solution consisting of (a) a salt of at least one anionic polymer; (b) at least 1% (w/v) taurine; (c) ⁇ 0.10% (w/v) of any salt other than said salt of said at least one anionic polymer; and (d) an effective amount of a preservative.
- composition as defined in any of the above, wherein said composition comprises a pharmaceutically effective amount of a pharmacologically active agent.
- said composition consists of an aqueous solution consisting of (a) a salt of at least one anionic polymer; (b) at least 1% (w/v) taurine; (c) ⁇ 0.10% (w/v) of any salt other than said salt of said at least one anionic polymer; and (d) a pharmaceutically effective amount of a pharmacologically active agent.
- said composition consists of an aqueous solution consisting of (a) a salt of at least one anionic polymer; (b) at least 1% (w/v) taurine; (c) ⁇ 0.10% (w/v) of any salt other than said salt of said at least one anionic polymer; (d) an effective amount of a preservative; and (e) a pharmaceutically effective amount of a pharmacologically active agent.
- composition comprises at least one substance selected from the group consisting of stabilizers, antioxidants, and buffers.
- said composition consists of an aqueous solution consisting of (a) a salt of at least one anionic polymer; (b) at least 1% (w/v) taurine; (c) ⁇ 0.10% (w/v) of any salt other than said salt of said at least one anionic polymer; (d) an effective amount of a preservative; (e) a pharmaceutically effective amount of a pharmacologically active agent; and (f) at least one substance selected from the group consisting of stabilizers, antioxidants, and buffers.
- said composition is in the form of a liquid. In some other preferred embodiments of the invention, said composition is in the form of a water-based gel.
- a topical ophthalmic composition as defined in any of the above, wherein said aqueous solution comprises 0.15% (w/v) sodium hyaluronate, 3.5% (w/v) taurine, preservative, and is characterized by a pH of about 7. In some preferred embodiments of the invention, the composition is characterized by a pH of 7.0.
- a topical ophthalmic composition as defined in any of the above, wherein said aqueous solution comprises 0.15% (w/v) sodium hyaluronate, 1.25% (w/v) taurine, and 1.8% (w/v) glycerol, and is characterized by a pH of about 7. In some preferred embodiments of the invention, the composition is characterized by a pH of 7.0.
- a topical ophthalmic composition consisting of an aqueous solution consisting of 0.15% (w/v) sodium hyaluronate and 3.5% (w/v) taurine, said topical ophthalmic composition characterized by a pH of about 7.
- the composition is characterized by a pH of 7.0.
- a topical ophthalmic composition consisting of an aqueous solution consisting of 0.15% (w/v) sodium hyaluronate, 3.5% (w/v) taurine, and preservative, said topical ophthalmic composition characterized by a pH of about 7.
- the composition is characterized by a pH of 7.0.
- a topical ophthalmic composition wherein said aqueous solution consists of 0.15% (w/v) sodium hyaluronate, 1.25% (w/v) taurine, and 1.8% (w/v) glycerol, and is characterized by a pH of about 7.
- the composition is characterized by a pH of 7.0.
- a topical ophthalmic composition wherein said aqueous solution consists of 0.15% (w/v) sodium hyaluronate, 1.25% (w/v) taurine, and 1.8% (w/v) glycerol, and preservative, and is characterized by a pH of about 7.
- the composition is characterized by a pH of 7.0.
- the topical ophthalmic composition as defined in any of the above for treatment of a condition selected from the group consisting of Occupational Dry Eye; Computer Vision Syndrome; and Meibomian Gland dysfunctions.
- said treatment comprises applying said composition to an affected eye 1 - 8 times daily.
- said treatment comprises applying said composition to an affected eye 1 - 8 times daily until a statistically significant reduction in severity of said condition is observed.
- said treatment comprises applying said topical ophthalmic composition three times daily for at least two weeks.
- said treatment comprises applying said composition to an affected eye three times daily for a period of at least two weeks.
- said treatment comprises applying said composition to an affected eye 1 - 8 times daily until said eye is characterized by a tear break up time of at least 9 seconds. In some preferred embodiments, said treatment comprises applying said composition to an affected eye three times daily until said eye is characterized by a tear break up time of at least 9 seconds.
- said alleviation comprises applying said composition to an affected eye 1 - 8 times daily.
- said alleviation comprises applying said composition to an affected eye 1 - 8 times daily until a statistically significant reduction in severity of said condition is observed.
- said alleviation comprises applying said composition to an affected eye three times daily for a period of at least two weeks.
- said alleviation comprises applying said composition to an affected eye 1 - 8 times daily until said eye is characterized by a tear break up time of at least 9 seconds. In some preferred embodiments, said alleviation comprises applying said composition to an affected eye three times daily until said eye is characterized by a tear break up time of at least 9 seconds.
- said prevention comprises applying said composition to an eye 1 - 8 times daily.
- said step of applying the composition to an affected eye comprises applying said composition to said affected eye 1 - 8 times daily.
- said step of applying the composition to an affected eye comprises applying said composition to said affected eye 1 - 8 times daily until a statistically significant reduction in severity of said condition is observed.
- said step of applying the composition to an affected eye comprises applying said composition to an affected eye three times daily for at least two weeks.
- said step of applying the composition to an affected eye comprises applying said composition to an affected eye 1 - 8 times daily until said eye is characterized by a tear break up time of at least 9 seconds. In some preferred embodiments of the invention, said step of applying the composition to an affected eye comprises applying said composition to an affected eye three times daily until said eye is characterized by a tear break up time of at least 9 seconds.
- said step of applying the composition to an affected eye comprises applying said composition to an affected eye 1 - 8 times daily.
- said step of applying the composition to an affected eye comprises applying said composition to an affected eye 1 - 8 times daily until a statistically significant reduction in severity of said condition is observed.
- said step of applying the composition to an affected eye comprises applying said composition to an affected eye three times daily for at least two weeks. In some preferred embodiments of the invention, said step of applying the composition to an affected eye comprises applying said composition to an affected eye 1 - 8 times daily until said eye is characterized by a tear break up time of at least 9 seconds. In some preferred embodiments of the invention, said step of applying the composition to an affected eye comprises applying said composition to an affected eye three times daily until said eye is characterized by a tear break up time of at least 9 seconds.
- said step of applying the composition to an eye comprises applying said composition to an affected eye 1 - 8 times daily.
- FIG. 1 is a graph showing viscosity profiles (shear viscosity as a function of shear rate) of an 0.15% (w/v) aqueous solution of sodium hyaluronate and for an aqueous solution containing 0.15% (w/v) sodium hyaluronate and 2.5% (w/v) glycerol;
- FIG. 2 is a graph showing a viscosity profile of one embodiment of the composition disclosed herein, in which the composition contains 3.5% (w/v) taurine and 0.15% (w/v) sodium hyaluronate;
- FIG. 3 is a graph showing a viscosity profile of a commercially available eye drop that contains 0.15% (w/v) sodium hyaluronate;
- FIG. 4 is a graph showing a viscosity profile of a solution containing 0.15% hyaluronate and sodium acetate at pH 7.0; and, [0039]
- FIG. 5 is a graph showing a viscosity profile of a solution containing 0.15% sodium hyaluronate and 4% Tris HC1 at pH 7.0.
- inorganic salt refers to a salt that is made up entirely of inorganic ions, i.e. the cation(s) and the anion(s) of an inorganic salt are all inorganic.
- inorganic salts destroy the non- Newtonian viscosity properties of a polymer solution, but salts containing organic ions do so as well, including salts that contain one organic ion and one inorganic ion.
- the pi of taurine is about 5.2, and thus at pH 7.0 (the pH required for an eye drop) it is nearly entirely ionized (i.e. in the form of a salt). It would thus be expected that an aqueous solution of a high molecular weight polymer and isotonic ( ⁇ 3 - 4%) taurine would show Newtonian viscosity properties.
- composition disclosed herein combines the advantages of a non-Newtonian viscosity profile with the benefits of an isotonic taurine concentration.
- the composition comprises an aqueous solution comprising one or more anionic polymers, an isotonic or nearly isotonic concentration of taurine, and less than 0.10% (w/v) inorganic salt.
- the composition may be in the form of an aqueous solution or in the form of a water-based gel.
- the polymer serves to control the viscosity of the composition, and is preferably of high molecular weight (MW).
- MW molecular weight
- the polymer is characterized by MW > 10,000 Dalton.
- the polymer is characterized by MW > 500,000 Dalton.
- Non-limiting examples of anionic polymers that can be used in the composition include hyaluronate, carbomers, and anionic polysaccharides.
- sodium hyaluronate is used as the anionic polymer. Since the polymer is anionic, in the absence of added salt, the solution has the additional advantage of having a non-Newtonian viscosity profile.
- the composition may be prepared according to standard procedures and transferred to and stored in a container appropriate for storing and/or dispensing it.
- the composition additionally comprises one or more preservatives. Any preservative known in the art for use with topical ophthalmological compositions may be used.
- the composition additionally comprises a pharmaceutically effective concentration of at least one pharmacologically active agent. If necessary, any stabilizer, preservative, antioxidant, buffer or combination thereof appropriate for use with the pharmacologically active agent may be added to the solution in any concentration suitable for the intended use.
- composition disclosed herein was prepared as follows:
- the osmolarity of the composition was measured, and found to be 280 mOsm/L, i.e. the composition is slightly hypotonic.
- a second non-limiting embodiment of the invention disclosed herein was prepared according to the composition of the previous example, except that no preservative was added and the composition was stored in a "preservative-free" bottle.
- a third non-limiting embodiment of the invention disclosed herein was prepared as follows:
- composition was packaged in single-dose vials or "preservative free” bottles.
- FIG. 1 presents viscosity profiles for an 0.15% aqueous solution of sodium hyaluronate (diamonds) and an aqueous solution of sodium hyaluronate and 2.5% (i.e., nearly isotonic) glycerol (squares).
- the shear viscosity in Pa-s is plotted as a function of the shear rate in s 1 .
- the x-axis is logarithmic. It can be seen that addition of a non-ionic component (glycerol) does not influence the non- Newtonian viscosity profile of sodium hyaluronate. As the shear rate increases from low to high values, the viscosity decreases by more than an order of magnitude.
- FIG. 2 presents a viscosity profile for the embodiment of the invention disclosed herein that is described in detail in Example 2.
- the graph shows that the composition disclosed herein has a typical non-Newtonian viscosity profile. Viscosity decreases slowly as a function of shear rate from a viscosity of about 0.13 Pa-s at a shear rate of 1 s 1 to 0.01 Pa-s at high shear rate, i.e. as with the solution of hyaluronate and glycerol, as the shear rate increases from low to high values, the viscosity decreases by more than an order of magnitude.
- FIG. 3 presents a viscosity profile for a commercially available eye drop marketed under the trade name HYABAK.
- the viscosity profile is for a sample that was purchased in Hungary.
- Tris 2-amino-2-(hydroxymethyl)propane-l,3- diol
- the osmolarity of the sample obtained for testing was determined to be 211 mOsm/L, implying a salt concentration of about 0.6%.
- the graph demonstrates that, as expected for a composition containing 0.6% salt, the viscosity profile of HYABAK eye drops is essentially Newtonian. As the shear rate increases from low to high values, the viscosity decreases from 0.006 Pa-s to 0.002 Pa-s, i.e. only 3-fold. Moreover, extrapolation of the measured values implies a viscosity at low shear rate of -0.01 Pa-s, as opposed to a low shear rate viscosity of > 0.1 Pa-s in the non-Newtonian formulations of the preceding examples .
- FIG. 4 presents a viscosity profile of a solution containing 0.15% hyaluronate + sodium acetate at pH 7.0 (1.23% sodium acetate), i.e. a solution containing an inorganic cation and organic anion.
- the osmolarity was determined to be 305 mOsm/L (i.e. nearly isotonic).
- the viscosity profile is essentially Newtonian; the viscosity falls rapidly at low shear rate such that at a shear rate of 5 s _i the viscosity has already decreased to 0.02 Pa-s.
- FIG. 5 presents a velocity profile of a solution containing 0.15% sodium hyaluronate and 4% Tris-HCl at pH 7.0, i.e. a solution containing a salt comprising an organic cation and an inorganic anion.
- the viscosity profile is essentially Newtonian in this case as well.
- eye drops having non-Newtonian rheological properties have advantages over those with Newtonian rheological properties, particularly in that they provide a more pleasant subjective feeling and that they enable the eye drops to stay on the cornea longer.
- Not every non-Newtonian eye drop will necessarily increase the tear stability as measured objectively by the tear break up time (TBUT), a clinical test used to assess the severity of evaporative dry eye disease.
- TBUT tear break up time
- TBUT was determined by instilling fluorescein into the subject's tear film and observing the tear film under a broad beam of cobalt blue illumination while the subject did not blink, and is recorded as the number of seconds that elapse between the last blink and the appearance of the first dry spot in the tear film. A TBUT under 10 seconds is considered abnormal.
- Results of the study are summarized in Table 1 and are expressed as mean TBUT in seconds +1 standard error of mean.
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Abstract
A novel composition for topical treatment, alleviation, and prevention of Occupational Dry Eye, Computer Vision Syndrome and Meibomian Gland Dysfunctions. The composition comprises an aqueous solution of a salt of an anionic polymer and taurine in the absence of any salt other than the salt of the anionic polymer, and has a remarkable non-Newtonian viscosity profile. In preferred embodiments of the invention, the composition is characterized by an isotonic or slightly hypotonic taurine concentration. The use of the composition in a method for treatment, alleviation, or prevention of Occupational Dry Eye, Computer Vision Syndrome, and Meibomian Gland Dysfunctions using the novel composition is also disclosed.
Description
TOPICAL OPTHALMOLOGICAL COMPOSITION CONTAINING HYALURONATE AND TAURINE HAVING NON-NEWTONIAN RHEOLOGICAL PROPERTIES
REFERENCE TO RELATED PUBLICATIONS
[0001] This application claims priority from Israel Pat. Appl. No. 272436, filed 3 February 2020.
FIELD OF THE INVENTION
[0002] This invention rates in general to compositions and methods for prevention and treatment of dry eye symptoms. It relates specifically to compositions containing hyaluronate and taurine that have non-Newtonian rheological properties and their use in the treatment or prevention of dry eye conditions that are due to a decreased rate of blinking, to the Meibomian glands not producing sufficient oily-wax secretion to the surface of cornea, or to occupational or environmental conditions that cause rapid evaporation of the tear film.
BACKGROUND OF THE INVENTION
[0003] Due to the ever-increasing use of devices that require intensive viewing that leads to reduced blinking such as computers, smartphones, and televisions, the occurrence of problems such as Occupational Dry Eye Syndrome, Computer Vision Syndrome and Meibomian gland dysfunction has much increased in the last 15 years. The most common current treatment is artificial tears. Among artificial tear compositions, those containing hyaluronate are preferred since hyaluronate eye drops tend to produce a pleasant subjective sensation as shown by the OSDI questionnaire. Objectively, hyaluronate eye drops are known to increase slightly the tear beak up time (TBUT), that is, they slightly stabilize the tear film.
[0004] Taurine is an amino acid present in the human body that is recognized as having antioxidant and cell stabilizing properties. The protective effects of ophthalmic formulations based on taurine and sodium hyaluronate on the ocular surface have been assessed (Bucolo, C.; Fidilio, A.; Platania, C.B.M.; Geraci, F.; Lazzara, F.; and Drago, F., "Antioxidant and Osmoprotecting Activity of Taurine in Dry Eye Models," J. Ocul. Pharmacol. Ther. 2018, 34, 188 - 194). Compositions containing 0.5% taurine and 0.4% sodium hyaluronate were discovered to reduce the production of reactive oxygen species on the ocular surface following oxidative stress to rabbit corneal epithelial cells.
[0005] Eye drops containing a 4% (isotonic) solution of taurine for treatment of cataracts and injuries to the cornea are marketed by EndoPharm under the trade name TAUFON.
[0006] Japanese Pat. Appl. Pub. No. 2002020279 discloses an eye drop formulation that contains 0.1% (w/v) sodium hyaluronate, 3% (w/v) taurine and about 1% inorganic salt. The inventors claim that a taurine concentration above 3% is irritating to the eyes.
[0007] The present inventor has previously disclosed, in U.S. Pat. No. 5,106,615 (henceforth '615), that a non-Newtonian viscosity profile can be advantageous for a topical ophthalmological composition, as it combines the advantages of being characterized by high viscosity while the eye is open, enabling the composition to remain longer on the cornea and thereby enhancing its activity, while being characterized by low viscosity during blinking, thereby lowering discomfort.
[0008] Despite these advances in the field, there remains a need for an improved topical treatment for the eyes that is specifically designed to treat dry eye conditions such as Occupational Dry Eye Syndrome, Computer Vision Syndrome, and Meibomian Gland Dysfunctions that are caused or exacerbated by reduced blinking rates, reduced production of Meibomian gland secretions, or other occupational or environmental causes. In particular, there remains a long-felt but as yet unmet need for a topical ophthalmological composition that not only produces a subjective feeling of comfort, but that also significantly increases tear film stability as measured by an increased tear break up time, and in addition has the advantages of non-Newtonian rheological properties.
SUMMARY OF THE INVENTION
[0009] The present invention provides an answer for this long-felt need. The invention discloses a topical ophthalmic composition, the primary active ingredients of which are an anionic polymer and taurine. In contrast to compositions known in the art, in which taurine is present at low concentrations, in the instant invention, taurine is present in isotonic or near isotonic concentration in the absence of any salt other than taurate and the salt of the anionic polymer. The combination of the effects of the relatively high concentration of taurate and the non-Newtonian viscosity profile provided by the anionic polymer yields an improved composition that is effective for treatment, prevention, and alleviation of conditions such as Occupational Dry Eye Syndrome, Computer Vision Syndrome, and Meibomian Gland Dysfunctions.
[0010] It is therefore an object of the present invention to disclose a topical ophthalmic composition, wherein said topical ophthalmic composition comprises an aqueous solution comprising (a) a salt of at least one anionic polymer; (b) at least 1% (w/v) taurine; and, (c)
<0.10% (w/v) of any salt other than said salt of said at least one anionic polymer. In some embodiments of the invention, said composition consists of an aqueous solution consisting of (a) a salt of at least one anionic polymer; (b) at least 1% (w/v) taurine; and, (c) <0.10% (w/v) of any salt other than said salt of said at least one anionic polymer. In some preferred embodiments of the invention, said composition comprises (a) a salt of at least one anionic polymer selected from the group consisting of hyaluronates, carbomers, and anionic polysaccharides; (b) >3% - 5% (w/v) taurine; and (c) <0.10% (w/v) of any salt other than said salt of said at least one anionic polymer. In some preferred embodiments of the invention, said composition comprises (a) a salt of at least one anionic polymer selected from the group consisting of hyaluronates, carbomers, and anionic polysaccharides; (b) 3.5% - 5% (w/v) taurine; and (c) <0.10% (w/v) of any salt other than said salt of said at least one anionic polymer. In some preferred embodiments of the invention, said composition consists of (a) a salt of at least one anionic polymer selected from the group consisting of hyaluronates, carbomers, and anionic polysaccharides; (b) >3% - 5% (w/v) taurine; (c) <0.10% (w/v) of any salt other than said salt of said at least one anionic polymer; and, optionally, (d) an effective amount of a preservative.
[0011] In some preferred embodiments of the invention, said least one anionic polymer is characterized by a molecular weight of at least 10,000 Dalton. In some especially preferred embodiments of the invention, said at least one anionic polymer is characterized by a molecular weight of at least 500,000 Dalton.
[0012] In some preferred embodiments of the invention, said solution comprises at least one anionic polymer and is characterized by a polymer concentration of between 0.05% and 5.0% (w/v). In some especially preferred embodiments of the invention, said solution comprises at least one anionic polymer and is characterized by a polymer concentration of between 0.1% and 0.2% (w/v). In some preferred embodiments of the invention, said salt of said anionic polymer is present in a concentration sufficient to bring an aqueous solution of said salt of said anionic polymer to a predetermined viscosity at a shear rate of 1 s 1 and a non-Newtonian viscosity profile. In some more preferred embodiments of the invention, said predetermined viscosity at a shear rate of 1 s 1 is between 0.1 and 0.2 Pa-s. In some yet more preferred embodiments of the invention, said predetermined viscosity at a shear rate of 1 s 1 is between 0.1 and 0.15 Pa-s. In some especially preferred embodiments of the invention, said predetermined viscosity at a shear rate of 1 s 1 is about 0.13 Pa-s.
[0013] It is a further object of this invention to disclose the topical ophthalmic composition as defined in any of the above, wherein said composition does not contain any polymer other than hyaluronate. In some preferred embodiments of the invention, said solution is characterized by a hyaluronate concentration of 0.15% (w/v).
[0014] It is a further object of this invention to disclose the topical ophthalmic composition as defined in any of the above, wherein said aqueous solution is characterized by a taurine concentration of between 1% and 5% (w/v). In some preferred embodiments of the invention, said aqueous solution is characterized by a taurine concentration in the range of >3% to 4% (w/v).
[0015] It is a further object of this invention to disclose the topical ophthalmic composition as defined in any of the above, wherein said solution is characterized by a taurine concentration that is hypotonic or isotonic. In some preferred embodiments of the invention, said solution is characterized by a taurine concentration that is isotonic.
[0016] It is a further object of this invention to disclose the topical ophthalmic composition as defined in any of the above, wherein said aqueous solution comprises glycerol. In some preferred embodiments of the invention, said aqueous solution is characterized by a glycerol concentration of between 0.05% and 4% (w/v).
[0017] It is a further object of this invention to disclose the topical ophthalmic composition as defined in any of the above, wherein said composition is characterized by a pH that is within a normal pH range of tears. In some preferred embodiments of the invention, said composition is characterized by a pH of between 6.5 and 7.6.
[0018] It is a further object of this invention to disclose the topical ophthalmic composition as defined in any of the above, wherein said composition comprises an effective amount of preservative. In some embodiments of the invention, said composition consists of an aqueous solution consisting of (a) a salt of at least one anionic polymer; (b) at least 1% (w/v) taurine; (c) <0.10% (w/v) of any salt other than said salt of said at least one anionic polymer; and (d) an effective amount of a preservative.
[0019] It is a further object of this invention to disclose the topical ophthalmic composition as defined in any of the above, wherein said composition comprises a pharmaceutically effective amount of a pharmacologically active agent. In some embodiments of the invention, said composition consists of an aqueous solution consisting of (a) a salt of at least one anionic polymer; (b) at least 1% (w/v) taurine; (c) <0.10% (w/v) of any salt other than said salt of said
at least one anionic polymer; and (d) a pharmaceutically effective amount of a pharmacologically active agent. In some embodiments of the invention, said composition consists of an aqueous solution consisting of (a) a salt of at least one anionic polymer; (b) at least 1% (w/v) taurine; (c) <0.10% (w/v) of any salt other than said salt of said at least one anionic polymer; (d) an effective amount of a preservative; and (e) a pharmaceutically effective amount of a pharmacologically active agent.
[0020] It is a further object of this invention to disclose the topical ophthalmic composition as defined in any of the above, wherein said composition comprises at least one substance selected from the group consisting of stabilizers, antioxidants, and buffers. In some embodiments of the invention, said composition consists of an aqueous solution consisting of (a) a salt of at least one anionic polymer; (b) at least 1% (w/v) taurine; (c) <0.10% (w/v) of any salt other than said salt of said at least one anionic polymer; (d) an effective amount of a preservative; (e) a pharmaceutically effective amount of a pharmacologically active agent; and (f) at least one substance selected from the group consisting of stabilizers, antioxidants, and buffers.
[0021] In some preferred embodiments of the invention, said composition is in the form of a liquid. In some other preferred embodiments of the invention, said composition is in the form of a water-based gel.
[0022] It is a further object of this invention to disclose a topical ophthalmic composition as defined in any of the above, wherein said aqueous solution comprises 0.15% (w/v) sodium hyaluronate, 3.5% (w/v) taurine, preservative, and is characterized by a pH of about 7. In some preferred embodiments of the invention, the composition is characterized by a pH of 7.0.
[0023] It is a further object of this invention to disclose a topical ophthalmic composition as defined in any of the above, wherein said aqueous solution comprises 0.15% (w/v) sodium hyaluronate, 1.25% (w/v) taurine, and 1.8% (w/v) glycerol, and is characterized by a pH of about 7. In some preferred embodiments of the invention, the composition is characterized by a pH of 7.0.
[0024] It is a further object of this invention to disclose a topical ophthalmic composition consisting of an aqueous solution consisting of 0.15% (w/v) sodium hyaluronate and 3.5% (w/v) taurine, said topical ophthalmic composition characterized by a pH of about 7. In some preferred embodiments of the invention, the composition is characterized by a pH of 7.0.
[0025] It is a further object of this invention to disclose a topical ophthalmic composition consisting of an aqueous solution consisting of 0.15% (w/v) sodium hyaluronate, 3.5% (w/v)
taurine, and preservative, said topical ophthalmic composition characterized by a pH of about 7. In some preferred embodiments of the invention, the composition is characterized by a pH of 7.0.
[0026] It is a further object of this invention to disclose a topical ophthalmic composition, wherein said aqueous solution consists of 0.15% (w/v) sodium hyaluronate, 1.25% (w/v) taurine, and 1.8% (w/v) glycerol, and is characterized by a pH of about 7. In some preferred embodiments of the invention, the composition is characterized by a pH of 7.0.
[0027] It is a further object of this invention to disclose a topical ophthalmic composition, wherein said aqueous solution consists of 0.15% (w/v) sodium hyaluronate, 1.25% (w/v) taurine, and 1.8% (w/v) glycerol, and preservative, and is characterized by a pH of about 7. In some preferred embodiments of the invention, the composition is characterized by a pH of 7.0.
[0028] It is a further object of this invention to disclose the topical ophthalmic composition as defined in any of the above for treatment of a condition selected from the group consisting of Occupational Dry Eye; Computer Vision Syndrome; and Meibomian Gland dysfunctions. In some preferred embodiments of the invention, said treatment comprises applying said composition to an affected eye 1 - 8 times daily. In some especially preferred embodiments of the invention, said treatment comprises applying said composition to an affected eye 1 - 8 times daily until a statistically significant reduction in severity of said condition is observed. In some preferred embodiments of the invention, said treatment comprises applying said topical ophthalmic composition three times daily for at least two weeks. In some preferred embodiments, said treatment comprises applying said composition to an affected eye three times daily for a period of at least two weeks. In some preferred embodiments, said treatment comprises applying said composition to an affected eye 1 - 8 times daily until said eye is characterized by a tear break up time of at least 9 seconds. In some preferred embodiments, said treatment comprises applying said composition to an affected eye three times daily until said eye is characterized by a tear break up time of at least 9 seconds.
[0029] It is a further object of this invention to disclose the topical ophthalmic composition as defined in any of the above for alleviation of symptoms of a condition selected from the group consisting of Occupational Dry Eye; Computer Vision Syndrome; and Meibomian Gland dysfunctions. In some preferred embodiments of the invention, said alleviation comprises applying said composition to an affected eye 1 - 8 times daily. In some especially preferred embodiments of the invention, said alleviation comprises applying said composition to an
affected eye 1 - 8 times daily until a statistically significant reduction in severity of said condition is observed. In some preferred embodiments, said alleviation comprises applying said composition to an affected eye three times daily for a period of at least two weeks. In some preferred embodiments, said alleviation comprises applying said composition to an affected eye 1 - 8 times daily until said eye is characterized by a tear break up time of at least 9 seconds. In some preferred embodiments, said alleviation comprises applying said composition to an affected eye three times daily until said eye is characterized by a tear break up time of at least 9 seconds.
[0030] It is a further object of this invention to disclose the topical ophthalmic composition as defined in any of the above for prevention of a condition selected from the group consisting of Occupational Dry Eye; Computer Vision Syndrome; and Meibomian Gland dysfunctions. In some preferred embodiments of the invention, said prevention comprises applying said composition to an eye 1 - 8 times daily.
[0031] It is a further object of this invention to disclose a method for treatment of a condition selected from the group consisting of Occupational Dry Eye; Computer Vision Syndrome; and Meibomian Gland dysfunctions, said method comprising applying the composition as defined in any of the above to an affected eye. In some preferred embodiments of the invention, said step of applying the composition to an affected eye comprises applying said composition to said affected eye 1 - 8 times daily. In some especially preferred embodiments of the invention, said step of applying the composition to an affected eye comprises applying said composition to said affected eye 1 - 8 times daily until a statistically significant reduction in severity of said condition is observed. In some preferred embodiments of the invention, said step of applying the composition to an affected eye comprises applying said composition to an affected eye three times daily for at least two weeks. In some preferred embodiments of the invention, said step of applying the composition to an affected eye comprises applying said composition to an affected eye 1 - 8 times daily until said eye is characterized by a tear break up time of at least 9 seconds. In some preferred embodiments of the invention, said step of applying the composition to an affected eye comprises applying said composition to an affected eye three times daily until said eye is characterized by a tear break up time of at least 9 seconds.
[0032] It is a further object of this invention to disclose a method for alleviation of symptoms of a condition selected from the group consisting of Occupational Dry Eye; Computer Vision Syndrome; and Meibomian Gland dysfunctions, said method comprising applying the composition as defined in any of the above to an affected eye. In some preferred embodiments
of the invention, said step of applying the composition to an affected eye comprises applying said composition to an affected eye 1 - 8 times daily. In some especially preferred embodiments of the invention, said step of applying the composition to an affected eye comprises applying said composition to an affected eye 1 - 8 times daily until a statistically significant reduction in severity of said condition is observed. In some preferred embodiments of the invention, said step of applying the composition to an affected eye comprises applying said composition to an affected eye three times daily for at least two weeks. In some preferred embodiments of the invention, said step of applying the composition to an affected eye comprises applying said composition to an affected eye 1 - 8 times daily until said eye is characterized by a tear break up time of at least 9 seconds. In some preferred embodiments of the invention, said step of applying the composition to an affected eye comprises applying said composition to an affected eye three times daily until said eye is characterized by a tear break up time of at least 9 seconds.
[0033] It is a further object of this invention to disclose a method for prevention of a condition selected from the group consisting of Occupational Dry Eye; Computer Vision Syndrome; and Meibomian Gland dysfunctions, said method comprising applying the composition as defined in any of the above to an eye. In some preferred embodiments of the invention, said step of applying the composition to an eye comprises applying said composition to an affected eye 1 - 8 times daily.
BRIEF DESCRIPTION OF THE FIGURES
[0034] The invention will now be described with reference to the figures, wherein:
[0035] FIG. 1 is a graph showing viscosity profiles (shear viscosity as a function of shear rate) of an 0.15% (w/v) aqueous solution of sodium hyaluronate and for an aqueous solution containing 0.15% (w/v) sodium hyaluronate and 2.5% (w/v) glycerol;
[0036] FIG. 2 is a graph showing a viscosity profile of one embodiment of the composition disclosed herein, in which the composition contains 3.5% (w/v) taurine and 0.15% (w/v) sodium hyaluronate;
[0037] FIG. 3 is a graph showing a viscosity profile of a commercially available eye drop that contains 0.15% (w/v) sodium hyaluronate;
[0038] FIG. 4 is a graph showing a viscosity profile of a solution containing 0.15% hyaluronate and sodium acetate at pH 7.0; and,
[0039] FIG. 5 is a graph showing a viscosity profile of a solution containing 0.15% sodium hyaluronate and 4% Tris HC1 at pH 7.0.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS [0040] In the following description, various aspects of the invention will be described. For the purposes of explanation, specific details are set forth in order to provide a thorough understanding of the invention. It will be apparent to one skilled in the art that there are other embodiments of the invention that differ in details without affecting the essential nature thereof. Therefore, the invention is to be considered as being defined only by the accompanying claims, with the proper scope determined only by the broadest interpretation of said claims.
[0041] In some cases, for clarity or conciseness, individual elements of the invention are discussed separately. Nonetheless, any combination of elements of the invention disclosed herein that is not self-contradictory is considered by the inventor to be within the scope of the invention. Furthermore, all embodiments of the invention that are described in terms of the embodiment "comprising" a listed set of components (i.e. the embodiment contains at least the components listed) are considered to include within their scope embodiments of the invention that "consist of" those components (i.e. the embodiment contains the components listed and no others).
[0042] Unless otherwise stated, all concentrations are given as percent w/v (grams per 100 ml solution).
[0043] Unless otherwise stated, all ranges are inclusive, i.e. the range is understood to include the stated endpoints.
[0044] Unless otherwise stated, all references to the "viscosity" of a fluid are to be understood to refer to the fluid's dynamic viscosity.
[0045] As used herein, all descriptions of molecular weights of polymers refer to the minimum molecular weight.
[0046] As used herein, with reference to numerical quantities, unless otherwise stated, the term "about" refers to a tolerance of ±25% about the nominal value.
[0047] As used herein, with reference to results of measurements, the term "statistically significant change" refers to a change of more than one standard error of the mean of the initial measurement.
[0048] As used herein, the term "inorganic salt" refers to a salt that is made up entirely of inorganic ions, i.e. the cation(s) and the anion(s) of an inorganic salt are all inorganic.
[0049] The advantages of a non-Newtonian viscosity profile for a topical ophthalmological composition were described above. The inventor of the present invention additionally disclosed in '615 that inorganic salts destroy the non-Newtonian viscosity properties of polymer solutions. Taurine-containing ophthalmological compositions known in the art are characterized either by taurine concentrations on the order of 0.1%, thereby reducing their effectiveness, or as containing on the order of 1% inorganic salt, thereby lacking the advantageous non-Newtonian viscosity properties.
[0050] As illustrated in Examples 7 and 8 below, not only do inorganic salts destroy the non- Newtonian viscosity properties of a polymer solution, but salts containing organic ions do so as well, including salts that contain one organic ion and one inorganic ion. The pi of taurine is about 5.2, and thus at pH 7.0 (the pH required for an eye drop) it is nearly entirely ionized (i.e. in the form of a salt). It would thus be expected that an aqueous solution of a high molecular weight polymer and isotonic (~3 - 4%) taurine would show Newtonian viscosity properties. The inventor has discovered, surprisingly, that such a composition unexpectedly retains the non-Newtonian viscosity properties of the polymer solution despite having a taurate salt concentration of several percent (w/v), a property that is unprecedented and to the inventor's knowledge not yet explained. Thus, in contrast to taurine-containing ophthalmological compositions known in the art, the composition disclosed herein combines the advantages of a non-Newtonian viscosity profile with the benefits of an isotonic taurine concentration.
[0051] In preferred embodiments of the invention, the composition comprises an aqueous solution comprising one or more anionic polymers, an isotonic or nearly isotonic concentration of taurine, and less than 0.10% (w/v) inorganic salt. The composition may be in the form of an aqueous solution or in the form of a water-based gel. The polymer serves to control the viscosity of the composition, and is preferably of high molecular weight (MW). In preferred embodiments of the invention, the polymer is characterized by MW > 10,000 Dalton. In especially preferred embodiments of the invention, the polymer is characterized by MW > 500,000 Dalton. Non-limiting examples of anionic polymers that can be used in the composition include hyaluronate, carbomers, and anionic polysaccharides. In preferred embodiments of the invention, sodium hyaluronate is used as the anionic polymer. Since the polymer is anionic, in the absence of added salt, the solution has the additional advantage of having a non-Newtonian viscosity profile.
[0052] The composition may be prepared according to standard procedures and transferred to and stored in a container appropriate for storing and/or dispensing it.
[0053] In some embodiments of the invention, the composition additionally comprises one or more preservatives. Any preservative known in the art for use with topical ophthalmological compositions may be used.
[0054] In some embodiments of the invention, the composition additionally comprises a pharmaceutically effective concentration of at least one pharmacologically active agent. If necessary, any stabilizer, preservative, antioxidant, buffer or combination thereof appropriate for use with the pharmacologically active agent may be added to the solution in any concentration suitable for the intended use.
[0055] The following examples are presented in order to assist a person skilled in the art to make and use the invention, and are not to be considered in any way limiting.
EXAMPLE 1
[0056] One non-limiting embodiment of the composition disclosed herein was prepared as follows:
[0057] Sodium hyaluronate 0.15 g
[0058] Taurine 3.5 g
[0059] Sodium perborate tetrahydrate (preservative) 0.028 g
[0060] Water to 100 ml
[0061] The pH of the solution was adjusted to 7.0.
[0062] The osmolarity of the composition was measured, and found to be 280 mOsm/L, i.e. the composition is slightly hypotonic.
EXAMPLE 2
[0063] A second non-limiting embodiment of the invention disclosed herein was prepared according to the composition of the previous example, except that no preservative was added and the composition was stored in a "preservative-free" bottle.
EXAMPLE 3
[0064] A third non-limiting embodiment of the invention disclosed herein was prepared as follows:
[0065] Sodium hyaluronate 0.15 g [0066] Taurine 1.25 g
[0067] Glycerol 1-80 g [0068] Water to 100 ml
[0069] The pH of the solution was adjusted to 7.0.
[0070] The composition was packaged in single-dose vials or "preservative free" bottles.
EXAMPLE 4
[0071] Reference is now made to FIG. 1, which presents viscosity profiles for an 0.15% aqueous solution of sodium hyaluronate (diamonds) and an aqueous solution of sodium hyaluronate and 2.5% (i.e., nearly isotonic) glycerol (squares). In the graph, the shear viscosity in Pa-s is plotted as a function of the shear rate in s 1. Note that the x-axis is logarithmic. It can be seen that addition of a non-ionic component (glycerol) does not influence the non- Newtonian viscosity profile of sodium hyaluronate. As the shear rate increases from low to high values, the viscosity decreases by more than an order of magnitude.
EXAMPLE 5
[0072] Reference is now made to FIG. 2, which presents a viscosity profile for the embodiment of the invention disclosed herein that is described in detail in Example 2. The graph shows that the composition disclosed herein has a typical non-Newtonian viscosity profile. Viscosity decreases slowly as a function of shear rate from a viscosity of about 0.13 Pa-s at a shear rate of 1 s 1 to 0.01 Pa-s at high shear rate, i.e. as with the solution of hyaluronate and glycerol, as the shear rate increases from low to high values, the viscosity decreases by more than an order of magnitude.
EXAMPLE 6
[0073] Reference is now made to FIG. 3, which presents a viscosity profile for a commercially available eye drop marketed under the trade name HYABAK. The viscosity profile is for a sample that was purchased in Hungary. The eye drop is an aqueous solution containing 0.15% hyaluronate along with NaCl and Tris-HCl ("Tris" = 2-amino-2-(hydroxymethyl)propane-l,3- diol) that serve to regulate the osmolarity. The osmolarity of the sample obtained for testing was determined to be 211 mOsm/L, implying a salt concentration of about 0.6%. The graph demonstrates that, as expected for a composition containing 0.6% salt, the viscosity profile of HYABAK eye drops is essentially Newtonian. As the shear rate increases from low to high values, the viscosity decreases from 0.006 Pa-s to 0.002 Pa-s, i.e. only 3-fold. Moreover, extrapolation of the measured values implies a viscosity at low shear rate of -0.01 Pa-s, as
opposed to a low shear rate viscosity of > 0.1 Pa-s in the non-Newtonian formulations of the preceding examples .
EXAMPLE 7
[0074] Reference is now made to FIG. 4s which presents a viscosity profile of a solution containing 0.15% hyaluronate + sodium acetate at pH 7.0 (1.23% sodium acetate), i.e. a solution containing an inorganic cation and organic anion. The osmolarity was determined to be 305 mOsm/L (i.e. nearly isotonic). The viscosity profile is essentially Newtonian; the viscosity falls rapidly at low shear rate such that at a shear rate of 5 s_i the viscosity has already decreased to 0.02 Pa-s.
EXAMPLE 8
[0075] Reference is now made to FIG. 5, which presents a velocity profile of a solution containing 0.15% sodium hyaluronate and 4% Tris-HCl at pH 7.0, i.e. a solution containing a salt comprising an organic cation and an inorganic anion. As with the preceding example, the viscosity profile is essentially Newtonian in this case as well.
EXAMPLE 9
[0076] As was discussed above, eye drops having non-Newtonian rheological properties have advantages over those with Newtonian rheological properties, particularly in that they provide a more pleasant subjective feeling and that they enable the eye drops to stay on the cornea longer. Not every non-Newtonian eye drop, however, will necessarily increase the tear stability as measured objectively by the tear break up time (TBUT), a clinical test used to assess the severity of evaporative dry eye disease. For example, it has been found that the composition disclosed as Example 3 of '615 does not significantly affect the TBUT despite having non- Newtonian rheological properties.
[0077] Thus, in order to demonstrate the benefits of the composition disclosed herein relative to eye drop compositions containing taurine that are known in the art, clinical trials were performed to determine the improvement in the TBUT provided by topical application of the composition disclosed herein. Subjects suffering from Occupational Dry Eye or Computer Vision Syndrome were given either HYABAK eye drops or the embodiment of the composition disclosed herein that is described in Example 1 above. The subjects applied the composition 3 times daily for 2 weeks. The TBUT was measured at the beginning and at the end of the study. TBUT was determined by instilling fluorescein into the subject's tear film and observing the tear film under a broad beam of cobalt blue illumination while the subject did not blink, and is
recorded as the number of seconds that elapse between the last blink and the appearance of the first dry spot in the tear film. A TBUT under 10 seconds is considered abnormal.
[0078] Results of the study are summarized in Table 1 and are expressed as mean TBUT in seconds +1 standard error of mean.
TABLE 1
Composition Number of patients TBUT, s (start) TBUT, s (end)
HYABAK 10 7.10 + 0.43 7.90 + 0.30 present invention 19 6.99 + 0.16 9.09 + 0.28
[0079] The table shows that while treatment with HYABAK increased the TBUT by about 10% over the course of the study, treatment with the composition disclosed herein increased the TBUT by nearly 30%. In other words, in contrast with eye drops known in the art, the eye drops disclosed herein returned the TBUT of people suffering from Occupational Dry Eye or Computer Vision Syndrome nearly to normal after only two weeks of use.
Claims
1. A topical ophthalmic composition, wherein said topical ophthalmic composition comprises an aqueous solution comprising: a salt of at least one anionic polymer selected from the group consisting of hyaluronates, carbomers, and anionic polysaccharides;
>3% - 5% (w/v) taurine; and,
<0.10% (w/v) of any salt other than said salt of said at least one anionic polymer.
2. The topical ophthalmic composition according to claim 1, wherein said topical ophthalmic composition consists of an aqueous solution consisting of: a salt of at least one anionic polymer selected from the group consisting of hyaluronates, carbomers, and anionic polysaccharides;
>3% - 5% (w/v) taurine;
<0.10% (w/v) of any salt other than said salt of said at least one anionic polymer; and, optionally, an effective an effective amount of preservative.
3. The topical ophthalmic composition according to either one of claim 1 or claim 2, wherein said at least one anionic polymer is characterized by a molecular weight of at least 10,000 Dalton.
4. The topical ophthalmic composition according to claim 3, wherein said at least one anionic polymer is characterized by a molecular weight of at least 500,000 Dalton.
5. The topical ophthalmic composition according to either one of claim 1 or claim 2, wherein said solution comprises is characterized by a polymer concentration of between 0.05% and 5.0% (w/v).
6. The topical ophthalmic composition according to claim 5, wherein said solution is characterized by a polymer concentration of between 0.1% and 0.2% (w/v).
7. The topical ophthalmic composition according to either one of claim 1 or claim 2, wherein said salt of said anionic polymer is present in a concentration sufficient to bring an aqueous solution of said salt of said anionic polymer to a non-Newtonian viscosity profile and a viscosity at a shear rate of 1 s 1 of between 0.1 and 0.2 Pa-s.
8. The topical ophthalmic composition according to either one of claim 1 or claim 2, wherein said composition does not contain any polymer other than hyaluronate.
9. The topical ophthalmic composition according to claim 8, wherein said solution is characterized by a hyaluronate concentration of 0.15% (w/v).
10. The topical ophthalmic composition according to either one of claim 1 or claim 2, wherein said solution is characterized by a taurine concentration of >3% - 4% (w/v).
11. The topical ophthalmic composition according to either one of claim 1 or claim 2, wherein said solution is characterized by a taurine concentration that is hypotonic or isotonic.
12. The topical ophthalmic composition according to claim 11, wherein said solution is characterized by a taurine concentration that is isotonic.
13. The topical ophthalmic composition according to either one of claim 1 or claim 2, wherein said composition is characterized by a pH that is within a normal pH range of tears.
14. The topical ophthalmic composition according to claim 13, wherein said composition is characterized by a pH of between 6.5 and 7.6.
15. The topical ophthalmic composition according to claim 1, comprising at least one substance selected from the group consisting of: an effective amount of preservative; a pharmaceutically effective amount of a pharmacologically active agent; stabilizers; antioxidants; and, buffers.
16. The topical ophthalmic composition according to either one of claim 1 or claim 2, wherein said composition is in the form of a liquid.
17. The topical ophthalmic composition according either one of claim 1 or claim 2, wherein said composition is in the form of a water-based gel.
18. The topical ophthalmic composition according to claim 1, wherein said aqueous solution comprises 0.15% (w/v) sodium hyaluronate, 3.5% (w/v) taurine, and preservative, and is characterized by a pH of about 7.
19. The topical ophthalmic composition according to claim 2, wherein said composition consists of an aqueous solution consisting of 0.15% (w/v) sodium hyaluronate, 3.5% (w/v) taurine, and preservative, and is characterized by a pH of about 7.
20. The topical ophthalmic composition according to either one of claim 1 or claim 2, for use in a treatment of a condition selected from the group consisting of Occupational Dry Eye; Computer Vision Syndrome; and Meibomian Gland dysfunctions.
21. The topical ophthalmic composition according to claim 20, wherein said treatment comprises applying said topical ophthalmic composition to an affected eye 1 - 8 times daily.
22. The topical ophthalmic composition according to claim 21, wherein said treatment comprises applying said topical ophthalmic composition to an affected eye 1 - 8 times daily until said eye is characterized by a tear break up time of at least 9 seconds.
23. The topical ophthalmic composition according to claim 20, wherein said treatment comprises applying said topical ophthalmic composition to an affected eye three times daily for at least two weeks.
24. The topical ophthalmic composition according to claim 23, wherein said treatment comprises applying said topical ophthalmic composition to an affected eye three times daily until said eye is characterized by a tear break up time of at least 9 seconds.
25. The topical ophthalmic composition according to either one of claim 1 or claim 2, for use in prevention of a condition selected from the group consisting of Occupational Dry Eye; Computer Vision Syndrome; and Meibomian Gland dysfunctions.
26. The topical ophthalmic composition according to claim 25, wherein said prevention of said condition comprises applying said topical ophthalmic composition to an eye 1 - 8 times daily.
27. The topical ophthalmic composition according to either one of claim 1 of claim 2, for use in alleviation of symptoms of a condition selected from the group consisting of Occupational Dry Eye; Computer Vision Syndrome; and Meibomian Gland dysfunctions.
28. The topical ophthalmic composition according to claim 27, wherein said alleviation of said symptoms comprises applying said topical ophthalmic composition to an eye 1 - 8 times daily.
29. The topical ophthalmic composition according to claim 28, wherein said alleviation of said symptoms comprises applying said topical ophthalmic composition to an affected eye 1 - 8 times daily until said eye is characterized by a tear break up time of at least 9 seconds.
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IL272436 | 2020-02-03 | ||
IL27243620 | 2020-02-03 |
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PCT/IL2021/050120 WO2021156856A1 (en) | 2020-02-03 | 2021-02-02 | Topical opthalmological composition containing hyaluronate and taurine having non-newtonian rheological properties |
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
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US5106615A (en) | 1986-10-14 | 1992-04-21 | Shabtay Dikstein | Eyedrops having non-newtonian rheological properties |
JP2002020279A (en) | 2000-06-30 | 2002-01-23 | Taisho Pharmaceut Co Ltd | Eye lotion |
WO2009006130A2 (en) * | 2007-06-28 | 2009-01-08 | Bausch & Lomb Incorporated | Salt free hyaluronate ophthalmic solution |
US20100069482A1 (en) * | 2006-12-22 | 2010-03-18 | Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. | Gel useful for the delivery of ophthalmic drugs |
RU2623205C1 (en) * | 2016-07-13 | 2017-06-22 | Станислав Анатольевич Кедик | Ophthalmologic gel of taurine |
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2021
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US5106615A (en) | 1986-10-14 | 1992-04-21 | Shabtay Dikstein | Eyedrops having non-newtonian rheological properties |
JP2002020279A (en) | 2000-06-30 | 2002-01-23 | Taisho Pharmaceut Co Ltd | Eye lotion |
US20100069482A1 (en) * | 2006-12-22 | 2010-03-18 | Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. | Gel useful for the delivery of ophthalmic drugs |
WO2009006130A2 (en) * | 2007-06-28 | 2009-01-08 | Bausch & Lomb Incorporated | Salt free hyaluronate ophthalmic solution |
RU2623205C1 (en) * | 2016-07-13 | 2017-06-22 | Станислав Анатольевич Кедик | Ophthalmologic gel of taurine |
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