Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
  • A61K31/736—Glucomannans or galactomannans, e.g. locust bean gum, guar gum
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0048—Eye, e.g. artificial tears
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
  • A61P27/04—Artificial tears; Irrigation solutions

Definitions

• the present invention relates to ophthalmic formulations comprising galactomannans, and more specifically to formulations comprising galactomannan and a diol alcohol compound in a quantity sufficient to stabilize the viscosity of the formulation.
• Ophthalmic formulations often comprise compounds that provide desirable properties to the formulation. When these formulations are instilled in the eye, the properties of such compounds can help prevent ophthalmic problems such as bioadhesion and the formation of friction-induced tissue damage, as well as encourage the natural healing and restoration of previously damaged tissues.
• Formulations are typically developed with a target viscosity to ensure that they are comfortable for the user and do not cause undesirable side effects such as blurring.
• a suitable formulation viscosity can help ensure that an ophthalmic formulation used in dry eye disorders will relieve dry eye-associated symptoms and/or treat the underlying disorder.
• the viscosity of ophthalmic formulations may be chosen to ensure that a pharmaceutical agent carried in the formulation remains in the eye for a desired length of time. Given its criticality, the viscosity of ophthalmic formulations should remain as stable as possible over time.
• the viscosity of formulations can be affected by storage conditions (e.g., environmental temperature, time of storage, ambient light, etc.). Also, ophthalmic formulations must be sterilized before use, and the sterilization process, particularly heat sterilization, can dramatically affect the viscosity of such formulations.
• Embodiments of the invention generally relate to ophthalmic formulations comprising galactomannan.
• the present inventors have unexpectedly discovered that diol alcohols can be included in such ophthalmic formulations to stabilize the viscosity of such solutions.
• the stabilization of the ophthalmic formulations by diol alcohols minimizes viscosity loss at elevated temperatures and ensures that the formulations can be stored safely for longer periods of time without viscosity loss.
• Another embodiment of the present invention is a method for stabilizing ophthalmic formulations comprising galactomannan and borate.
• the method comprises adding a diol alcohol and, optionally, a pharmaceutically acceptable divalent cation salt such as magnesium chloride.
• the formulations of the present invention comprise a galactomannan and a borate in aqueous solution.
• the cross-linking behavior of the galactomannan and the borate contributes to the viscosity of the formulations.
• the present invention is directed to the use of diol alcohols such as sorbitol and propylene glycol to stabilize the viscosity of ophthalmic formulations, presumably by modifying the cross-linking of the borate and galactomannan.
• the use of such diol alcohols also stabilizes the molecular weight of galactomannan polymers during sterilization of formulations comprising such polymers.
• the diol alcohol sorbitol is used in preferred formulations of the present invention.
• the diol alcohol compounds that may be used with embodiments of the present invention include, but are not limited to, hydrophilic carbohydrates such as sorbitol or mannitol that comprise cis-diol groups (hydroxyl groups attached to adjacent carbon atoms).
• Other diol alcohol compounds of the present invention include polyethylene glycols, polypropylene glycols, and glycerol.
• Particularly preferred diol compounds are sorbitol and mannitol.
• the diol compounds are present at concentrations of about 0.5 to 5.0 w/v % in the formulations of the present invention, and are preferably present at a concentration of about 0.5 to 2.0 w/v %.
• galactomannans typically derived from guar gum, locust bean gum and tara gum.
• galactomannan refers to polysaccharides derived from the above natural gums or similar natural or synthetic gums containing mannose or galactose moieties, or both groups, as the main structural components.
• Preferred galactomannans of the present invention are made up of linear chains of (1-4)- ⁇ -D-mannopyranosyl units with ⁇ -D-galactopyranosyl units attached by (1-6) linkages. With the preferred galactomannans, 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.
• 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 formulation of the present invention at a concentration of about 0.01 to about 10 w/v %, preferably at about 0.05 w/v % to about 2.0 w/v %, and most preferably at about 0.05 to about 0.5 w/v %.
• Preferred galactomannans of the present invention are guar, hydroxypropyl guar, and hydroxypropyl guar galactomannan.
• Native guar such as the guar produced by a process set forth in U.S. Patent Application Publication No. 2010/0196415 entitled “Process for Purifying Guar” filed Feb. 5, 2010 (the entire contents of which are herein incorporated by reference) is also a preferred galactomannan.
• Borate is typically present at a concentration of about 0.05 to about 2.0 w/v %, and preferably about 0.1 to 1.5 w/v %.
• the term “borate” refers to all pharmaceutically suitable forms of borates, including but not limited to boric acid, and alkali metal borates such as sodium borate and potassium borate. Boric acid is the preferred borate used with embodiments of the present invention.
• Borate compounds which may be used in the compositions of the present invention are boric acid and other pharmaceutically acceptable salts such as sodium borate (borax) and potassium borate.
• the term “borate” refers to all pharmaceutically suitable forms of borates. Borates are common excipients in ophthalmic formulations due to weak buffering capacity at physiological pH and well known safety and compatibility with a wide range of drugs and preservatives. Borates also have inherent bacteriostatic and fungistatic properties, and therefore aid in the preservation of the compositions.
• excipients may be used in formulations of the present invention including water, mixtures of water and water-miscible solvents, such as vegetable oils or mineral oils comprising from 0.5 to 5% non-toxic water-soluble polymers, natural products, such as alginates, pectins, tragacanth, karaya gum, xanthan gum, carrageenin, agar and acacia, starch derivatives, such as starch acetate and hydroxypropyl starch, and also other synthetic products such as polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl methyl ether, polyethylene oxide, and preferably cross-linked polyacrylic acid and mixtures of those products.
• vegetable oils or mineral oils comprising from 0.5 to 5% non-toxic water-soluble polymers
• natural products such as alginates, pectins, tragacanth, karaya gum, xanthan gum, carrageenin, agar and acacia
• starch derivatives such as
• Demulcents used with embodiments of the present invention include, but are not limited to, glycerin, polyvinyl pyrrolidone, polyethylene oxide, polyethylene glycol, propylene glycol and polyacrylic acid. Particularly preferred demulcents are propylene glycol and polyethylene glycol 400.
• Suitable tonicity-adjusting agents include, but are not limited to, mannitol, sodium chloride, glycerin, and the like.
• Suitable buffering agents include, but are not limited to, phosphates, acetates and the like, and amino alcohols such as 2-amino-2-methyl-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, poloxamers such as Pluronic° F68, and block copolymers such as poly(oxyethylene)-poly(oxybutylene) compounds set forth in U.S. Patent Application Publication No. 2008/0138310 entitled “Use of PEO-PBO Block Copolymers in Ophthalmic Compositions” filed Dec. 10, 2007 (the entire contents of which are herein incorporated by reference).
• Formulations of the present invention are ophthalmically suitable for application to a subject's eyes.
• aqueous typically denotes an aqueous formulation wherein the excipient is >50%, more preferably >75% and in particular >90% by weight water.
• These drops may be delivered from a single dose ampoule which may preferably be sterile and thus render bacteriostatic components of the formulation unnecessary.
• the drops may be delivered from a multi-dose bottle which may preferably comprise a device which extracts any preservative from the formulation as it is delivered, such devices being known in the art.
• compositions of the present invention can also be used to administer pharmaceutically active compounds.
• pharmaceutically active compounds include, but are not limited to, glaucoma therapeutics, pain relievers, anti-inflammatory and anti-allergy medications, and anti-microbials. More specific examples of pharmaceutically active compounds include betaxolol, timolol, pilocarpine, carbonic anhydrase inhibitors and prostglandins; dopaminergic antagonists; post-surgical antihypertensive agents, such as para-amino clonidine (apraclonidine); anti-infectives such as ciprofloxacin, moxifloxacin, and tobramycin; non-steroidal and steroidal anti-inflammatories, such as naproxen, diclofenac, nepafenac, suprofen, ketorolac, tetrahydrocortisol and dexamethasone; dry eye therapeutics such as PDE4 inhibitors; and anti-allergy medications such
• concentrations of the ingredients comprising the formulations of the present invention can vary.
• concentrations can vary depending on the addition, substitution, and/or subtraction of ingredients in a given formulation.
• Preferred formulations are prepared using a buffering system that maintains the formulation at a pH of about 6.5 to a pH of about 8.0.
• Topical formulations are preferred which have a physiological pH matching the tissue to which the formulation will be applied or dispensed.
• a formulation of the present invention is administered once a day.
• the formulations may also be formulated for administration at any frequency of administration, including once a week, once every 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.
• the viscosity of various solutions of the present invention and control solutions was evaluated using a controlled stress rheometer (AR 2000ex, TA Instruments, Inc.).
• the measurement system was a 40 mm acrylic 2° cone and plate with a sample volume of 0.58 mL. A temperature of 25° C. +/ ⁇ 0.1° C. was maintained and a cover was placed over the measurement system to prevent evaporation of the solutions.
• Solution 89B has the highest initial viscosity of the formulations tested.
• 89B is the formulation with just the removal of dissolved O 2 .
• the initial viscosity of solution 89B at a shear rate of 10s ⁇ 1 is 17.62 cP. After 5 weeks at room temperature, there is a small drop in viscosity of 3.22%. After 5 weeks at 40° C., there is a much greater drop in viscosity of 15.95%.
• 89B has a similar breakdown through the stability. However the initial viscosity is maintained at a level of 0.1 ppm dissolved O 2 .
• Solution 89C has 0.19 w/v % MgCl 2 added to the formulation.
• the initial viscosity of solution 89C at a shear rate of 10s ⁇ 1 is 14.55 cP. After 5 weeks at room temperature, there is a small drop in viscosity of 1.51%. After 5 weeks at 40° C., there is a drop in viscosity of 7.97%.
• Solution 89C with magnesium demonstrates a greater initial viscosity and enhanced stability compared to the control solution (solution 89A) at both room and elevated temperature.
• Solution 89D comprising 1.0 w/v % sorbitol shows the best stability of the tested formulations.
• the initial viscosity of solution 89D at a shear rate of 10s ⁇ 1 is 13.30 cP. After 5 weeks at room temperature there is a small drop in viscosity of 0.68%. After 5 weeks at 40° C. there is a drop in viscosity of 2.85%.
• Native guar with a molecular weight of 3.0M Daltons manufactured according to the process described in U.S. Patent Application Publication No. 2010/0196415 was formulated in test formulations A-C set forth in Table 4 below. Following sterilization by autoclaving, the molecular weight of native guar in each formulation was measured. Compared to formulations B and C, the native guar in formulation A not containing a diol compound (sorbitol or glycerol) had a significantly lower measured molecular weight. The use of diol compounds in the guar formulations has a preservation effect on the molecular weight of guar during the sterilization process.
• a diol compound sorbitol or glycerol

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