Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—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

Definitions

• the present invention relates to ophthalmic pharmaceutical compositions and their use to provide relief to eye conditions.
• KCS keratoconjunctivitis sicca
• Sjogren's syndrome is a chronic disorder in which white blood cells attack the moisture- producing glands, such as lacrimal and salivary glands.
• Dry eye may afflict individuals with differing severity. In mild cases, a patient may experience burning, a feeling of dryness, and other symptoms of ocular discomfort. In severe cases, vision may be substantially impaired. Although dry eye may have a variety of unrelated pathogenic causes, they all share as a common effect the breakdown of the ocular tear film, with dehydration of and subsequent damage to the exposed outer ocular surfaces.
• the present invention provides ophthalmic pharmaceutical compositions for relieving discomfort in an eye.
• such discomfort results from an ocular condition, such as allergy, infection, inflammation, or dry eye syndrome.
• an ocular condition such as allergy, infection, inflammation, or dry eye syndrome.
• such discomfort may result from a treatment of another condition of the eye, such as an eye surgery (e.g., glaucoma surgery, cataract surgery, or surgery to treat a back-of-the-eye condition).
• an eye surgery e.g., glaucoma surgery, cataract surgery, or surgery to treat a back-of-the-eye condition.
• an ophthalmic pharmaceutical composition of the present invention comprises a material that allows the composition to remain on an ocular surface for an extended period of time.
• an ophthalmic pharmaceutical composition of the present invention comprises a demulcent.
• an ophthalmic pharmaceutical composition of the present invention is devoid of preservatives that can produce discomfort in the eye.
• an ophthalmic pharmaceutical composition of the present invention is devoid of preservatives.
• the present invention provides a method for relieving discomfort in an eye, the method comprising administering into an affected eye a composition that comprises a material that allows the composition to remain on an ocular surface for an extended period of time and that is devoid of preservatives that can produce other discomfort in said eye.
• compositions of the present invention comprise ingredients and are prepared according methods as shown in the following description.
• the main batch tank should have the capacity to accommodate the entire batch weight.
• a mechanical dispersion device such as an In-line SLIM or Eductor or equivalent may be used to improve the addition rate and dispersion of the material. After the addition is complete, begin recirculation of batch.
• Tank must be maintained under positive pressure with sterile air during cool down, storage and filling activities.
• the temperature of the product to be filled should be between 20° and
• Advanced Eye Relief Long Lasting product (BL-700-DDE09) is a sterile, buffered, preservative free, hypotonic solution intended for use as an artificial tear and lubricant for providing soothing therapy to dry irritated eyes.
• the solution is a non- blurring, low viscosity liquid that contains propylene glycol and glycerin as demulcents which lubricate and soothe the irritated corneal epithelium.
• the solution also contains alginate, a hydrocolloid, which serves to interact with the mucin layer in the tear film and holds moisture for a long time. This helps to keep the tear film intact and provides long term relief to the dry eyes.
• the product is manufactured as a single phase process and batch transferred to a sterile hemisphere through 0.22 ⁇ m sterile elements.
• the product is packaged in a single dose unit configuration via a form-fill-seal process.
• Sterilizing filter Millipore CVGL71TP3 (0.22 micron) hydrophilic filter.
• Blend the following ingredients together for not less than 15 minutes. Blend should not contain clumps.
• a material that allows the composition to remain on an ocular surface for an extended period of time after the composition has been administered to said ocular surface can be a demulcent.
• an extended period of time means a period of time of at least 1 hour.
• a demulcent can be a material that is water soluble, sparingly soluble, or substantially soluble in water.
• such a material is selected from the group consisting of lightly cross-linked, carboxyl-containing polymers that are substantially insoluble or only sparingly soluble in water.
• the material is selected from the group consisting of cellulose derivatives (such as sodium carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, or methyl cellulose), dextran 70, gelatin, polyethylene glycol, propylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, polyacrylic acid, polymethacrylic acid, combinations thereof, and mixtures thereof.
• a preferred material comprises a Carbopol polymer, such as Carbopol 980 or Carbopol 976.
• Suitable materials include, but are not limited to, ethacrylic acid, ⁇ - methylacrylic acid (crotonic acid), cis- ⁇ -methylcrotonic acid (angelic acid), trans- ⁇ - methylcrotonic acid (tiglic acid), ⁇ -butylcrotonic acid, ⁇ -phenylacrylic acid, ⁇ - benzylacrylic acid, ⁇ -cyclohexylacrylic acid, ⁇ -phenylacrylic acid (cinnamic acid), coumaric acid (o-hydroxycinnamic acid), unibellic acid (p-hydroxycoumaric acid), and the like and can be used in addition to, or instead of, acrylic acid.
• crotonic acid ⁇ - methylacrylic acid
• angelic acid cis- ⁇ -methylcrotonic acid
• trans- ⁇ - methylcrotonic acid tiglic acid
• ⁇ -butylcrotonic acid ⁇ -phenylacrylic acid
• ⁇ -benzylacrylic acid
• Such polymers may be crosslinked by a polyfunctional crosslinking agent, preferably a difunctional crosslinking agent.
• the amount of crosslinking should be sufficient to form polymers that are substantially insoluble or sparingly soluble in water.
• the polymers are only lightly crosslinked.
• the crosslinking agent is used in an amount of from about 0.01% to about 5%, preferably from about 0.1% to about 2%, and more preferably from about 0.2% to about 1%, based on the total weight of monomers present.
• crosslinking agents include non-polyalkenyl polyether difunctional crosslinking monomers such as divinyl glycol; 2,3- dihydroxyhexa-l,5-diene; 2,5-dimethyl-l,5-hexadiene; divinylbenzene; N 5 N- diallylacrylamide; N,N-diallymethacrylamide and the like.
• Diolefinic non-hydrophilic macromeric crosslinking agents having molecular weights of from about 400 to about 8,000, such as insoluble di- and polyacrylates and methacrylates of diols and polyols, diisocyanate-hydroxyalkyl acrylate or methacrylate reaction products of isocyanate terminated prepolymers derived from polyester diols, polyether diols or polysiloxane diols with hydroxyalkylmethacrylates, and the like, can also be used as the crosslinking agents; see, e.g., Mueller et al. U.S. Patents 4,192,827 and 4,136,250, the entire contents of each patent being incorporated herein by reference.
• Such a polymer is present in a composition of the instant invention in an amount from about 0.01 to about 5% (by weight).
• such a polymer is present in an amount from about 0.01 to about 2%, or from about 0.01 to about 1%, or from about 0.01 to about 0.5%, or from about 0.01 to about 0.2%, or from about 0.01 to about 0.1% (by weight).
• a composition of the present invention is in a form of a suspension or dispersion.
• the suspension or dispersion is based on an aqueous solution.
• a composition of the present invention can comprise sterile saline solution.
• the suspension or dispersion is an oil-based formulation.
• the formulation can include an oil selected from the group consisting of vegetable oil, peanut oil, olive oil, coconut oil, sesame oil, cottonseed oil, corn oil, sunflower oil, fish-liver oil, arachis oil, liquid paraffin, and mixtures thereof.
• a composition of the present invention can further comprise a non-ionic surfactant, such as polysorbates (such as polysorbate 80 (polyoxyethylene sorbitan monooleate), polysorbate 60 (polyoxyethylene sorbitan monostearate), polysorbate 20 (polyoxyethylene sorbitan monolaurate), commonly known by their trade names of Tween® 80, Tween® 60, Tween® 20), poloxamers (synthetic block polymers of ethylene oxide and propylene oxide, such as those commonly known by their trade names of Pluronic®; e.g., Pluronic® F127 or Pluronic® F 108) ), or poloxamines (synthetic block polymers of ethylene oxide and propylene oxide attached to ethylene diamine, such as those commonly known by their trade names of Tetronic®; e.g., Tetronic® 1508 or Tetronic® 908, etc., other nonionic surfactants such as Brij®, Myrj®, and
• concentration of a non-ionic surfactant, when present, in a composition of the present invention can be in the range from about 0.001 to about 5 weight percent (or alternatively, from about 0.01 to about 4, or from about 0.01 to about 2, or from about 0.01 to about 1 weight percent).
• a composition of the present invention can include additives such as buffers, diluents, carriers, adjuvants, or excipients. Any pharmacologically acceptable buffer suitable for application to the eye may be used. Other agents may be employed in the composition for a variety of purposes. For example, buffering agents, co-solvents, humectants, emollients, stabilizers, or antioxidants may be employed. Suitable water- soluble buffering agents that may be employed are sodium carbonate, sodium borate, sodium phosphate, sodium acetate, sodium bicarbonate, etc., as approved by the United States Food and Drug Administration (“US FDA”) for the desired route of administration.
• US FDA United States Food and Drug Administration
• These agents may be present in amounts sufficient to maintain a pH of the system of between about 2 and about 11. As such the buffering agent may be as much as about 5% on a weight to weight basis of the total composition. Electrolytes such as, but not limited to, sodium chloride and potassium chloride may also be included in the formulation.
• the pH of the composition is in the range from about 4.5 to about 11.
• the pH of the composition is in the range from about 6 to about 9, or from about 6.5 to about 8.
• the composition comprises a buffer having a pH in one of said pH ranges.
• the composition has a pH of about 7.
• the composition has a pH in a range from about 7 to about 7.5.
• the composition has a pH of about 7.4.
• a composition of the present invention formulated for the treatment of dry eye-type diseases and disorders may also comprise carriers designed to provide immediate, short-term relief of dry eye-type conditions.
• Such carriers can be formulated as a phospholipid carrier or an artificial tears carrier, or mixtures of both.
• a phospholipid carrier comprises one or more phospholipids that lubricate, wet, approximate the consistency of endogenous tears, aid in natural tear build-up, or otherwise provide temporary relief of dry eye symptoms and conditions upon ocular administration.
• Non-limiting examples of phospholipid carrier formulations include those disclosed in U.S.
• a composition also can comprise a viscosity-modifying compound designed to lubricate, wet, approximate the consistency of endogenous tears, aid in natural tear build-up, or otherwise provide temporary relief of dry eye symptoms and conditions upon ocular administration the eye.
• Such compounds may enhance the viscosity of the composition, and include, but are not limited to: monomeric polyols, such as, glycerol, propylene glycol, ethylene glycol; polymeric polyols, such as, polyethylene glycol; various polymers of the cellulose family, such as hydroxypropylmethyl cellulose ("HPMC"), carboxymethyl cellulose ("CMC”) sodium, hydroxypropyl cellulose (“HPC”); polysaccharides, such as hyaluronic acid and its salts, chondroitin sulfate and its salts, dextrans, such as, dextran 70; water soluble proteins, such as gelatin; vinyl polymers, such as, polyvinyl alcohol, polyvinylpyrrolidone, povidone; carbomers, such as carbomer 934P, carbomer 941, carbomer 940, or carbomer 974P; and acrylic acid polymers.
• monomeric polyols such as, glycerol, propylene glyco
• a desired viscosity can be in the range from about 1 to about 400 centipoises (“cps"), or from about 1 to about 200 cps, or from about 1 to about 100 cps.
• a viscosity-modifying compound is water soluble.
• a method for preparing a composition of the present invention comprises combining at least a material that allows the composition to remain in an ocular environment (such as on an ocular surface) for an extended period of time with a pharmaceutically acceptable carrier.
• a pharmaceutically acceptable carrier can be a sterile saline solution or a physiologically acceptable buffer.
• Physiologically acceptable buffers include, but are not limited to, a phosphate buffer or a Tris-HCl buffer (comprising tris(hydroxvmethyl)aminomethane and HCl).
• a Tris-HCl buffer having pH of 7.4 comprises 3 g/1 of tris(hydroxymethyl)aminomethane and 0.76 g/1 of HCl.
• the buffer is 1OX phosphate buffer saline (“PBS”) or 5X PBS solution.
• buffers also may be found suitable or desirable in some circumstances, such as buffers based on HEPES (N- ⁇ 2-hydroxyethyl ⁇ eperazine-N'- ⁇ 2-ethanesulfonic acid ⁇ ) having pK * of 7.5 at 25 0 C and pH in the range of about 6.8-8.2; BES (N,N-bis ⁇ 2- hydroxyethyl ⁇ 2-aminoethanesulfonic acid) having pK a of 7.1 at 25 0 C and pH in the range of about 6.4-7.8; MOPS (3- ⁇ N-morpholino ⁇ propanesulfonic acid) having pK ⁇ of 7.2 at 25°C and pH in the range of about 6.5-7.9; TES (N-tris ⁇ hydroxymethyl ⁇ -methyl- 2-aminoethanesulfonic acid) having pK ⁇ of 7.4 at 25°C and pH in the range of about 6.8- 8.2; MOBS (4- ⁇ N-morpholino ⁇ butanesulfonic acid) having
• a composition of the present invention is formulated in a buffer having a slight acidic pH, such as from about 6 to about 6.8.
• the buffer capacity of the composition desirably allows the composition to come rapidly to a physiological pH after being administered to into the patient.
• a compositionof the present invention has a pH from about 6.5 to about 7.5.
• a method for providing relief to a discomfort of the eye comprises: (a) providing a composition comprising a material that allows the composition to remain in an ocular environment (such as on an ocular surface) for an extended period of time; and (b) administering to said eye an amount of the composition at a frequency sufficient to provide relief to said discomfort of said eye.
• composition of the present invention is administered topically under an eyelid or on the ocular surface of the subject.
• a composition of the present invention is injected into the conjunctival tissue of the subject.
• composition of the present invention is administered topically once daily, several times per day, once every other day, or once a week, as necessary to provide relief to a discomfort of the eye.
• a composition of the present invention can comprise an active ingredient selected from the group consisting of anti-allergic agents, anti- inflammatory agents, anti-infective agents.
• an active ingredient can be present in an amount from about 0.001 to about 2% (by weight) (or from about 0.001 to about 1%, or from about 0.01 to about 0.5%, or from about 0.01 to about 0.2%, or from about 0.01 to about 0.1% by weight).
• anti-allergic agents include antihistamines, mast- cell stabilizers, and combinations thereof.
• Non-limiting examples of anti-infectives include antibacterial agents, antfungal agents, antiviral agents, antiprotozoal agents, and combinations thereof.
• Non-limiting examples of anti-inflammatory agents include non-steroidal anti-inflammatory drugs ("NSAIDs”), glucocorticoids, antagonists to or inhibitors of proinflammatory cytokines, and combinations thereof.
• NSAIDs non-steroidal anti-inflammatory drugs
• glucocorticoids glucocorticoids
• antagonists to or inhibitors of proinflammatory cytokines and combinations thereof.

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• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
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• 2007
  • 2007-08-21 US US11/842,394 patent/US20080057022A1/en not_active Abandoned
  • 2007-08-24 EP EP07841297A patent/EP2068821A2/en not_active Withdrawn
  • 2007-08-24 CN CN200780031963A patent/CN101636146A/zh active Pending
  • 2007-08-24 WO PCT/US2007/076700 patent/WO2008027793A2/en not_active Ceased
  • 2007-08-24 JP JP2009526819A patent/JP2010502634A/ja active Pending

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