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WO2007076274A2 - Solution de larmes artificielles contenant des lipides de glycol polyethylenique maleimide (peg) - Google Patents

Solution de larmes artificielles contenant des lipides de glycol polyethylenique maleimide (peg) Download PDF

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Publication number
WO2007076274A2
WO2007076274A2 PCT/US2006/062024 US2006062024W WO2007076274A2 WO 2007076274 A2 WO2007076274 A2 WO 2007076274A2 US 2006062024 W US2006062024 W US 2006062024W WO 2007076274 A2 WO2007076274 A2 WO 2007076274A2
Authority
WO
WIPO (PCT)
Prior art keywords
composition
peg
buffer
weight
lipid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2006/062024
Other languages
English (en)
Other versions
WO2007076274A3 (fr
Inventor
Erning Xia
Zhenze Hu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bausch and Lomb Inc
Original Assignee
Bausch and Lomb Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bausch and Lomb Inc filed Critical Bausch and Lomb Inc
Publication of WO2007076274A2 publication Critical patent/WO2007076274A2/fr
Publication of WO2007076274A3 publication Critical patent/WO2007076274A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/543—Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine
    • A61K47/544—Phospholipids
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol

Definitions

  • This invention relates to artificial tear formulations. More particularly, this invention relates to artificial tear formulations particularly suitable for the alleviation of dry eye conditions.
  • Dry eye states act to decrease visual acuity, produce discomfort ranging from mild to intense and eventually, if allowed to remain untreated and uncorrected, result in permanent damage with degradation of the exposed ocular tissues, with a complete breakdown of corneal tissue necessitating, in the extreme, corneal transplants.
  • the ocular retention time is not a direct function of the vehicle viscosity.
  • the use of highly viscous polymeric solutions also results in unpleasant side effects to the user thereof. For example, insufficient lubrication of the lids and the tendency for encrustations to form at the lid margins produces irritation and discomfort.
  • hydrophilic polymeries such as polyvinyl alcohol and polyvinyl pyrrolidone, among others, combining good film-generating properties with relatively low viscosities in aqueous solution.
  • Such formulations however, remain less than satisfactory inasmuch as they do not provide good wettability.
  • Phosopholipids have been patented for their utility in the artificial tear solution to enhance the tear film stability.
  • ⁇ -methyl-polyethyleneglycol-conjugated anionic lipids have been developed and used as liposomes, notably ⁇ -Me-PEG-phosphatidylethanolamines (MePEG-PE).
  • a PEG-lipid such as PEG-DMPE (l,2-diacyl-sn-glydero-3- phosphoethanolamine-N-[poly(ethylene glycol)]), would be useful in providing additional artificial tear solutions. Because of their possession of the extremely hydrophilic PEG tail, the PEG-lipids could more favorably interact with both the superficial lipid layer and the underlying mucous layer of the natural tear film. Because the hydrophilic component such as PEG contains a hydrophobic component at only a single end of the hydrophilic molecule, the tendency of the PEG-lipids to form liposomes would be minimized.
  • PEG-DMPE l,2-diacyl-sn-glydero-3- phosphoethanolamine-N-[poly(ethylene glycol)]
  • composition containing PEG-lipids should not interfere with the integrity of the tear lipid film, mix with tear biopolymers and affect the clarity of the aqueous tear layer.
  • PEG-lipids- containing composition in-eye application of the PEG-lipids- containing composition is expected to effectively relieve the dry eye symptoms with great comfort.
  • the PEG-lipids can be used in combination with viscosity-adjusting agents , such as celluloses and their derivatives as well as other materials commonly used in ophthalmic solutions.
  • Another object of the present invention is to provide an artificial tear formulation which in use will effectively alleviate dry eye symptoms.
  • a further object of the present invention is to provide an artificial tear formulation which is non-contaminating and non-interfering with visual clarity.
  • an artificial tear composition comprising a sterile, hypotonic aqueous solution of PEG-lipid and a viscosity-adjusting agent.
  • Suitable formulations contain PEG-lipid, preferably PEG-DMPE, in an amount of from about 0.01 to about 2 percent weight/weight, preferably in an amount of from 0.1 to about 0.5 percent weight/weight.
  • amphiphilic molecules of the invention or "amphiphiles” will preferably include a biocompatible hydrophilic compound or polymeric residue.
  • biocompatible is meant that the hydrophilic compound and the resultant amphiphilic molecule do not elicit significant adverse or untoward reactions upon administration to the particular animal in which they are intended for use. Determinations of biocompatibility are readily made by those of ordinary skill in the art, and include assessing the known properties of compounds, as described in the scientific literature, prior to generating an amphiphilic molecule and the testing of the molecule in appropriate in vitro and in vivo studies.
  • the hydrophilic compound or polymer components of the amphiphiles will preferably have an average molecular weight of between about 100 and about 100,000 Daltons, with all intermediate molecular weights between these ranges being contemplated.
  • an appropriate hydrophilic compound for use herewith may have an average molecular weight of about 100, 200, 500, 1,000, 2,000, 5,000, 10,000, 20,000, 50,000, 75,000 and about 100,000 or more.
  • the molecular weight of the hydrophilic component will be between about 100 and about 20,000, between about 100 and about 10,000, between about 2,000 and about 20,000, between about 2,000 and about 10,000, or between about 100 and about 10,000 or so.
  • Carboxy-containing polymers may also be used in the formulations of the invention herein.
  • Typical carboxy-containing polymers are carboxymethylcellulose (CMC), Alginate, Caopomers, Pectin, Xanthan gum etc.
  • hydrophobic moiety or residue is preferably a hydrophobic component that is sterically compatible with typical lamellar lipid bilayers, such that they are capable of spontaneously forming bilayers, or intercalating into bilayers, and are generally selected so as to achieve a good steric fit without significant perturbation of the normal packing geometry of lamellar bilayers. Wide varieties of such molecules are known to those of skill in the art and are suitable for use herewith.
  • hydrophobic residues of short, medium or long lipid chains may be employed.
  • Short chain lipids generally have less than about eight carbon atoms (8C).
  • 8C the number of carbon atoms
  • PEG-lipid compound for use in this invention is provided in general formula I below:
  • Rl C12 to C30, saturated and unsaturated
  • compositions of the present invention may also contain mono or divalent cations typically found in tear fluids.
  • the viscosity-adjusting agent of the composition is present in amounts of from about 0.1 to about 20 percent weight/weight, preferably in amounts of from about 2.5 to about 5.0 percent weight/weight. It has been found that suitable viscosity-adjusting agent for the purposes of this invention are those selected from methyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol and hydroxyethyl cellulose. Suitable viscosities will typically be below 50 cps.
  • compositions not only possess surface tensions approximating those of natural tears, providing corneal wetting, but additionally spread uniformly over the coated surface.
  • the tonicity of the artificial tear composition may be adjusted to the desired values by the addition thereto of sodium chloride or other soluble salts, such as potassium chloride, in amounts sufficient to impart the desired tonicity thereto.
  • Other tonicity adjusting agents such as dextrose, and sorbitol may also be advantageously employed, in combination with water-soluble salts. Suitable tonicity values are achieved by the inclusion of the tomcity-adjusting agent, or agents, in amounts of from about 1 to about 5 percent weight/weight.
  • the basic compositions include such additional components as non- ionic surfactants and sequestering, preservative and buffering agents.
  • a non-ionic surfactant such as polyoxyalkylene oleic esters of sorbitol anhydrides may be included in amounts of from about 2 to about 10 percent weight/weight.
  • Disodiurn edentate, citric acid, sodium citrate and the like, or combination thereof, in amounts of from about 0.05 to about 2.0 percent weight/weight, are suitable as sequestering agents in the present compositions.
  • Disodium edentate is particularly desirable, providing as it does a measure of protection against pseudomonal contamination while additionally functioning as a chelating or wate ⁇ -softening agent.
  • Suitable preservative agents include sodium ethylmecurithiosalicylate, benzalkonium chloride, Alexidine hydrochloride or the like, present in amounts of from about 0.001% to about 0.5%.
  • alkali metal borates such as sodium and potassium borate, or mixtures thereof, along with boric acid are particularly suitable for use in the present compositions, generally present in amounts of from about 0.1 to about 1.0 percent weight/weight.
  • suitable buffers would include phosphate buffer, borate buffer, MOPS buffer, citrate buffer, an aminoalcohol buffer and combinations thereof.
  • Formulation of the artificial tear compositions may be effected in any convenient manner known to the art, such as by simply admixing the desired amount of the specified ingredients and providing the necessary amount of sterile water to provide the necessary dilution.
  • compositions of the present invention topically applied, provides relief for both aqueous-deficient and mucus-deficient eyes; provide highly effective Kpid-masking and scavenging layers, effective also therapeutically in situations where lipid abnormalities exist.
  • Use of the artificial tear compositions is conveniently effected by instilling the composition, drop-wise, into the eye or eyes of the user.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Biophysics (AREA)
  • Ophthalmology & Optometry (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne des formulations de larmes artificielles. Il s’agit en particulier de formulations qui conviennent particulièrement au soulagement des conditions de kératoconjonctivite sèche.
PCT/US2006/062024 2005-12-22 2006-12-13 Solution de larmes artificielles contenant des lipides de glycol polyethylenique maleimide (peg) Ceased WO2007076274A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US75321005P 2005-12-22 2005-12-22
US60/753,210 2005-12-22

Publications (2)

Publication Number Publication Date
WO2007076274A2 true WO2007076274A2 (fr) 2007-07-05
WO2007076274A3 WO2007076274A3 (fr) 2007-11-08

Family

ID=38218765

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2006/062024 Ceased WO2007076274A2 (fr) 2005-12-22 2006-12-13 Solution de larmes artificielles contenant des lipides de glycol polyethylenique maleimide (peg)

Country Status (1)

Country Link
WO (1) WO2007076274A2 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2094281A4 (fr) * 2006-11-14 2012-01-04 Yissum Res Dev Co Utilisation de conjugués lipidiques dans le traitement de maladies ou de troubles oculaires
EP2887958A4 (fr) * 2012-08-21 2016-01-20 Opko Pharmaceuticals Llc Formulations liposomales
US11458199B2 (en) 2012-08-21 2022-10-04 Opko Pharmaceuticals, Llc Liposome formulations
EP3246048B1 (fr) * 2009-02-18 2024-04-03 Calm Water Therapeutics LLC Utilisation d'un copolymère bifonctionnel pour des applications ophtalmiques

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040077603A1 (en) * 1998-08-28 2004-04-22 Wilhelm Stoffel Synthetic tear fluid
DE60208454T2 (de) * 2001-03-02 2006-09-07 Nof Corp. Polyalkylenoxid-modifizierte Phospholipide und Verfahren zu ihrer Herstellung
ITMI20021033A1 (it) * 2002-05-15 2003-11-17 Acraf Composizione oftalmica acquosa comprendente un lipide mesomorfico liotropico
EP1551417B1 (fr) * 2002-10-18 2008-09-10 Joel S. Echols Formulation lacrymale a trois couches

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8865681B2 (en) 2004-03-02 2014-10-21 Yissum Research Development Company of the Hebrew Unitersity of Jerusalem Use of lipid conjugates in the treatment of diseases or disorders of the eye
EP2094281A4 (fr) * 2006-11-14 2012-01-04 Yissum Res Dev Co Utilisation de conjugués lipidiques dans le traitement de maladies ou de troubles oculaires
AU2007320736B2 (en) * 2006-11-14 2014-02-20 Celsus Therapeutics Plc Use of lipid conjugates in the treatment of diseases or disorders of the eye
EP3246048B1 (fr) * 2009-02-18 2024-04-03 Calm Water Therapeutics LLC Utilisation d'un copolymère bifonctionnel pour des applications ophtalmiques
EP2887958A4 (fr) * 2012-08-21 2016-01-20 Opko Pharmaceuticals Llc Formulations liposomales
US10548841B2 (en) 2012-08-21 2020-02-04 Opko Pharmaceuticals, Llc Liposome formulations
US11458199B2 (en) 2012-08-21 2022-10-04 Opko Pharmaceuticals, Llc Liposome formulations
US11712419B2 (en) 2012-08-21 2023-08-01 Opko Pharmaceuticals, Llc Liposome formulations

Also Published As

Publication number Publication date
WO2007076274A3 (fr) 2007-11-08

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