WO2007076274A2 - Artificial tear solution containing poly (ethylene glycol) peg lipids - Google Patents
Artificial tear solution containing poly (ethylene glycol) peg lipids Download PDFInfo
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- 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
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- composition
- peg
- buffer
- weight
- lipid
- Prior art date
Links
- 239000000607 artificial tear Substances 0.000 title claims abstract description 17
- 150000002632 lipids Chemical class 0.000 title claims description 12
- 239000000243 solution Substances 0.000 title claims description 8
- 229920001223 polyethylene glycol Polymers 0.000 title description 7
- 239000000203 mixture Substances 0.000 claims abstract description 52
- 239000000872 buffer Substances 0.000 claims description 7
- 239000004034 viscosity adjusting agent Substances 0.000 claims description 7
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 4
- 239000003755 preservative agent Substances 0.000 claims description 4
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims description 3
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims description 3
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 3
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 3
- 239000006172 buffering agent Substances 0.000 claims description 3
- 150000001768 cations Chemical class 0.000 claims description 3
- 150000004665 fatty acids Chemical class 0.000 claims description 3
- 239000012530 fluid Substances 0.000 claims description 3
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims description 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 3
- 229920000609 methyl cellulose Polymers 0.000 claims description 3
- 239000001923 methylcellulose Substances 0.000 claims description 3
- 235000010981 methylcellulose Nutrition 0.000 claims description 3
- 239000002736 nonionic surfactant Substances 0.000 claims description 3
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 3
- BRJJFBHTDVWTCJ-UHFFFAOYSA-N 1-[n'-[6-[[amino-[[n'-(2-ethylhexyl)carbamimidoyl]amino]methylidene]amino]hexyl]carbamimidoyl]-2-(2-ethylhexyl)guanidine;dihydrochloride Chemical group Cl.Cl.CCCCC(CC)CN=C(N)NC(N)=NCCCCCCN=C(N)NC(N)=NCC(CC)CCCC BRJJFBHTDVWTCJ-UHFFFAOYSA-N 0.000 claims description 2
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims description 2
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 2
- 239000007993 MOPS buffer Substances 0.000 claims description 2
- 239000007979 citrate buffer Substances 0.000 claims description 2
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 2
- 239000000194 fatty acid Substances 0.000 claims description 2
- 229930195729 fatty acid Natural products 0.000 claims description 2
- 239000008363 phosphate buffer Substances 0.000 claims description 2
- 235000019422 polyvinyl alcohol Nutrition 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 claims 3
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims 3
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims 3
- 238000009472 formulation Methods 0.000 abstract description 18
- 208000003556 Dry Eye Syndromes Diseases 0.000 abstract description 12
- 206010013774 Dry eye Diseases 0.000 abstract description 12
- -1 POLY(ETHYLENE GLYCOL) Polymers 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 150000002433 hydrophilic molecules Chemical class 0.000 description 5
- 235000002639 sodium chloride Nutrition 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000002950 deficient Effects 0.000 description 3
- 230000002209 hydrophobic effect Effects 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 0 ****P(OCC(COC(*)=O)OC(I)=O)(ONC#*)=O Chemical compound ****P(OCC(COC(*)=O)OC(I)=O)(ONC#*)=O 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 241000289690 Xenarthra Species 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 229920003086 cellulose ether Polymers 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 125000001165 hydrophobic group Chemical group 0.000 description 2
- 230000007794 irritation Effects 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 239000003352 sequestering agent Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- 241000234282 Allium Species 0.000 description 1
- 235000002732 Allium cepa var. cepa Nutrition 0.000 description 1
- 241000272814 Anser sp. Species 0.000 description 1
- 241000919811 Collyria Species 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 239000000232 Lipid Bilayer Substances 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000004902 Softening Agent Substances 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 229920001222 biopolymer Polymers 0.000 description 1
- 208000010217 blepharitis Diseases 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 238000002405 diagnostic procedure Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 235000014103 egg white Nutrition 0.000 description 1
- 210000000969 egg white Anatomy 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 210000000744 eyelid Anatomy 0.000 description 1
- 125000005313 fatty acid group Chemical group 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000009830 intercalation Methods 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- 238000005461 lubrication Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 210000004175 meibomian gland Anatomy 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid group Chemical group C(CCCCCCC\C=C/CCCCCCCC)(=O)O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 239000002997 ophthalmic solution Substances 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229940021222 peritoneal dialysis isotonic solution Drugs 0.000 description 1
- 229940067605 phosphatidylethanolamines Drugs 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 230000002000 scavenging effect Effects 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 108010019783 tear proteins Proteins 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- WUUHFRRPHJEEKV-UHFFFAOYSA-N tripotassium borate Chemical compound [K+].[K+].[K+].[O-]B([O-])[O-] WUUHFRRPHJEEKV-UHFFFAOYSA-N 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- 230000004304 visual acuity Effects 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
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
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.
Description
ARTIFICIAL TEAR SOLUTION CONTAINING POLY(ETHYLENE GLYCOL) PEG LIPIDS
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.
A diminution of the quantity of tears produced and distributed through the lachrymal ducts or a decrease in the stability of the tear film produced, results in a condition of the eye referred to as dry eye. 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.
There has been no diagnostic method findings associated with these dry eye states. Rather, therapy is usually predicated on the symptoms rather than on results of objective testing. Thus, in the consideration of dry eye states, replenishment or buttressing of the deficient tear flow or certain tear components is necessary to prevent permanent damage to the ocular tissue. BACKGROUND OF THE PRIOR ART
The condition of dry eye is not new and various compositions for treating dry eye have been proposed and put into use over the years. For example, the treatments employed by ancient Greek physicians for this condition dominated medical practice throughout the Middle Ages and into the nineteenth century. The selection of components for ancient collyria, or for any of the eye treatment preparations of the time, suggests either an instinctive or empirical knowledge of the composition of tears and tear
films. Egg whites, very rich in albumen which is a major tear protein, and goose fat, a lipid admixture which, like meibomian lipids, become fluid at temperatures approximating normal body temperatures.
Use has also been made of substances which serve to induce a measure of irritation, presumably to induce reflex tearing. Such substances as alcohols, acetic acid values of vinegar, onion fermentates and the like have been utilized in this approach. Obviously, such methods are less than totally acceptable.
Other solutions offered for the alleviation of dry eye in more recent years, i.e., during the 19th century and early 20th century, have included aqueous solutions of common table salt, glycerol, various oils, and isotonic solutions of various salts, known as Ringer's and Locke's solutions.
Approximately thirty years ago, the employment of aqueous solutions of inert, substituted cellulose ethers such as methyl cellulose was proposed, and such formulations are currently in use. Other substituted cellulose ethers such as hydroxyethyl cellulose, hydroxypropyl methyl cellulose, and hydroxypropyl cellulose have been subsequently utilized as polymeric components in artificial tear formulations. Each of these polymeries imparts high viscosities to the tear formulations, even when employed in relatively low concentrations as, for example, on the order of from about 4 to about 500 Cps. It has been this impartation of high viscosity to the formulations which has been believed to prolong retention time of the tear substitute in the fornices and over the preocular surface.
However, it has been subsequently demonstrated that the ocular retention time is not a direct function of the vehicle viscosity. Further, 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.
Subsequently, other 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.
Localized dysfunctions of the glands, which produce the ocular tear film, can also contribute to dry eye. The most common disorder, anterior blepharitis, is an inflammation of the eye lids, affecting the meibomian glands that secret the lipid layer of the ocular surface. The lack of an adequate lipid layer contributes to rapid evaporation of the water component of the tear film thus causing discomfort. OBJECTS OF THE INVENTION
Recently, certain ώ-methyl-polyethyleneglycol-conjugated anionic lipids have been developed and used as liposomes, notably ώ -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. Further, the 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. Collectively, 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.
It is an object of the present invention to provide an artificial tear formulation.
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. STATEMENT OF THE INVENTION
According to the present invention, there is provided 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.
The amphiphilic molecules of the invention or "amphiphiles" will preferably include a biocompatible hydrophilic compound or polymeric residue. By the term "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. For example, 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. In certain preferred embodiments, 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.
The "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.
In general terms, hydrophobic residues of short, medium or long lipid chains may be employed. Short chain lipids generally have less than about eight carbon atoms (8C).
In more preferred embodiments, it is believed that advantages will result from the use of hydrophobic residues having between about 8 carbon atoms (8C) and about 30 carbon atoms (30C), with those having between about 12 carbon atoms (12C) and about 20 carbon atoms (20C) being generally preferred.
Examples of preferred PEG-lipid compound for use in this invention is provided in general formula I below:
X = CO or
CO(CH2)2CO or CO(CH2)3CO Another example of suitable PEG-lipids for use in the invention herein is provided in general formula II below:
The 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.
It has been found that such 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.
Preferably, the basic compositions include such additional components as non- ionic surfactants and sequestering, preservative and buffering agents.
Suitably, 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 wateτ-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%.
As buffering agents, 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. Other 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.
The 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.
Non-limiting examples of the composition of this invention is set forth below: EXAMPLES
EXAMPLE 1
EXAMPLE 2
EXAMPLE 6
Tear Breakup Times(TFBUT in Sec.) for Systane™ and Examples 1-5
The invention, in its broader aspects, is not limited to the specific details shown and described, and departures may be made from such details without departing from the principles thereof and without sacrificing the chief advantages thereof.
Claims
1. An artificial tear composition comprising a sterile aqueous solution containing from about 0.01 to 2 percent weight/weight PEG-Hpid; from about 0.1 to about 20 percent by weight of a viscosity-adjusting agent and a buffer.
2. The composition of claim 1 wherein the viscosity-adjusting agent is selected from the group selected from the group consisting of methyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol and hydroxyethyl cellulose.
3. A composition as defined by claim 2 wherein the viscosity-adjusting agent is carboxymethyl cellulose.
4. A composition as defined by claim 1 wherein said PEG-lipid is of the following formula I:
CO(CH2)2C0 or
CO(CH2)3CO.
5. A composition as defined by claim 3 wherein the carboxymethyl cellulose is present in an amount of from about 0.1 to about 2 percent weight/weight of the composition.
6. A composition as defined by claim 1 further including a preservative agent, a buffering agent and a non-ionic surfactant.
7. A composition as defined by claim 6, wherein said preservative agent is Alexidine hydrochloride.
8. A composition as defined by claim 1 wherein said PEG-lipid is of the following formula II:
9. A composition as defined by claim 1 wherein said PEG-lipid is of the following formula III:
10. The composition of claim 1, having a viscosity that is a maximum of about 500 Cps.
11. The composition of claim 1, wherein the concentration of lipid is a minimum of about 0.01 wt % to about 5 wt.% based upon the total weight of the solution.
12. The composition of claim 1, wherein the composition further contains cations selected from the group consisting of mono or divalent cations typically found in tear fluids.
13. The composition of claim 1, wherein the buffer is selected from the group consisting of phosphate buffer, borate buffer, MOPS buffer, citrate buffer, an aminoalcohol buffer and combinations thereof.
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 (en) | 2007-07-05 |
| WO2007076274A3 WO2007076274A3 (en) | 2007-11-08 |
Family
ID=38218765
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US2006/062024 WO2007076274A2 (en) | 2005-12-22 | 2006-12-13 | Artificial tear solution containing poly (ethylene glycol) peg lipids |
Country Status (1)
| Country | Link |
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| WO (1) | WO2007076274A2 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2094281A4 (en) * | 2006-11-14 | 2012-01-04 | Yissum Res Dev Co | Use of lipid conjugates in the treatment of diseases or disorders of the eye |
| EP2887958A4 (en) * | 2012-08-21 | 2016-01-20 | Opko Pharmaceuticals Llc | LIPOSOMAL FORMULATIONS |
| US11458199B2 (en) | 2012-08-21 | 2022-10-04 | Opko Pharmaceuticals, Llc | Liposome formulations |
| EP3246048B1 (en) * | 2009-02-18 | 2024-04-03 | Calm Water Therapeutics LLC | Bi-functional co-polymer use for ophthalmic applications |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040077603A1 (en) * | 1998-08-28 | 2004-04-22 | Wilhelm Stoffel | Synthetic tear fluid |
| CN1243759C (en) * | 2001-03-02 | 2006-03-01 | 日本油脂株式会社 | Phospholipid modified by polyalkylene oxide and preparation method thereof |
| ITMI20021033A1 (en) * | 2002-05-15 | 2003-11-17 | Acraf | WATER OPHTHALMIC COMPOSITION INCLUDING A LIOTROPIC MESOMORPHIC LIPID |
| JP2006507275A (en) * | 2002-10-18 | 2006-03-02 | エコールス，ジョエル，エス． | 3-layer tear preparation |
-
2006
- 2006-12-13 WO PCT/US2006/062024 patent/WO2007076274A2/en active Application Filing
Cited By (8)
| 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 (en) * | 2006-11-14 | 2012-01-04 | Yissum Res Dev Co | Use of lipid conjugates in the treatment of diseases or disorders of the eye |
| 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 (en) * | 2009-02-18 | 2024-04-03 | Calm Water Therapeutics LLC | Bi-functional co-polymer use for ophthalmic applications |
| EP2887958A4 (en) * | 2012-08-21 | 2016-01-20 | Opko Pharmaceuticals Llc | LIPOSOMAL FORMULATIONS |
| 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 |
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| Publication number | Publication date |
|---|---|
| WO2007076274A3 (en) | 2007-11-08 |
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